Neville, Oral and Maxillofacial Pathology, 3e.pdf

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THIRD EDITION
BRAD W. NEVILLE, DDS
Distinguished University Professor
Director, Division of Oral and Maxillofacial Pathology
Department of Stomatology
College of Dental Medicine
Medical University of South Carolina
Charleston, South Carolina
DOUGLAS D. DAMM, DDS
Professor
Division of Oral and Maxillofacial Pathology
College of Dentistry
University of Kentucky
Lexington, Kentucky
CARL M. ALLEN, DDS, MSD
Professor and Director
Oral and Maxillofacial Pathology
College of Dentistry
The Ohio State University
Columbus, Ohio
Professor
Department of Pathology
College of Medicine and Public Health
The Ohio State University
Columbus, Ohio
JERRY E. BOUQUOT, DDS, MSD
Professor and Chair
Department of Diagnostic Sciences
University of Texas
Dental Branch at Houston
Houston, Texas
Consultant in Pediatric Oral Pathology
Division of Dentistry
Pittsburgh Children’s Hospital
Pittsburgh, Pennsylvania
Consultant in Oral Pathology
Department of Pathology
New York Eye and Ear Inﬁrmary
New York, New York
Adjunct Professor
Department of Rural Health and Community
Dentistry
School of Dentistry
West Virginia University
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This book is dedicated to three of our mentors:
CHARLES A. WALDRON
WILLIAM G. SHAFER
ROBERT J. GORLIN
in appreciation for all that they taught us
and in recognition of their contributions to the ﬁeld
of oral and maxillofacial pathology. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Contributors
ANGELA C. CHI, DMD
Assistant Professor
Division of Oral and Maxillofacial Pathology
Department of Stomatology
College of Dental Medicine
Medical University of South Carolina
Charleston, South Carolina
THERESA S. GONZALES, DMD, MS, MS
Consultant in Orofacial Pain
Consultant in Oral and Maxillofacial Pathology
Consultant in Forensic Odontology
Carl R. Darnall Army Medical Center
Fort Hood, Texas
Diplomate, American Board of Orofacial Pain
Diplomate, American Board of Oral and Maxillofacial
Pathology
EDWARD E. HERSCHAFT, DDS, MA,
FACD, FICD
Professor
Department of Biomedical Sciences
University of Nevada–Las Vegas
School of Dental Medicine
Las Vegas, Nevada
Professor Emeritus
Department of Stomatology
College of Dental Medicine
Medical University of South Carolina
Charleston, South Carolina
Diplomate, American Board of Forensic Odontology and
Oral Medicine
Fellow, American Academy of Forensic Sciences
Consulting Forensic Odontologist
Ofﬁce of the Coroner/Medical Examiner, Clark County
Las Vegas, Nevada
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Preface
Oral and maxillofacial pathology is the specialty of
dentistry and the discipline of pathology that addresses
the nature, identiﬁcation, and management of diseases
affecting the oral and maxillofacial regions. As such, it
occupies a unique position in the health care commu-
nity for both the dental and medical professions. Natu-
rally, members of the dental profession (including
general practitioners, specialists, and dental hygienists)
must have a good knowledge of the pathogenesis, clini-
cal features, treatment, and prognosis for oral and
paraoral diseases. Likewise, such knowledge is impor-
tant for those in the medical profession, especially for
physicians who specialize in such areas as otolaryngol-
ogy, dermatology, and pathology.
ORGANIZATION
The purpose of the third edition of this text remains
the same: to provide the reader with a comprehensive
discussion of the wide variety of diseases that may
affect the oral and maxillofacial region. Oral and Maxil-
lofacial Pathology has been organized to serve as a
primary teaching text, although it should also be a
valuable reference source for the practicing clinician.
Chapters have been created that include disease pro-
cesses of a similar source (e.g., “Bacterial Infections,”
“Salivary Gland Pathology,” “Bone Pathology,” “Der-
matologic Diseases”), because the basic understanding
of pathology is facilitated by discussing diseases of a
similar nature at the same time. Only after attaining
this basic understanding can the clinician tackle the
difﬁcult task of clinical diagnosis and treatment. With
this in mind, a comprehensive appendix is included
at the end of the book to help the clinician with the
differential diagnosis of oral and maxillofacial disease
processes.
It is impossible to write a book that perfectly matches
the requirements of every reader. Because all the
authors are involved in teaching, the subjects selected
for inclusion in this text primarily reﬂect what is taught
in courses on oral and maxillofacial pathology. Al-
though dental caries is undeniably a common and
important disease affecting the oral cavity, it is usually
not taught in an oral and maxillofacial pathology course;
rather, it is taught elsewhere in most dental schools’
curricula. Therefore, we have not included a chapter
on dental caries. Similarly, our discussion on common
gingivitis and periodontitis is limited in scope, although
a more in-depth discussion is provided for other condi-
tions that affect the periodontium. In other areas, the
text offers greater detail than necessary for some
primary courses in oral and maxillofacial pathology.
However, because this book is also intended as a refer-
ence source for the practicing clinician, this additional
material has been included.
NEW TO THIS EDITION
It has been seven years since the publication of the
second edition of this text. Although this is seemingly
a short time, many signiﬁcant advances have been
made in our understanding of various oral diseases
during this period. We have added a number of new
topics, including:
● Bisphosphonate-associated osteonecrosis
● Hemangiopericytoma–solitary ﬁbrous tumor
●Transient lingual papillitis
●Tongue splitting and charm needles
●Hereditary mucoepithelial dysplasia
●Chronic ulcerative stomatitis
● Plasminogen deﬁciency
●Oral manifestions of methamphetamine abuse
We also have included more than 200 new illustra-
tions in this latest edition.
This new edition features an accompanying Evolve
site. A speciﬁc listing of the Evolve assets for students
can be found in the front of the book.
ACKNOWLEDGMENTS
Obviously, this book could not have been accomplished
without the help of many individuals. We wish to thank
Dr. Edward E. Herschaft, who thoroughly updated his
excellent chapter on forensic dentistry. For this third
edition, we are deeply indebted to Dr. Angela C. Chi,
who revised the chapters on Epithelial Pathology and
Bone Pathology. We are also grateful to Dr. Theresa S.
Gonzales, who updated the chapter on Facial Pain and
Neuromuscular Diseases. We must thank our many
colleagues who shared cases with us, and they have
been credited in the legends of the illustrations.
Although these individuals are too numerous to cite
here, one person in particular, Dr. George Blozis,
deserves special recognition for his generosity in
sharing his excellent teaching collection. We have
attempted to be as thorough as possible in listing credit
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for all the cases shared with us. However, if someone’s
name has been inadvertently omitted, please accept
our apologies.
Since its inception, this book has been dedicated to
three of our mentors: Drs. Charles Waldron, William
Shafer, and Robert Gorlin. For the ﬁrst edition of this
text, we were fortunate to have Dr. Waldron write two
outstanding chapters on areas of his special interest
and expertise, “Bone Pathology” and “Odontogenic
Cysts and Tumors.” We and those in the oral pathology
community were tremendously saddened by his death
in 1995. Chuck’s unique expertise has been greatly
missed during the revision of these chapters, but their
content still reﬂects much of his basic philosophy. In
2000, we were sorry to learn of the death of Dr. Shafer,
who was the principal author of the well-known and
respected book, A Textbook of Oral Pathology. This valu-
able resource was the “bible” that we all used for many
years to learn about and teach our specialty. We also
mourn the death in 2006 of Dr. Robert Gorlin, one of
the true geniuses in the ﬁelds of oral pathology and
genetics. Dr. Gorlin, who was still active in patient care
and research at the time of his death at the age
of 83, offered numerous excellent suggestions for
improvements in the second and third editions of our
book. We truly have stood on the shoulders of
giants.
We would like to acknowledge the people at Else-
vier Health Sciences for their hard work in making this
book a success. We must praise Courtney Sprehe and
John Dolan, who helped us at every step and did an
excellent job coordinating the many aspects of the pub-
lishing process. Tripp Narup provided valuable guid-
ance to help us with the digitization of the illustrations.
Many thanks go to Jonathan Taylor, who was responsi-
ble for the primary editing of the manuscript and cor-
recting our many mistakes. In addition, even though
she has now moved on to more important responsibili-
ties, we still must recognize Penny Rudolph, who
handled us with aplomb through the ﬁrst two editions
of the book.
Finally, our deepest thanks must go to our families
for their support during the writing of this book. They
have had to endure our neglect during the long hours
of work, and this project could never have been com-
pleted without their love and encouragement.
BRAD W. NEVILLE
DOUGLAS D. DAMM
CARL M. ALLEN
JERRY E. BOUQUOT
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Contents
CHAPTER 1
Developmental Defects of the Oral and
Maxillofacial Region, 1
Orofacial Clefts, 1
Commissural Lip Pits, 5
Paramedian Lip Pits, 5
Double Lip, 6
Fordyce Granules, 7
Leukoedema, 8
Microglossia, 9
Macroglossia, 10
Ankyloglossia, 11
Lingual Thyroid, 12
Fissured Tongue, 13
Hairy Tongue, 13
Varicosities, 15
Caliber-Persistent Artery, 16
Lateral Soft Palate Fistulas, 16
Coronoid Hyperplasia, 17
Condylar Hyperplasia, 17
Condylar Hypoplasia, 18
Biﬁd Condyle, 19
Exostoses, 19
Torus Palatinus, 21
Torus Mandibularis, 22
Eagle Syndrome, 23
Stafne Defect, 24
Developmental Cysts, 25
Palatal Cysts of the Newborn, 26
Nasolabial Cyst, 27
“Globulomaxillary Cyst,” 28
Nasopalatine Duct Cyst, 28
Median Palatal (Palatine) Cyst, 31
“Median Mandibular Cyst,” 32
Follicular Cysts of the Skin, 32
Dermoid Cyst, 33
Thyroglossal Duct Cyst, 35
Branchial Cleft Cyst, 36
Oral Lymphoepithelial Cyst, 37
Other Rare Developmental Anomalies, 38
Hemihyperplasia, 38
Progressive Hemifacial Atrophy, 40
Segmental Odontomaxillary Dysplasia, 41
Crouzon Syndrome, 42
Apert Syndrome, 43
Mandibulofacial Dysostosis, 45
CHAPTER 2
Abnormalities of Teeth, 54
Environmental Alterations of Teeth, 54
Environmental Effects on Tooth Structure Development, 55
Postdevelopmental Loss of Tooth Structure, 60
Environmental Discoloration of Teeth, 70
Localized Disturbances in Eruption, 74
Developmental Alterations of Teeth, 77
Developmental Alterations in the Number of Teeth, 77
Developmental Alterations in the Size of Teeth, 83
Developmental Alterations in the Shape of Teeth, 84
Developmental Alterations in the Structure of Teeth, 99
CHAPTER 3
Pulpal and Periapical Disease, 120
Pulpitis, 120
Secondary and Tertiary Dentin, 123
Pulpal Calciﬁcations, 126
Periapical Granuloma, 127
Periapical Cyst, 130
Periapical Abscess, 135
Cellulitis, 138
Osteomyelitis, 141
Diffuse Sclerosing Osteomyelitis, 144
Condensing Osteitis, 147
Osteomyelitis with Proliferative Periostitis, 148
Alveolar Osteitis, 150
CHAPTER 4
Periodontal Diseases, 154
Gingivitis, 154
Necrotizing Ulcerative Gingivitis, 157
Plasma Cell Gingivitis, 159
Granulomatous Gingivitis, 160
Desquamative Gingivitis, 162
Drug-Related Gingival Hyperplasia, 163
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xii Contents
Gingival Fibromatosis, 166
Periodontitis, 168
Aggressive Periodontitis, 173
Papillon-Lefèvre Syndrome, 176
CHAPTER 5
Bacterial Infections, 181
Impetigo, 181
Erysipelas, 182
Streptococcal Tonsillitis and Pharyngitis, 183
Scarlet Fever, 184
Tonsillar Concretions and Tonsillolithiasis, 185
Diphtheria, 186
Syphilis, 188
Gonorrhea, 193
Tuberculosis, 195
Leprosy, 198
Noma, 201
Actinomycosis, 203
Cat-Scratch Disease, 205
Sinusitis, 207
CHAPTER 6
Fungal and Protozoal Diseases, 213
Candidiasis, 213
Histoplasmosis, 224
Blastomycosis, 226
Paracoccidioidomycosis, 229
Coccidioidomycosis, 230
Cryptococcosis, 231
Zygomycosis, 232
Aspergillosis, 234
Toxoplasmosis, 235
CHAPTER 7
Viral Infections, 240
Human Herpes Viruses, 240
Herpes Simplex Virus, 241
Varicella, 248
Herpes Zoster, 250
Infectious Mononucleosis, 253
Cytomegalovirus, 255
Enteroviruses, 256
Rubeola, 259
Rubella, 261
Mumps, 263
Human Immunodeﬁciency Virus and Acquired
Immunodeﬁciency Syndrome, 264
CHAPTER 8
Physical and Chemical Injuries, 285
Linea Alba, 285
Morsicatio Buccarum, 286
Traumatic Ulcerations, 287
Electrical and Thermal Burns, 289
Chemical Injuries of the Oral Mucosa, 291
Noninfectious Oral Complications of Antineoplastic Therapy,
294
Bisphosphonate-Associated Osteonecrosis, 299
Orofacial Complications of Methamphetamine Abuse, 303
Anesthetic Necrosis, 303
Exfoliative Cheilitis, 304
Submucosal Hemorrhage, 305
Oral Trauma from Sexual Practices, 307
Amalgam Tattoo and Other Localized Exogenous Pigmentations,
308
Oral Piercings and Other Body Modiﬁcations, 311
Systemic Metallic Intoxication, 313
Smoker’s Melanosis, 316
Drug-Related Discolorations of the Oral Mucosa, 317
Reactive Osseous and Chondromatous Metaplasia, 318
Oral Ulceration with Bone Sequestration, 319
Pseudocysts and Cysts of the Maxillary Sinus, 320
Cervicofacial Emphysema, 323
Myospherulosis, 324
CHAPTER 9
Allergies and Immunologic Diseases, 330
Transient Lingual Papillitis, 330
Recurrent Aphthous Stomatitis, 331
Behçet’s Syndrome, 336
Sarcoidosis, 338
Orofacial Granulomatosis, 341
Wegener’s Granulomatosis, 345
Allergic Mucosal Reactions to Systemic Drug Administration,
347
Allergic Contact Stomatitis, 350
Perioral Dermatitis, 352
Contact Stomatitis from Artiﬁcial Cinnamon Flavoring, 352
Lichenoid Contact Stomatitis from Dental Restorative Materials,
354
Angioedema, 356
CHAPTER 10
Epithelial Pathology, 362
Revised by ANGELA C. CHI
Squamous Papilloma, 362
Verruca Vulgaris, 364
Condyloma Acuminatum, 366
Multifocal Epithelial Hyperplasia, 367 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Contents XIII
Sinonasal Papillomas, 368
Molluscum Contagiosum, 371
Verruciform Xanthoma, 372
Seborrheic Keratosis, 374
Sebaceous Hyperplasia, 375
Ephelis, 376
Actinic Lentigo, 377
Lentigo Simplex, 378
Melasma, 378
Oral Melanotic Macule, 379
Oral Melanoacanthoma, 380
Acquired Melanocytic Nevus, 382
Variants of Melanocytic Nevus, 385
Leukoplakia, 388
Erythroplakia, 397
Smokeless Tobacco Use and Smokeless Tobacco Keratosis, 398
Oral Submucous Fibrosis, 401
Nicotine Stomatitis, 403
Actinic Keratosis, 404
Actinic Cheilosis, 405
Keratoacanthoma, 406
Squamous Cell Carcinoma, 409
Verrucous Carcinoma, 422
Spindle Cell Carcinoma, 423
Adenosquamous Carcinoma, 425
Basaloid Squamous Carcinoma, 425
Carcinoma of the Maxillary Sinus, 426
Sinonasal Undifferentiated Carcinoma, 427
Nasopharyngeal Carcinoma, 428
Basal Cell Carcinoma, 429
Merkel Cell Carcinoma, 432
Melanoma, 433
CHAPTER 11
Salivary Gland Pathology, 453
Salivary Gland Aplasia, 453
Mucocele, 454
Ranula, 456
Salivary Duct Cyst, 457
Sialolithiasis, 459
Sialadenitis, 461
Cheilitis Glandularis, 462
Sialorrhea, 463
Xerostomia, 464
Benign Lymphoepithelial Lesion, 465
Sjögren Syndrome, 466
Sialadenosis, 470
Adenomatoid Hyperplasia of the Minor Salivary Glands, 471
Necrotizing Sialometaplasia, 471
Salivary Gland Tumors, 473
General Considerations, 473
Pleomorphic Adenoma, 477
Oncocytoma, 480
Oncocytosis, 481
Warthin Tumor, 482
Monomorphic Adenoma, 483
Canalicular Adenoma, 484
Basal Cell Adenoma, 484
Ductal Papillomas, 485
Mucoepidermoid Carcinoma, 487
Intraosseous Mucoepidermoid Carcinoma, 490
Acinic Cell Adenocarcinoma, 491
Malignant Mixed Tumors, 492
Adenoid Cystic Carcinoma, 495
Polymorphous Low-Grade Adenocarcinoma, 497
Salivary Adenocarcinoma, Not Otherwise Speciﬁed, 498
CHAPTER 12
Soft Tissue Tumors, 507
Fibroma, 507
Giant Cell Fibroma, 509
Epulis Fissuratum, 510
Inﬂammatory Papillary Hyperplasia, 512
Fibrous Histiocytoma, 514
Fibromatosis, 515
Myoﬁbroma, 515
Oral Focal Mucinosis, 516
Pyogenic Granuloma, 517
Peripheral Giant Cell Granuloma, 520
Peripheral Ossifying Fibroma, 521
Lipoma, 523
Traumatic Neuroma, 524
Palisaded Encapsulated Neuroma, 525
Neurilemoma, 526
Neuroﬁbroma, 528
Neuroﬁbromatosis Type I, 529
Multiple Endocrine Neoplasia Type 2B, 532
Melanotic Neuroectodermal Tumor of Infancy, 533
Paraganglioma, 535
Granular Cell Tumor, 536
Congenital Epulis, 537
Hemangioma and Vascular Malformations, 538
Sturge-Weber Angiomatosis, 543
Nasopharyngeal Angioﬁbroma, 544
Hemangiopericytoma–Solitary Fibrous Tumor, 546
Lymphangioma, 547
Leiomyoma, 549
Rhabdomyoma, 550
Osseous and Cartilaginous Choristomas, 552
Soft Tissue Sarcomas, 552
Fibrosarcoma, 553
Malignant Fibrous Histiocytoma, 553
Liposarcoma, 554
Malignant Peripheral Nerve Sheath Tumor, 555 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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xiv Contents
Olfactory Neuroblastoma, 555
Angiosarcoma, 556
Kaposi’s Sarcoma, 557
Leiomyosarcoma, 559
Rhabdomyosarcoma, 559
Synovial Sarcoma, 561
Alveolar Soft-Part Sarcoma, 562
Metastases to the Oral Soft Tissues, 563
CHAPTER 13
Hematologic Disorders, 571
Lymphoid Hyperplasia, 571
Hemophilia, 573
Plasminogen Deﬁciency, 575
Anemia, 576
Sickle Cell Anemia, 576
Thalassemia, 578
Aplastic Anemia, 580
Neutropenia, 581
Agranulocytosis, 582
Cyclic Neutropenia, 583
Thrombocytopenia, 584
Polycythemia Vera, 586
Leukemia, 587
Langerhans Cell Histiocytosis, 590
Hodgkin’s Lymphoma, 592
Non-Hodgkin’s Lymphoma, 595
Mycosis Fungoides, 598
Burkitt’s Lymphoma, 600
Extranodal NK/T-cell Lymphoma, Nasal-Type, 602
Multiple Myeloma, 604
Plasmacytoma, 606
CHAPTER 14
Bone Pathology, 613
Revised By ANGELA C. CHI
Osteogenesis Imperfecta, 613
Osteopetrosis, 615
Cleidocranial Dysplasia, 618
Focal Osteoporotic Marrow Defect, 619
Idiopathic Osteosclerosis, 620
Massive Osteolysis, 622
Paget’s Disease of Bone, 623
Central Giant Cell Granuloma, 626
Cherubism, 629
Simple Bone Cyst, 631
Aneurysmal Bone Cyst, 634
Fibro-Osseous Lesions of the Jaws, 635
Fibrous Dysplasia, 635
Cemento-Osseous Dysplasias, 640
Familial Gigantiform Cementoma, 645
Ossifying Fibroma, 646
Juvenile Ossifying Fibroma, 648
Osteoma, 650
Gardner Syndrome, 651
Osteoblastoma and Osteoid Osteoma, 653
Cementoblastoma, 655
Chondroma, 656
Chondromyxoid Fibroma, 657
Synovial Chondromatosis, 657
Desmoplastic Fibroma, 658
Osteosarcoma, 660
Chondrosarcoma, 664
Ewing Sarcoma, 667
Metastatic Tumors to the Jaws, 669
CHAPTER 15
Odontogenic Cysts and Tumors, 678
Odontogenic Cysts, 678
Dentigerous Cyst, 679
Eruption Cyst, 682
Primordial Cyst, 683
Odontogenic Keratocyst, 683
Orthokeratinized Odontogenic Cyst, 687
Nevoid Basal Cell Carcinoma Syndrome, 688
Gingival (Alveolar) Cyst of the Newborn, 691
Gingival Cyst of the Adult, 692
Lateral Periodontal Cyst, 692
Calcifying Odontogenic Cyst, 695
Glandular Odontogenic Cyst, 697
Buccal Bifurcation Cyst, 698
Carcinoma Arising in Odontogenic Cysts, 700
Odontogenic Tumors, 701
Tumors of Odontogenic Epithelium, 702
Ameloblastoma, 702
Malignant Ameloblastoma and Ameloblastic Carcinoma, 711
Clear Cell Odontogenic Carcinoma, 712
Adenomatoid Odontogenic Tumor, 713
Calcifying Epithelial Odontogenic Tumor, 716
Squamous Odontogenic Tumor, 718
Mixed Odontogenic Tumors, 719
Ameloblastic Fibroma, 719
Ameloblastic Fibro-Odontoma, 721
Ameloblastic Fibrosarcoma, 722
Odontoameloblastoma, 723
Odontoma, 724
Tumors of Odontogenic Ectomesenchyme, 726
Central Odontogenic Fibroma, 726
Peripheral Odontogenic Fibroma, 727 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Contents xv
Granular Cell Odontogenic Tumor, 729
Odontogenic Myxoma, 729
Cementoblastoma, 731
CHAPTER 16
Dermatologic Diseases, 741
Ectodermal Dysplasia, 741
White Sponge Nevus, 743
Hereditary Benign Intraepithelial Dyskeratosis, 744
Pachyonychia Congenita, 745
Dyskeratosis Congenita, 746
Xeroderma Pigmentosum, 747
Hereditary Mucoepithelial Dysplasia, 748
Incontinentia Pigmenti, 750
Darier’s Disease, 751
Warty Dyskeratoma, 752
Peutz-Jeghers Syndrome, 753
Hereditary Hemorrhagic Telangiectasia, 754
Ehlers-Danlos Syndromes, 755
Tuberous Sclerosis, 757
Multiple Hamartoma Syndrome, 760
Epidermolysis Bullosa, 761
Immune-Mediated Diseases and Their
Evaluation, 764
Pemphigus, 765
Paraneoplastic Pemphigus, 769
Mucous Membrane Pemphigoid, 771
Bullous Pemphigoid, 775
Erythema Multiforme, 776
Erythema Migrans, 779
Reactive Arthritis, 781
Lichen Planus, 782
Chronic Ulcerative Stomatitis, 788
Graft-versus-Host Disease, 790
Psoriasis, 793
Lupus Erythematosus, 794
Systemic Sclerosis, 798
CREST Syndrome, 801
Acanthosis Nigricans, 803
CHAPTER 17
Oral Manifestations of Systemic
Diseases, 816
Mucopolysaccharidosis, 816
Lipid Reticuloendothelioses, 818
Lipoid Proteinosis, 820
Jaundice, 821
Amyloidosis, 822
Vitamin Deﬁciency, 825
Iron-Deﬁciency Anemia, 827
Plummer-Vinson Syndrome, 828
Pernicious Anemia, 829
Pituitary Dwarﬁsm, 831
Gigantism, 831
Acromegaly, 832
Hypothyroidism, 834
Hyperthyroidism, 835
Hypoparathyroidism, 837
Pseudohypoparathyroidism, 837
Hyperparathyroidism, 838
Hypercortisolism, 840
Addison’s Disease, 841
Diabetes Mellitus, 842
Hypophosphatasia, 845
Vitamin D–Resistant Rickets, 847
Crohn’s Disease, 848
Pyostomatitis Vegetans, 850
Uremic Stomatitis, 851
CHAPTER 18
Facial Pain and Neuromuscular
Diseases, 859
Revised by THERESA S. GONZALES
Bell’s Palsy, 859
Trigeminal Neuralgia, 861
Glossopharyngeal Neuralgia, 863
Postherpetic Neuralgia, 864
Atypical Facial Pain, 865
Neuralgia-Inducing Cavitational Osteonecrosis, 866
Cluster Headache, 868
Paroxysmal Hemicrania, 869
Migraine, 870
Temporal Arteritis, 871
Myasthenia Gravis, 872
Motor Neuron Disease, 873
Burning Mouth Syndrome, 873
Dysgeusia and Hypogeusia, 875
Frey Syndrome, 876
Osteoarthritis, 877
Rheumatoid Arthritis, 878
Temporomandibular Joint Dysfunction, 880
Temporomandibular Joint Ankylosis, 882
CHAPTER 19
Forensic Dentistry, 887
EDWARD E. HERSCHAFT
Record Management, 887
Identiﬁcation, 889
Bite Pattern Evidence, 903
Human Abuse, 911 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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xvi Contents
Dentists as Expert Witnesses, 914
Summary, 914
APPENDIX
Differential Diagnosis of Oral and
Maxillofacial Diseases, 917
Part 1: Mucosal and Soft Tissue Pathology: Color Changes, 920
Part 2: Mucosal and Soft Tissue Pathology: Surface Alterations,
924
Part 3: Mucosal and Soft Tissue Pathology: Masses or
Enlargements, 926
Part 4: Radiographic Pathology, 929
Part 5: Pathology of Teeth, 934
Index, 937 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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1
1
Developmental Defects of the Oral
and Maxillofacial Region
CHAPTER OUTLINE
Orofacial Clefts
Commissural Lip Pits
Paramedian Lip Pits
Double Lip
Fordyce Granules
Leukoedema
Microglossia
Macroglossia
Ankyloglossia
Lingual Thyroid
Fissured Tongue
Hairy Tongue
Varicosities
Caliber-Persistent Artery
Lateral Soft Palate Fistulas
Coronoid Hyperplasia
Condylar Hyperplasia
Condylar Hypoplasia
Biﬁd Condyle
Exostoses
Torus Palatinus
Torus Mandibularis
Development of the central face begins around the
end of the fourth week of human development, with
the appearance of the nasal (olfactory) placodes on
either side of the inferior aspect of the frontonasal
process. Proliferation of ectomesenchyme on both
sides of each placode results in the formation of the
medial and lateral nasal processes. Between each pair
OROFACIAL CLEFTS
The formation of the face and oral cavity is complex in
nature and involves the development of multiple tissue
processes that must merge and fuse in a highly orches-
trated fashion. Disturbances in the growth of these
tissue processes or their fusion may result in the forma-
tion of orofacial clefts.
Eagle Syndrome
Stafne Defect
DEVELOPMENTAL CYSTS
Palatal Cysts of the Newborn
Nasolabial Cyst
“Globulomaxillary Cyst”
Nasopalatine Duct Cyst
Median Palatal Cyst
“Median Mandibular Cyst”
Follicular Cysts of the Skin
Dermoid Cyst
Thyroglossal Duct Cyst
Branchial Cleft Cyst
Oral Lymphoepithelial Cyst
OTHER RARE DEVELOPMENTAL ANOMALIES
Hemihyperplasia
Progressive Hemifacial Atrophy
Segmental Odontomaxillary Dysplasia
Crouzon Syndrome
Apert Syndrome
Mandibulofacial Dysostosis `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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2 ORAL AND MAXILLOFACIAL PATHOLOGY
of processes is a depression, or nasal pit, that represents
the primitive nostril.
During the sixth and seventh weeks of development,
the upper lip forms when the medial nasal processes
merge with each other and with the maxillary pro-
cesses of the ﬁrst branchial arches. Thus the midpor-
tion of the upper lip is derived from the medial nasal
processes, and the lateral portions are derived from the
maxillary processes. The lateral nasal processes are not
involved in the formation of the upper lip, but they give
rise to the alae of the nose.
The primary palate also is formed by the merger
of the medial nasal processes to form the intermaxil-
lary segment. This segment gives rise to the premaxilla,
a triangular-shaped piece of bone that will include the
four incisor teeth. The secondary palate, which makes
up 90% of the hard and soft palates, is formed from the
maxillary processes of the ﬁrst branchial arches.
During the sixth week, bilateral projections emerge
from the medial aspects of the maxillary processes to
form the palatal shelves. Initially, these shelves are ori-
ented in a vertical position on each side of the develop-
ing tongue. As the mandible grows, the tongue drops
down, allowing the palatal shelves to rotate to a horizon-
tal position and grow toward one another. By the eighth
week, sufﬁcient growth has occurred to allow the ante-
rior aspects of these shelves to begin fusion with one
another. The palatal shelves also fuse with the primary
palate and the nasal septum. The fusion of the palatal
shelves begins in the anterior palate and progresses pos-
teriorly; it is completed by the twelfth week.
Defective fusion of the medial nasal process with
the maxillary process leads to cleft lip (CL). Likewise,
failure of the palatal shelves to fuse results in cleft
palate (CP). Frequently, CL and CP occur together.
Approximately 45% of cases are CL + CP, with 30%
being CP only (CPO) and 25% being isolated CL. Both
isolated CL and CL associated with CP are thought to
be etiologically related conditions and can be consid-
ered as a group: CL, with or without CP (i.e., CL ± CP).
Isolated CPO appears to represent a separate entity
from CL ± CP.
The cause of CL ± CP and CPO is still being debated.
First of all, distinguishing isolated clefts from cases
associated with speciﬁc syndromes is important.
Although many facial clefts are isolated anomalies,
more than 350 developmental syndromes have been
identiﬁed that may be associated with CL ± CP or CPO.
Recent studies have suggested that up to 30% of patients
with CL ± CP and 50% of those with CPO have associ-
ated anomalies. Some of these cases are single-gene
syndromes that may follow autosomal dominant, auto-
somal recessive, or X-linked inheritance patterns.
Other syndromes are the result of chromosome anom-
alies or are idiopathic.
The cause of nonsyndromic clefts does not follow
any simple mendelian pattern of inheritance but
appears to be heterogeneous (Box 1-1). Thus the pro-
pensity for cleft development may be related to a
number of major genes, minor genes, and environmen-
tal factors that can combine to surpass a developmental
threshold. A number of candidate clefting genes and
loci have been identiﬁed on different chromosome
regions, such as 1q, 2p, 4q, 6p, 14q, 17q, and 19q.
Maternal alcohol consumption has been associated
with an increased risk for both syndromic and nonsyn-
dromic clefts. Maternal cigarette smoking at least
doubles the frequency of cleft development compared
with nonsmoking mothers. Multiple studies have dem-
onstrated that a deﬁciency of folic acid increases the
risk for CL and CP. Maternal corticosteroid use has
been associated with a 3.4 times greater risk of orofa-
cial clefting. An increased frequency also has been
related to anticonvulsant therapy, especially phenytoin,
which causes a nearly tenfold greater risk of cleft
formation.
CL ± CP and CPO represent the vast majority of
orofacial clefts. However, other rare clefts also may
occur.
The lateral facial cleft is caused by lack of fusion
of the maxillary and mandibular processes and repre-
sents 0.3% of all facial clefts. This cleft may be unilateral
or bilateral, extending from the commissure toward
Box 1-1
Genetic and Environmental Causes of
Nonsyndromic Orofacial Clefts
GENETIC FACTORS
Gene Locus
SKI/MTHFR 1p36
TGFB2 1q41
TGFA 2p13
MSX1 4p16, 4q31, 6p23
PVRL1 11q23
TGFB3 14q24
GABRB3 15q11
RARA 17q21
BCL3 19q13
ENVIRONMENTAL FACTORS
●Maternal alcohol consumption
●Maternal cigarette smoking
●Folic acid deﬁciency
● Corticosteroid use
● Anticonvulsant therapy
Adapted from Murray JC: Gene/environment causes of cleft lip and/or
palate, Clin Genet 61:248-256, 2002; Eppley BL, van Aalst JA, Robey A
et al: The spectrum of orofacial clefting, Plast Reconstr Surg 115:101e-
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Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 3
the ear, resulting in macrostomia. The lateral facial
cleft may occur as an isolated defect, but more often
it is associated with other disorders, such as the
following:
●Mandibulofacial dysostosis (see page 45)
●Oculo-auriculo-vertebral spectrum (hemifacial
microsomia)
●Nager acrofacial dysostosis
●Amniotic rupture sequence
The oblique facial cleft extends from the upper lip
to the eye. It is nearly always associated with CP, and
severe forms often are incompatible with life. The
oblique facial cleft may involve the nostril, as in CL, or
it may bypass the nose laterally as it extends to the eye.
This cleft is rare, representing only 1 in 1300 facial
clefts. Some of these clefts may represent failure of
fusion of the lateral nasal process with the maxillary
process; amniotic bands may cause others.
Median cleft of the upper lip is an extremely rare
anomaly that results from failure of fusion of the medial
nasal processes. It may be associated with a number of
syndromes, including the oral-facial-digital syndromes
and Ellis-van Creveld syndrome. Most apparent median
clefts of the upper lip actually represent agenesis of the
primary palate associated with holoprosencephaly.
CLINICAL AND RADIOGRAPHIC
FEATURES
Clefting is one of the most common major congenital
defects in humans. Considerable racial variation in
prevalence is seen. In whites, CL ± CP occurs in 1 of
every 700 to 1000 births. The frequency of CL ± CP in
Asian populations is about 1.5 times higher than in
whites. In contrast, the prevalence of CL ± CP in blacks
is much lower, occurring in 0.4 of 1000 births. Native
Americans appear to have the highest frequency,
around 3.6 of 1000 births. CPO is less common than
CL ± CP, with a frequency of 0.4 of 1000 births in
whites and blacks.
CL ± CP is more common in males than in females.
The more severe the defect, the greater the male pre-
dilection; the male-to-female ratio for isolated CL is
1.5:1; the ratio for CL + CP is 2:1. In contrast, CPO is
more common in females. Likewise, the more severe
the cleft, the greater the female predilection. Clefts of
both the hard and soft palates are twice as common in
females, but the ratio is nearly equal for clefts of the
soft palate only.
Approximately 80% of cases of CL will be unilateral,
with 20% bilateral (Fig. 1-1). Approximately 70% of uni-
lateral CLs occur on the left side. In addition, about
70% of unilateral CLs will be associated with CP,
whereas the frequency of concomitant CP increases to
85% for patients with bilateral CL. A complete CL
extends upward into the nostril, but an incomplete CL
does not involve the nose. Complete clefts involving
the alveolus usually occur between the lateral incisor
and cuspid. It is not unusual for teeth, especially the
lateral incisor, to be missing in the cleft area. Con-
versely, supernumerary teeth may be discovered. The
bony defect can be observed on radiographs.
A CP shows considerable range in severity (Fig. 1-2).
The defect may involve the hard and soft palates or the
soft palate alone. The minimal manifestation of CP is a
cleft or biﬁd uvula (Fig. 1-3). The prevalence of cleft
uvula is much higher than that of CP, with a frequency
of 1 in every 80 white individuals. The frequency in
Asian and Native American populations is as high as
1 in 10. Cleft uvula is less common in blacks, occurring
in 1 out of every 250 persons.
In some instances a submucous palatal cleft devel-
ops. The surface mucosa is intact, but a defect exists in
the underlying musculature of the soft palate (Fig. 1-4).
Frequently a notch in the bone is present along the
Fig. 1-1 Cleft lip (CL). Infant with bilateral cleft of the
upper lip. (Courtesy of Dr. William Bruce.)
Fig. 1-2 Cleft palate (CP). Palatal defect resulting in
communication with the nasal cavity. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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4 ORAL AND MAXILLOFACIAL PATHOLOGY
posterior margin of the hard palate. This incomplete
cleft occasionally appears as a bluish midline discolor-
ation but is best identiﬁed by palpation with a blunt
instrument. An associated cleft uvula is also usually
seen.
The Pierre Robin sequence (Pierre Robin anoma-
lad) (Fig. 1-5) is a well-recognized presentation char-
acterized by CP, mandibular micrognathia, and
glossoptosis (airway obstruction caused by lower, pos-
terior displacement of the tongue). The Pierre Robin
sequence may occur as an isolated phenomenon, or it
may be associated with a wide variety of syndromes or
other anomalies. Stickler syndrome and velocardiofa-
cial syndrome are the two most frequently associated
genetic disorders. Researchers have theorized that
constraint of mandibular growth in utero results in
failure of the tongue to descend, thus preventing fusion
of the palatal shelves. The retruded mandible results in
the following:
●Posterior displacement of the tongue
●Lack of support of the tongue musculature
● Airway obstruction
Respiratory difﬁculty, especially when the child is in
a supine position, is usually noted from birth and can
cause asphyxiation. The palatal cleft is often U-shaped
and wider than isolated CP.
The patient with a cleft is burdened with a variety
of problems, some obvious and some less so. The most
obvious problem is the clinical appearance, which may
lead to psychosocial difﬁculties. Feeding and speech
difﬁculties are inherent, especially with CP. Malocclu-
sion is caused by collapse of the maxillary arch, possi-
bly along with missing teeth, supernumerary teeth, or
both.
TREATMENT AND PROGNOSIS
The management of the patient with an orofacial cleft
is challenging. Ideally, treatment should involve a mul-
tidisciplinary approach, including (but not limited to)
a pediatrician, oral and maxillofacial surgeon, otolar-
yngologist, plastic surgeon, pediatric dentist, orthodon-
tist, prosthodontist, speech pathologist, and geneticist.
Surgical repair often involves multiple primary and
secondary procedures throughout childhood. The spe-
ciﬁc types of surgical procedures and their timing will
vary, depending on the severity of the defect and the
philosophy of the treatment team. A detailed discus-
sion of these procedures is beyond the scope of this
text. However, primary lip closure is usually accom-
plished during the ﬁrst few months of life, followed
later by repair of the palate. Prosthetic and orthopedic
appliances often are used to mold or expand the maxil-
lary segments before closure of the palatal defect. Later
in childhood, autogenous bone grafts can be placed in
the area of the alveolar bone defect. Secondary soft
tissue and orthognathic procedures may be used to
Fig. 1-3 Biﬁd uvula.
Fig. 1-4 Submucous palatal cleft. A cleft of the midline
palatal bone exists, but the overlying mucosa is intact. A biﬁd
uvula also is present.
Fig. 1-5 Pierre Robin sequence. Micrognathic mandible in
an infant with cleft palate (CP). (Courtesy of Dr. Robert Gorlin.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 5
improve function and cosmetic appearance. Distrac-
tion osteogenesis of the maxilla can prove useful in
patients in whom palatal scarring limits the amount of
advancement possible at the time of osteotomy.
Genetic counseling is important for the patient and
family. In nonsyndromic cases, the risk for cleft devel-
opment in a sibling or offspring of an affected person
is 3% to 5% if no other ﬁrst-degree relatives also are
affected. The risk increases to 10% to 20% if other ﬁrst-
degree relatives are affected. The risk may be even
higher for those with clefts that are associated with
syndromes, depending on the possible inheritance
pattern.
COMMISSURAL LIP PITS
Commissural lip pits are small mucosal invaginations
that occur at the corners of the mouth on the vermilion
border. Their location suggests that they may represent
a failure of normal fusion of the embryonal maxillary
and mandibular processes.
Commissural lip pits appear to be common in adults,
where they have been reported in 12% to 20% of the
population. Their prevalence in children is consider-
ably lower, ranging from 0.2% to 0.7% of those
examined.
Although commissural lip pits are generally consid-
ered to be congenital lesions, these ﬁgures suggest that
these invaginations often develop later in life. Commis-
sural pits are seen more often in males than in females.
A family history suggestive of autosomal dominant
transmission has been noted in some cases.
CLINICAL FEATURES
Commissural lip pits are usually discovered on routine
examination, and the patient often is unaware of their
presence. These pits may be unilateral or bilateral.
They manifest as blind ﬁstulas that may extend to a
depth of 1 to 4 mm (Fig. 1-6). In some cases a small
amount of ﬂuid may be expressed from the pit when
the pit is squeezed, presumably representing saliva
from minor salivary glands that drain into the depth of
the invagination.
Unlike paramedian lip pits (described in the fol-
lowing section), commissural lip pits are not associated
with facial or palatal clefts. However, there does appear
to be a signiﬁcantly higher prevalence of preauricular
pits (aural sinuses) in these patients.
HISTOPATHOLOGIC FEATURES
Although biopsy rarely is performed for patients with
commissural lip pits, microscopic examination reveals
a narrow invagination lined by stratiﬁed squamous epi-
thelium. Ducts from minor salivary glands may drain
into this invagination.
TREATMENT AND PROGNOSIS
Because commissural lip pits are virtually always
asymptomatic and innocuous, no treatment is usually
necessary. In extremely rare instances, salivary secre-
tions may be excessive or secondary infection may
occur, necessitating surgical excision of the pit.
PARAMEDIAN LIP PITS (CONGENITAL
FISTULAS OF THE LOWER LIP;
CONGENITAL LIP PITS)
Paramedian lip pits are rare congenital invaginations
of the lower lip. They are believed to arise from persis-
tent lateral sulci on the embryonic mandibular arch.
These sulci normally disappear by 6 weeks of embry-
onic age.
CLINICAL FEATURES
Paramedian lip pits typically appear as bilateral and
symmetric ﬁstulas on either side of the midline of the
vermilion of the lower lip (Fig. 1-7). Their appearance
can range from subtle depressions to prominent humps.
These blind sinuses can extend down to a depth of 1.5
cm and may express salivary secretions. Occasionally,
only a single pit is present that may be centrally located
or lateral to the midline.
The greatest signiﬁcance of paramedian lip pits is
that they are usually inherited as an autosomal domi-
nant trait in combination with cleft lip (CL) and/or cleft
palate (CP) (van der Woude syndrome). Van der
Woude syndrome is the most common form of syn-
dromic clefting and accounts for 2% of all cases of CL
Fig. 1-6 Commissural lip pit. Depression at the labial
commissure. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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6 ORAL AND MAXILLOFACIAL PATHOLOGY
and CP. Associated hypodontia also may be observed.
Genetic studies have shown that this condition is
caused by mutations in the gene that encodes inter-
feron regulatory factor 6, which has been mapped to
chromosome locus 1q32-q41. Some people who carry
the trait may not demonstrate clefts or may have a
submucous CP; however, they may pass the full syn-
drome to their offspring.
Paramedian lip pits also may be a feature of the
popliteal pterygium syndrome and Kabuki syn-
drome. Popliteal webbing (pterygia), CL and/or CP,
genital abnormalities, and congenital bands connect-
ing the upper and lower jaws (syngnathia) character-
ize popliteal pterygium syndrome, which is closely
related to van der Woude syndrome. Kabuki syndrome
received its name because affected patients exhibit
eversion of the lower lateral eyelids, which is reminis-
cent of the makeup used by actors in Kabuki, the tra-
ditional form of Japanese theater. Other common
ﬁndings include mental retardation, large ears, CL
and/or CP, hypodontia, joint laxity, and various skeletal
abnormalities.
HISTOPATHOLOGIC FEATURES
Microscopic examination of a paramedian lip pit shows
a tract that is lined by stratiﬁed squamous epithelium.
Minor salivary glands may communicate with the
sinus. A chronic inﬂammatory cell inﬁltrate often is
noted in the surrounding connective tissue.
TREATMENT AND PROGNOSIS
If necessary, the labial pits may be excised for cosmetic
reasons. The most signiﬁcant problems are related to
associated congenital anomalies, such as CL and/or
CP, and the potential for transmission of the trait to
subsequent generations.
DOUBLE LIP
Double lip is a rare oral anomaly characterized by a
redundant fold of tissue on the mucosal side of the lip.
It is most often congenital in nature, but it may be
acquired later in life. Congenital cases are believed to
arise during the second to third month of gestation as
a result of the persistence of the sulcus between the
pars glabrosa and pars villosa of the lip. Acquired
double lip may be a component of Ascher syndrome,
or it may result from trauma or oral habits, such as
sucking on the lip.
CLINICAL FEATURES
In a patient with double lip, the upper lip is affected
much more often than the lower lip; occasionally, both
lips are involved. With the lips at rest, the condition is
usually unnoticeable, but when the patient smiles or
when the lips are tensed, the excess fold of tissue is
visible (Fig. 1-8).
Ascher syndrome is characterized by a triad of
features:
● Double lip
● Blepharochalasis
●Nontoxic thyroid enlargement
In a person with blepharochalasis, recurring edema
of the upper eyelid leads to sagging of the lid at the
outer canthus of the eye (Fig. 1-9). This drooping may
be severe enough to interfere with vision. Both the
double lip and blepharochalasis usually occur abruptly
and simultaneously, but in some cases they develop
more gradually.
Fig. 1-7 Paramedian lip pits. Bilateral pits (arrows) on the
lower lip in a patient with van der Woude syndrome.
Fig. 1-8 Double lip. Redundant fold of tissue on the upper
lip in a patient with Ascher syndrome. (Courtesy of Dr. R.C.
Zeigler.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 7
The nontoxic thyroid enlargement occurs in as many
as 50% of patients with Ascher syndrome and may be
mild in degree. The cause of Ascher syndrome is not
certain; autosomal dominant inheritance has been
suggested in some cases.
HISTOPATHOLOGIC FEATURES
On microscopic examination, double lip shows essen-
tially normal structures. Often there is an abundance
of minor salivary glands. The blepharochalasis of
Ascher syndrome usually shows hyperplasia of the lac-
rimal glands or prolapse of orbital fat.
TREATMENT AND PROGNOSIS
In mild cases of double lip, no treatment may be
required. In more severe cases, simple surgical exci-
sion of the excess tissue can be performed for aesthetic
purposes.
FORDYCE GRANULES
Fordyce granules are sebaceous glands that occur on
the oral mucosa. Similar lesions also have been reported
on the genital mucosa. Because sebaceous glands are
typically considered to be dermal adnexal structures,
those found in the oral cavity often have been consid-
ered to be “ectopic.” However, because Fordyce gran-
ules have been reported in more than 80% of the
population, their presence must be considered a normal
anatomic variation.
CLINICAL FEATURES
Fordyce granules appear as multiple yellow or yellow-
white papular lesions that are most common on the
buccal mucosa and the lateral portion of the vermilion
of the upper lip (Figs. 1-10 and 1-11). Occasionally,
these glands also may appear in the retromolar area
and anterior tonsillar pillar. They are more common in
adults than in children, probably as a result of hor-
monal factors; puberty appears to stimulate their
development. The lesions are typically asymptomatic,
although patients may be able to feel a slight roughness
to the mucosa. Considerable clinical variation may
exist; some patients may have only a few lesions,
whereas others may have literally hundreds of these
“granules.”
HISTOPATHOLOGIC FEATURES
Except for the absence of associated hair follicles,
Fordyce granules are closely similar to normal seba-
ceous glands found in the skin. Acinar lobules can be
seen immediately beneath the epithelial surface, often
communicating with the surface through a central duct
(Fig. 1-12). The sebaceous cells in these lobules are
Fig. 1-9 Ascher syndrome. Edema of the upper eyelids
(blepharochalasis).
Fig. 1-10 Fordyce granules. Yellow papules on the
vermilion of the upper lip.
Fig. 1-11 Fordyce granules. Lesions at the commissure. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

8 ORAL AND MAXILLOFACIAL PATHOLOGY
polygonal in shape, containing centrally located nuclei
and abundant foamy cytoplasm.
TREATMENT AND PROGNOSIS
Because Fordyce granules represent a normal ana-
tomic variation and are asymptomatic, no treatment is
indicated. Usually, the clinical appearance is charac-
teristic and biopsy is not necessary for diagnosis.
On occasion, Fordyce granules may become hyper-
plastic or may form keratin-ﬁlled pseudocysts. Tumors
arising from these glands are exceedingly rare.
LEUKOEDEMA
Leukoedema is a common oral mucosal condition of
unknown cause. It occurs more commonly in blacks
than in whites, supporting the likelihood of an ethnic
predisposition to its development. Leukoedema has
been reported in 70% to 90% of black adults and in 50%
of black children. The prevalence in whites is consider-
ably less, although published reports have ranged from
less than 10% to more than 90%. This variation may
reﬂect differing population groups, examination condi-
tions, and stringency of criteria used to make the diag-
nosis. At any rate, leukoedema shows a much milder
presentation in whites and often is hardly noticeable.
The difference in racial predilection may be explained
by the presence of background mucosal pigmentation
in blacks that makes the edematous changes more
noticeable.
Because leukoedema is so common, it can reason-
ably be argued that it represents a variation of normal
rather than a disease. The ﬁnding of similar edematous
mucosa in the vagina and larynx further supports
this argument. Although leukoedema appears to be
developmental in nature, some studies have indicated
that it is more common and more severe in smokers
and becomes less pronounced with cessation of
smoking.
CLINICAL FEATURES
Leukoedema is characterized by a diffuse, gray-white,
milky, opalescent appearance of the mucosa (Fig.
1-13). The surface frequently appears folded, resulting
in wrinkles or whitish streaks. The lesions do not rub
off. Leukoedema typically occurs bilaterally on the
buccal mucosa and may extend forward onto the labial
mucosa. On rare occasions, it can also involve the ﬂoor
of the mouth and palatopharyngeal tissues. Leuko-
edema can be easily diagnosed clinically because the
white appearance greatly diminishes or disappears
when the cheek is everted and stretched (Fig. 1-14).
HISTOPATHOLOGIC FEATURES
Biopsy specimens of leukoedema demonstrate an
increase in thickness of the epithelium, with striking
intracellular edema of the spinous layer (Fig. 1-15).
These vacuolated cells appear large and have pyknotic
nuclei. The epithelial surface is frequently parakera-
tinized, and the rete ridges are broad and elongated.
TREATMENT AND PROGNOSIS
Leukoedema is a benign condition, and no treatment
is required. The characteristic milky-white, opalescent
lesions of the buccal mucosa that disappear when
stretched help distinguish it from other common white
lesions, such as leukoplakia, candidiasis, and lichen
Fig. 1-12 Fordyce granules. Multiple sebaceous glands
below the surface epithelium.
Fig. 1-13 Leukoedema. White, wrinkled appearance of the
buccal mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 9
planus. The affected mucosa always should be stretched
during clinical examination to rule out any underlying
lesions that may be hidden by the edematous change.
MICROGLOSSIA (HYPOGLOSSIA)
CLINICAL FEATURES
Microglossia is an uncommon developmental condi-
tion of unknown cause that is characterized by an
abnormally small tongue. In rare instances, virtually
the entire tongue may be missing (aglossia). Isolated
microglossia is known to occur, and mild degrees of
microglossia may be difﬁcult to detect and may go
unnoticed. However, most reported cases have been
associated with one of a group of overlapping condi-
tions known as oromandibular-limb hypogenesis
syndromes. These syndromes feature associated limb
anomalies, such as hypodactylia (i.e., absence of digits)
and hypomelia (i.e., hypoplasia of part or all of a limb).
Other patients have had coexisting anomalies, such
as cleft palate, intraoral bands, and situs inversus. Micro-
glossia frequently is associated with hypoplasia of
the mandible, and the lower incisors may be missing
(Fig. 1-16).
TREATMENT AND PROGNOSIS
Treatment of the patient with microglossia depends on
the nature and severity of the condition. Surgery and
orthodontics may improve oral function. Surprisingly,
speech development often is quite good but depends
on tongue size.
A
B
Fig. 1-14 Leukoedema. A, Diffuse white appearance of the
buccal mucosa. B, Whiteness disappears when the cheek is
stretched.
Fig. 1-15 Leukoedema. Parakeratosis and intracellular
edema of the spinous layer.
A
B
Fig. 1-16 Microglossia. A, Abnormally small tongue
associated with constricted mandibular arch. B, Same patient
with associated constriction of the maxillary arch. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

10 ORAL AND MAXILLOFACIAL PATHOLOGY
MACROGLOSSIA
Macroglossia is an uncommon condition character-
ized by enlargement of the tongue. The enlargement
may be caused by a wide variety of conditions, includ-
ing congenital malformations and acquired diseases.
The most frequent causes are vascular malformations
and muscular hypertrophy. Box 1-2 lists the most
common and important causes of macroglossia. Many
of these diseases are discussed in greater detail in sub-
sequent chapters of this book.
CLINICAL FEATURES
Macroglossia most commonly occurs in children and
can range from mild to severe (Fig. 1-17). In infants,
macroglossia may be manifested ﬁrst by noisy breath-
ing, drooling, and difﬁculty in eating. The tongue
enlargement may result in a lisping speech. The pres-
sure of the tongue against the mandible and teeth can
produce a crenated lateral border to the tongue (Fig.
1-18), open bite, and mandibular prognathism. If the
tongue constantly protrudes from the mouth, it may
ulcerate and become secondarily infected or may even
undergo necrosis. Severe macroglossia can produce
airway obstruction.
Macroglossia is a characteristic feature of Beck-
with-Wiedemann syndrome, a rare hereditary con-
dition that includes many other possible defects, such
as the following:
●Omphalocele (i.e., protrusion of part of the intes-
tine through a defect in the abdominal wall at the
umbilicus)
● Visceromegaly
● Gigantism
● Neonatal hypoglycemia
Individuals with Beckwith-Wiedemann syndrome
have an increased risk for several childhood visceral
tumors, including Wilms’ tumor, adrenal carcinoma,
hepatoblastoma, rhabdomyosarcoma, and neuroblas-
toma. Facial features may include nevus ﬂammeus of
the forehead and eyelids, linear indentations of the
earlobes, and maxillary hypoplasia (resulting in rela-
tive mandibular prognathism). Most examples of Beck-
with-Wiedemann syndrome are sporadic, but 10% to
15% of cases show autosomal dominant inheritance
with preferential maternal transmission. The genetic
basis is complex, involving a variety of alterations
within two domains of imprinted growth-regulatory
genes on chromosome 11p15.
Box 1-2
Causes of Macroglossia
CONGENITAL AND HEREDITARY
● Vascular malformations
● Lymphangioma
● Hemangioma
● Hemihyperplasia
● Cretinism
● Beckwith-Wiedemann syndrome
● Down syndrome
● Mucopolysaccharidoses
● Neuroﬁbromatosis type I
●Multiple endocrine neoplasia, type 2B
ACQUIRED
● Edentulous patients
● Amyloidosis
● Myxedema
● Acromegaly
● Angioedema
●Carcinoma and other tumors
Fig. 1-17 Macroglossia. Large tongue in a patient with
Down syndrome. (Courtesy of Dr. Sanford Fenton.)
Fig. 1-18 Macroglossia. The tongue enlargement has
resulted in a crenated border that corresponds to the
embrasures between the teeth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 11
In patients with hypothyroidism (see page 843) or
Beckwith-Wiedemann syndrome, the tongue usually
shows a diffuse, smooth, generalized enlargement. In
those with other forms of macroglossia, the tongue
usually has a multinodular appearance. Examples of
this nodular type include amyloidosis (see page 822)
and neoplastic conditions, such as neuroﬁbromatosis
(see page 529) and multiple endocrine neoplasia,
type 2B (see page 532).
In patients with lymphangiomas (see page 547),
the tongue surface is characteristically pebbly and
exhibits multiple vesicle-like blebs that represent
superﬁcial dilated lymphatic channels. The enlarged
tongue in those with Down syndrome typically dem-
onstrates a papillary, ﬁssured surface.
In patients with hemifacial hyperplasia (see
page 38), the enlargement will be unilateral. Some
patients with neuroﬁbromatosis also can have unilat-
eral lingual enlargement.
In edentulous patients, the tongue often appears
elevated and tends to spread out laterally because of
loss of the surrounding teeth; as a result, wearing a
denture may become difﬁcult.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of macroglossia depends
on the speciﬁc cause. In some cases, such as the tongue
enlargement seen with Down syndrome or in edentu-
lous patients, no histologic abnormality can be detected.
When macroglossia is due to tumor, a neoplastic pro-
liferation of a particular tissue can be found (e.g., lym-
phatic vessels, blood vessels, neural tissue). Muscular
enlargement occurs in those with hemihyperplasia and
Beckwith-Wiedemann syndrome. In the patient with
amyloidosis, an abnormal protein material is deposited
in the tongue.
TREATMENT AND PROGNOSIS
The treatment and prognosis of macroglossia depend
on the cause and severity of the condition. In mild
cases, surgical treatment may not be necessary,
although speech therapy may be helpful if speech is
affected. In symptomatic patients, reduction glossec-
tomy may be needed.
ANKYLOGLOSSIA (TONGUE-TIE)
Ankyloglossia is a developmental anomaly of the
tongue characterized by a short, thick lingual frenum
resulting in limitation of tongue movement. It has been
reported to occur in 1.7% to 4.4% of neonates and is
four times more common in boys than in girls. In adults,
mild forms are not unusual, but severe ankyloglossia
is a relatively uncommon condition that has been
estimated to occur in about 2 to 3 of every 10,000
people.
CLINICAL FEATURES
Ankyloglossia can range in severity from mild cases
with little clinical signiﬁcance to rare examples of com-
plete ankyloglossia in which the tongue is actually
fused to the ﬂoor of the mouth (Fig. 1-19). Sometimes
the frenum extends forward and attaches to the tip of
the tongue, and slight clefting of the tip may be seen.
Some investigators have speculated that ankyloglos-
sia may contribute to the development of an anterior
open bite because the inability to raise the tongue to
the roof of the mouth prevents development of the
normal adult swallowing pattern. However, others
have questioned this theory. It also is possible that a
high mucogingival attachment of the lingual frenum
may lead to periodontal problems.
It has been suggested that tongue-tie may result in
speech defects. Usually, however, the shortened frenum
results in only minor difﬁculties because most people
can compensate for the limitation in tongue move-
ment. Yet there are rare examples of patients who have
experienced an immediate noticeable improvement in
speech after surgical correction of ankyloglossia. With
the increase in popularity of breast-feeding over the
past several decades, some clinicians have related
tongue-tie with feeding problems, such as nipple pain
or difﬁculty in the baby attaching to the breast. Recent
reports from Japan have theorized that some ankylo-
glossia cases can be associated with an upward and
forward displacement of the epiglottis and larynx,
resulting in various degrees of dyspnea.
Fig. 1-19 Ankyloglossia. Abnormal attachment of the
lingual frenum, limiting tongue mobility. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

12 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
Because most cases of ankyloglossia result in few or no
clinical problems, treatment is often unnecessary. For
infants with speciﬁc breast-feeding problems, a frenot-
omy (“clipping” or simple release of the frenulum) can
be performed. In children or adults with associated
functional or periodontal difﬁculties, a frenuloplasty
(release with plastic repair) may allow greater freedom
of tongue movement. In young children it often is rec-
ommended that surgery be postponed until age 4 or 5.
Because the tongue is always short at birth, assessing
the degree of tongue limitation caused by ankyloglossia
is difﬁcult in the infant’s early life. As the infant grows,
the tongue becomes longer and thinner at the tip, often
decreasing the severity of the tongue-tie. The condition
probably is self-correcting in many cases because it is
less common in adults.
LINGUAL THYROID
During the third to fourth week of fetal life, the thyroid
gland begins as an epithelial proliferation in the ﬂoor
of the pharyngeal gut. By the seventh embryonic week,
this thyroid bud normally descends into the neck to its
ﬁnal resting position anterior to the trachea and larynx.
The site where this descending bud invaginates later
becomes the foramen cecum, located at the junction of
the anterior two thirds and posterior third of the tongue
in the midline. If the primitive gland does not descend
normally, ectopic thyroid tissue may be found between
the foramen cecum and the epiglottis. Of all ectopic
thyroids, 90% are found in this region.
CLINICAL FEATURES
Based on autopsy studies, small asymptomatic rem-
nants of thyroid tissue can be discovered on the poste-
rior dorsal tongue in about 10% of both men and
women. However, clinically evident or symptomatic
lingual thyroids are much less common and are four
to seven times more frequent in females, presumably
because of hormonal inﬂuences. Symptoms most often
develop during puberty, adolescence, pregnancy, or
menopause. In 70% of cases, this ectopic gland is the
patient’s only thyroid tissue.
Lingual thyroids may range from small, asymptom-
atic, nodular lesions to large masses that can block the
airway (Fig. 1-20). The most common clinical symp-
toms are dysphagia, dysphonia, and dyspnea. The mass
often is vascular, but the physical appearance is vari-
able and there are no reliable features to distinguish it
from other masses that might develop in this area.
Hypothyroidism has been reported in up to 33% of
patients. Many authors say that lingual thyroid enlarge-
ment is a secondary phenomenon, compensating for
thyroid hypofunction. Interestingly, as many as 75%
of patients with infantile hypothyroidism have some
ectopic thyroid tissue.
Diagnosis is best established by thyroid scan using
iodine isotopes or technetium-99m. Computed tomog-
raphy (CT) and magnetic resonance imaging (MRI) can
be helpful in delineating the size and extent of the
lesion. Biopsy is often avoided because of the risk of
hemorrhage and because the mass may represent the
patient’s only functioning thyroid tissue. In some cases,
incisional biopsy may be needed to conﬁrm the diag-
nosis or to rule out malignant changes.
TREATMENT AND PROGNOSIS
No treatment except periodic follow-up is required for
patients with asymptomatic lingual thyroids. In symp-
tomatic patients, suppressive therapy with supplemen-
tal thyroid hormone often can reduce the size of the
lesion. Some authors advise that this treatment also
A
B
Fig. 1-20 Lingual thyroid. A, Nodular mass of the posterior
dorsal midline of the tongue in a 4-year-old girl. B, Thyroid
scan of the same patient. The scan shows localization (central
dark zone) of iodine isotope in the tongue mass and minimal
uptake in the neck. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 13
should be tried in asymptomatic patients to prevent
possible subsequent enlargement. If hormone therapy
does not eliminate symptoms, surgical removal or abla-
tion with radioactive iodine-131 can be performed. If
the mass is surgically excised, autotransplantation to
another body site can be attempted to maintain func-
tional thyroid tissue and to prevent hypothyroidism.
Rare examples of carcinomas arising in lingual thy-
roids have been reported; malignancy develops in
about 1% of identiﬁed cases. Although lingual thyroids
are decidedly more common in females, this predilec-
tion for females is less pronounced for lingual thyroid
carcinomas. Because a disproportionate number of
these malignancies have been documented in males,
some authors have advocated prophylactic excision of
lingual thyroids in men older than 30 years of age.
FISSURED TONGUE
(SCROTAL TONGUE)
Fissured tongue is a relatively common condition that
is characterized by the presence of numerous grooves,
or ﬁssures, on the dorsal tongue surface. The cause is
uncertain, but heredity appears to play a signiﬁcant
role. Evidence indicates that the condition may be
either a polygenic trait or an autosomal dominant
trait with incomplete penetrance. Aging or local
environmental factors also may contribute to its
development.
CLINICAL FEATURES
Patients with ﬁssured tongue exhibit multiple grooves,
or furrows, on the surface of the tongue, ranging from
2 to 6 mm in depth (Fig. 1-21). Considerable variation
can be seen. In the most severe cases, numerous ﬁs-
sures cover the entire dorsal surface and divide the
tongue papillae into multiple separate “islands.” Some
patients have ﬁssures that are located mostly on the
dorsolateral areas of the tongue. Other patients exhibit
a large central ﬁssure, with smaller ﬁssures branching
outward at right angles. The condition is usually asymp-
tomatic, although some patients may complain of mild
burning or soreness.
Most studies have shown that the prevalence of ﬁs-
sured tongue ranges from 2% to 5% of the overall popu-
lation. The condition may be seen in children or adults,
but the prevalence and severity appear to increase with
age, with some studies noting the presence of ﬁssured
tongue in as many as 30% of older adults. In some
investigations, a male predilection has been noted.
A strong association has been found between ﬁs-
sured tongue and geographic tongue (see page 779),
with many patients having both conditions. A heredi-
tary basis also has been suggested for geographic
tongue, and the same gene or genes may possibly be
linked to both conditions. In fact, it even has been sug-
gested that geographic tongue may cause ﬁssured
tongue. Fissured tongue also may be a component of
Melkersson-Rosenthal syndrome (see page 342).
HISTOPATHOLOGIC FEATURES
Microscopic examination of ﬁssured tongue reveals
hyperplasia of the rete ridges and loss of the keratin
“hairs” on the surface of the ﬁliform papillae. The papil-
lae vary in size and often are separated by deep grooves.
Polymorphonuclear leukocytes can be seen migrating
into the epithelium, often forming microabscesses in
the upper epithelial layers. A mixed inﬂammatory cell
inﬁltrate is present in the lamina propria.
TREATMENT AND PROGNOSIS
Fissured tongue is a benign condition, and no speciﬁc
treatment is indicated. The patient should be encour-
aged to brush the tongue, because food or debris
entrapped in the grooves may act as a source of
irritation.
HAIRY TONGUE (BLACK HAIRY
TONGUE; COATED TONGUE)
Hairy tongue is characterized by marked accumula-
tion of keratin on the ﬁliform papillae of the dorsal
tongue, resulting in a hairlike appearance. The condi-
tion apparently represents an increase in keratin pro-
duction or a decrease in normal keratin desquamation.
Hairy tongue is found in about 0.5% of adults. Although
the cause is uncertain, many affected people are heavy
smokers. Other possible associated factors include
Fig. 1-21 Fissured tongue. Extensive ﬁssuring involving the
entire dorsal tongue surface. (Courtesy of Chris Neville.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

14 ORAL AND MAXILLOFACIAL PATHOLOGY
general debilitation, poor oral hygiene, and a history of
radiation therapy to the head and neck.
CLINICAL FEATURES
Hairy tongue most commonly affects the midline just
anterior to the circumvallate papillae, sparing the
lateral and anterior borders (Fig. 1-22). The elongated
papillae are usually brown, yellow, or black as a result
of growth of pigment-producing bacteria or staining
from tobacco and food. Sometimes most of the dorsal
tongue may be involved, resulting in a thick, matted
appearance (Fig. 1-23). Multiple individual elongated
ﬁliform papillae may be elevated by using gauze
or a dental instrument. The condition is typically
asymptomatic, although occasionally patients com-
plain of a gagging sensation or a bad taste in the mouth.
Because the diagnosis usually can be made from the
clinical appearance, biopsy is unnecessary in most
instances.
Because of the similarity in names, care should be
taken to avoid confusing hairy tongue with hairy leu-
koplakia (see page 268), which typically occurs on the
lateral border of the tongue. Hairy leukoplakia is caused
by the Epstein-Barr virus and is usually associated with
human immunodeﬁciency virus (HIV) infection or
other immunosuppressive conditions.
In some individuals, numerous bacteria and desqua-
mated epithelial cells accumulate on the dorsal tongue
surface, but without the hairlike ﬁliform projections
(Fig. 1-24). Such cases, which are often designated as
a coated tongue, also may be the source of oral
malodor.
HISTOPATHOLOGIC FEATURES
On histopathologic examination, hairy tongue is
characterized by marked elongation and hyperpara-
keratosis of the ﬁliform papillae (Fig. 1-25). Usually,
numerous bacteria can be seen growing on the
epithelial surface.
Fig. 1-22 Hairy tongue. Elongated, yellow-brown ﬁliform
papillae on the posterior dorsal surface of the tongue.
Fig. 1-23 Hairy tongue. Marked elongation and brown
staining of the ﬁliform papillae, resulting in a hairlike
appearance.
Fig. 1-24 Coated tongue. The dorsal tongue appears white
and thickened from the accumulation of keratin and bacteria
on the surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 15
TREATMENT AND PROGNOSIS
Hairy or coated tongue is a benign condition with no
serious sequelae. The major concern is often the aes-
thetic appearance of the tongue along with possible
associated bad breath. Any predisposing factors, such
as tobacco, antibiotics, or mouthwashes, should be
eliminated, and excellent oral hygiene should be
encouraged. Periodic scraping or brushing with a
toothbrush or tongue scraper can promote desquama-
tion of the hyperkeratotic papillae and surface debris.
Keratolytic agents, such as podophyllin, also have been
tried with success, but for safety reasons their use prob-
ably should not be encouraged.
VARICOSITIES (VARICES)
Varicosities, or varices, are abnormally dilated and
tortuous veins. Age appears to be an important etio-
logic factor because varices are rare in children but
common in older adults. This suggests that their devel-
opment may be an age-related degeneration, in which
a loss of connective tissue tone supporting the vessels
occurs. Oral varices have not been associated with sys-
temic hypertension or other cardiopulmonary diseases,
although one study did ﬁnd that people with varicose
veins of the legs were more likely to have varicosities
of the tongue.
CLINICAL FEATURES
The most common type of oral varicosity is the sublin-
gual varix, which occurs in two thirds of people older
than 60 years of age. Sublingual varicosities classically
present as multiple blue-purple, elevated or papular
blebs on the ventral and lateral border of the tongue
(Fig. 1-26). The lesions are usually asymptomatic,
except in rare instances when secondary thrombosis
occurs.
Less frequently, solitary varices occur in other areas
of the mouth, especially the lips and buccal mucosa.
These isolated varicosities often are ﬁrst noticed after
they have become thrombosed (Fig. 1-27). Clinically, a
thrombosed varix presents as a ﬁrm, nontender, blue-
purple nodule that may feel like a piece of buckshot
beneath the mucosal surface.
HISTOPATHOLOGIC FEATURES
Microscopic examination of a varix reveals a dilated
vein, the wall of which shows little smooth muscle and
poorly developed elastic tissue. If secondary thrombo-
sis has occurred, then the lumen may contain concen-
trically layered zones of platelets and erythrocytes
Fig. 1-25 Hairy tongue. Elongation and marked
hyperkeratosis of the ﬁliform papillae, with bacterial
accumulation on the surface.
Fig. 1-26 Varicosities. Multiple purple dilated veins on the
ventral and lateral surface of the tongue.
Fig. 1-27 Varicosity. Firm, thrombosed varix on the lower
lip. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

16 ORAL AND MAXILLOFACIAL PATHOLOGY
(lines of Zahn). The clot can undergo organization via
granulation tissue, with subsequent recanalization.
Older thrombi may exhibit dystrophic calciﬁcation,
resulting in formation of a phlebolith (phlebo = vein;
lith = stone).
TREATMENT AND PROGNOSIS
Sublingual varicosities are typically asymptomatic, and
no treatment is indicated. Solitary varicosities of the
lips and buccal mucosa may need to be surgically
removed to conﬁrm the diagnosis, because of second-
ary thrombus formation or for aesthetic purposes.
CALIBER-PERSISTENT ARTERY
A caliber-persistent artery is a common vascular
anomaly in which a main arterial branch extends up
into the superﬁcial submucosal tissues without a reduc-
tion in its diameter. Similar to oral varices, caliber-
persistent arteries are seen more frequently in older
adults. This suggests that their development may be an
age-related degenerative phenomenon in which there
is a loss of tone in the surrounding supporting connec-
tive tissue.
CLINICAL FEATURES
The caliber-persistent artery occurs almost exclusively
on the lip mucosa. Either lip may be affected, and some
patients have bilateral lesions or lesions on both lips.
The average patient age is 58 years, and the gender
ratio is nearly equal. The lesion presents as a linear,
arcuate, or papular elevation that ranges from pale to
normal to bluish in color (Fig. 1-28). Stretching the lip
usually causes the artery to become inconspicuous. The
unique feature is pulsation—not only vertically but also
in a lateral direction. However, usually it is not possible
to feel a pulse in a caliber-persistent artery with gloved
ﬁngers.
The lesion is usually asymptomatic, being discov-
ered as an incidental ﬁnding during an oral examina-
tion; rarely a patient may notice a pulsatile lip nodule.
A few cases have been associated with ulceration of the
overlying mucosa. In addition, a couple of examples
have been found adjacent to labial squamous cell car-
cinomas, although this is probably coincidental.
HISTOPATHOLOGIC FEATURES
Microscopic examination shows a thick-walled artery
situated close to the mucosal surface (Fig. 1-29).
TREATMENT AND PROGNOSIS
If the true nature of the caliber-persistent artery can be
recognized clinically, no treatment is necessary. Often-
times a biopsy is performed when the lesion is mis-
taken for a mucocele or another vascular lesion, such
as a varix or hemangioma. Brisk bleeding is typically
encountered if the lesion is removed.
LATERAL SOFT PALATE FISTULAS
Lateral soft palate ﬁstulas are rare anomalies of
uncertain pathogenesis. Many cases appear to be con-
genital, possibly related to a defect in the development
of the second pharyngeal pouch. Some ﬁstulas may
be the result of infection or surgery of the tonsillar
region.
CLINICAL FEATURES
Lateral soft palate ﬁstulas are usually bilateral, but they
may occur only on one side. They are more common on
the anterior tonsillar pillar (Fig. 1-30), but they also may
Fig. 1-28 Caliber-persistent artery. Linear, arcuate lesion
on the upper labial mucosa (arrow). (Courtesy of Dr. John Lovas.)
Fig. 1-29 Caliber-persistent artery. Thick-walled artery
located just beneath the mucosal surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 17
involve the posterior pillar. The perforations are typi-
cally asymptomatic, ranging from a few millimeters to
more than 1 cm. A few cases have been associated with
other anomalies, such as absence or hypoplasia of the
palatine tonsils, hearing loss, and preauricular ﬁstulas.
TREATMENT AND PROGNOSIS
The lesions are innocuous, and no treatment is
necessary.
CORONOID HYPERPLASIA
Hyperplasia of the coronoid process of the mandible
is a rare developmental anomaly that may result
in limitation of mandibular movement. The cause of
coronoid hyperplasia is unknown, but the overall
male-to-female ratio is 5:1. Because most cases have
been seen in pubertal males, an endocrine inﬂuence
has been suggested. Heredity also may play a role,
because cases have been noted in siblings.
Coronoid hyperplasia may be unilateral or bilateral,
although bilateral cases are nearly ﬁve times more
common than unilateral examples. Unilateral enlarge-
ment of the coronoid process also can result from a
true tumor, such as an osteoma or osteochondroma,
and such cases should be distinguished from pure cor-
onoid hyperplasia. However, some cases reported as
tumors of the coronoid process actually may have been
hyperplastic processes rather than true neoplasms.
CLINICAL AND RADIOGRAPHIC
FEATURES
In a person with unilateral coronoid hyperplasia,
the enlarged coronoid process impinges on the poste-
rior surface of the zygoma, restricting mandibular
opening. In addition, the mandible may deviate toward
the affected side. Usually, there is no pain or associated
abnormality in occlusion. Radiographs may reveal an
irregular, nodular growth of the tip of the coronoid
process.
In bilateral coronoid hyperplasia, the limitation of
mandibular opening may progressively worsen over
several years during childhood, reaching maximum
severity during the late teens. The radiographic appear-
ance is characterized by regular elongation of both
processes. Because the coronoid process is often super-
imposed on the zygoma on conventional radiographs,
tomograms or CT scans often demonstrate the hyper-
plasia more effectively.
TREATMENT AND PROGNOSIS
Treatment of coronoid hyperplasia consists of surgical
removal of the elongated coronoid process or processes
to allow freedom of mandibular motion. Coronoidec-
tomy or coronoidotomy is usually accomplished via an
intraoral approach. Although initial improvement in
oral opening can be effected, the long-term results
sometimes can be disappointing because of surgically
induced ﬁbrosis and the tendency for coronoid
regrowth. Postoperative physiotherapy is important for
reestablishing normal function.
CONDYLAR HYPERPLASIA
Condylar hyperplasia is an uncommon malformation
of the mandible created by excessive growth of one of
the condyles. The cause of this hyperplasia is unknown,
but local circulatory problems, endocrine disturbances,
and trauma have been suggested as possible etiologic
factors.
A B
Fig. 1-30 Lateral palatal ﬁstula. A, Asymptomatic “hole” in the anterior tonsillar pillar.
B, Periodontal probe has been used to demonstrate the communication of the lesion with the
tonsillar fossa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

18 ORAL AND MAXILLOFACIAL PATHOLOGY
Condylar hyperplasia can be difﬁcult to distinguish
from hemifacial hyperplasia (see page 38); however,
in the latter condition the associated soft tissues and
teeth also may be enlarged.
CLINICAL AND
RADIOGRAPHIC FEATURES
Condylar hyperplasia may manifest itself in a variety
of ways, including facial asymmetry, prognathism,
crossbite, and open bite (Fig. 1-31). Sometimes com-
pensatory maxillary growth and tilting of the occlusal
plane occurs. The condition most commonly is discov-
ered in adolescents and young adults.
The radiographic features are quite variable. Some
patients have an enlargement of the condylar head,
and others show elongation of the condylar neck (Fig.
1-32). Many cases also demonstrate hyperplasia of the
entire ramus, suggesting that the condition sometimes
affects more than just the condyle. Scintigraphy using
99m
Tc-MDP has been advocated as a useful method for
assessing the degree of bone activity in condylar
hyperplasia.
HISTOPATHOLOGIC FEATURES
During active growth, proliferation of the condylar car-
tilage is noted. Once condylar growth has ceased, the
condyle has a normal histologic appearance.
TREATMENT AND PROGNOSIS
Condylar hyperplasia is a self-limiting condition, and
treatment is determined by the degree of functional
difﬁculty and aesthetic change. Some patients can be
treated with unilateral condylectomy, whereas others
require unilateral or bilateral mandibular osteotomies.
In patients with compensatory maxillary growth, a
maxillary osteotomy also may be needed. Concomitant
orthodontic therapy frequently is necessary.
CONDYLAR HYPOPLASIA
Condylar hypoplasia, or underdevelopment of the
mandibular condyle, can be either congenital or
acquired. Congenital condylar hypoplasia often is
Fig. 1-31 Condylar hyperplasia. Enlargement of the
patient’s left condyle has displaced the mandible to the right
and resulted in facial asymmetry.
Fig. 1-32 Condylar hyperplasia. Enlargement of the left mandibular condyle (arrow).
(Courtesy of Dr. Gary Reinhart.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 19
associated with head and neck syndromes, including
mandibulofacial dysostosis (see page 45), oculoau-
riculovertebral syndrome (Goldenhar syndrome),
and hemifacial microsomia. In the most severe cases,
complete agenesis of the condyle or ramus (condylar
aplasia) is seen.
Acquired condylar hypoplasia results from dis-
turbances of the growth center of the developing
condyle. The most frequent cause is trauma to the con-
dylar region during infancy or childhood. Other causes
include infections, radiation therapy, and rheumatoid
or degenerative arthritis.
CLINICAL AND
RADIOGRAPHIC FEATURES
Condylar hypoplasia can be unilateral or bilateral, pro-
ducing a small mandible with a Class II malocclusion.
Unilateral hypoplasia results in distortion and depres-
sion of the face on the affected side. The mandibular
midline shifts to the involved side when the mouth is
opened, accentuating the deformity. Ankylosis of the
temporomandibular joint (TMJ) can develop in cases
caused by trauma.
The deformity is observed easily on panoramic ﬁlms
and can range in severity. In severe cases the condyle
or ramus may be totally absent. Milder types demon-
strate a short condylar process, shallow sigmoid notch,
and poorly formed condylar head. A prominent ante-
gonial notch may be present. CT scans may be helpful
in evaluating the condyles.
TREATMENT AND PROGNOSIS
Treatment of the patient with condylar hypoplasia
depends on the cause and severity of the defect, but
surgery often is required. If the condyle is missing, then
a costochondral rib graft can be placed to help estab-
lish an active growth center. In addition, osteotomies
sometimes provide a cosmetically acceptable result. In
certain instances, distraction osteogenesis can be used
to stimulate new bone formation.
BIFID CONDYLE
A biﬁd condyle is a rare developmental anomaly
characterized by a double-headed mandibular condyle.
Most biﬁd condyles have a medial and lateral head
divided by an anteroposterior groove. Some condyles
may be divided into an anterior and posterior
head.
The cause of biﬁd condyle is uncertain. Anteropos-
terior biﬁd condyles may be of traumatic origin, such
as a childhood fracture. Mediolaterally divided con-
dyles may result from trauma, abnormal muscle attach-
ment, teratogenic agents, or persistence of a ﬁbrous
septum within the condylar cartilage.
CLINICAL AND
RADIOGRAPHIC FEATURES
A biﬁd condyle is usually unilateral, but occasionally
both sides may be affected. The malformation is often
asymptomatic and may be discovered on routine radio-
graphs, although some patients may have a “pop” or
“click” of the TMJ when opening their mouths. Pan-
oramic radiographs and CT scans will demonstrate a
bilobed appearance of the condylar head (Fig. 1-33).
TREATMENT AND PROGNOSIS
Because a biﬁd condyle is usually asymptomatic, most
of the time no treatment is necessary. If the patient has
joint complaints, the appropriate temporomandibular
therapy may be required.
EXOSTOSES
Exostoses are localized bony protuberances that arise
from the cortical plate. These benign growths fre-
quently affect the jaws. The best-known oral exostoses,
the torus palatinus and the torus mandibularis, are
described later in the chapter. Other types of exostoses
also may affect the jaws and are considered here.
CLINICAL AND
RADIOGRAPHIC FEATURES
Exostoses are discovered most often in adults. Buccal
exostoses occur as a bilateral row of bony hard nodules
along the facial aspect of the maxillary and/or
Fig. 1-33 Biﬁd condyle. Radiograph of the mandibular
condyle showing a double head (arrow). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

20 ORAL AND MAXILLOFACIAL PATHOLOGY
mandibular alveolar ridge (Fig. 1-34). They are usually
asymptomatic, unless the thin overlying mucosa
becomes ulcerated from trauma. One study reported
that buccal exostoses were found in nearly 1 of every
1000 adults (0.09%); however, a more recent survey
found a much higher prevalence of nearly 19%. This
variation may be due to the different populations being
studied or to the clinical criteria used to make the
diagnosis.
Palatal exostoses (palatal tubercles) are similar
bony protuberances that develop from the lingual
aspect of the maxillary tuberosities. These lesions are
usually bilateral but may affect only one side (Fig.
1-35). They are more common in males and have been
reported in 8% to 69% of various populations. Many
patients with buccal or palatal exostoses also will have
palatal or mandibular tori.
Less commonly, solitary exostoses may occur, pos-
sibly in response to local irritation. Such lesions may
develop from the alveolar bone beneath free gingival
grafts and skin grafts. Presumably placement of the
graft acts as a stimulant to the periosteum to form new
bone.
Another uncommon, interesting variant is the reac-
tive subpontine exostosis (subpontic osseous pro-
liferation, subpontic osseous hyperplasia), which
may develop from the alveolar crestal bone beneath
the pontic of a posterior bridge (Fig. 1-36).
If enough excess bone is present, exostoses may
exhibit a relative radiopacity on dental radiographs
(see Fig. 1-35, B). In rare instances an exostosis may
become so large that distinguishing it from a tumor,
such as an osteoma, is difﬁcult (see page 650).
HISTOPATHOLOGIC FEATURES
Microscopic examination reveals a mass of dense,
lamellar, cortical bone with a small amount of ﬁbro-
fatty marrow. In some cases an inner zone of trabecular
bone also is present.
TREATMENT AND PROGNOSIS
Most exostoses are distinctive enough clinically to
make biopsy unnecessary. If the diagnosis is uncertain,
biopsy should be performed to rule out other bony
Fig. 1-34 Exostoses. Multiple buccal exostoses of the
maxillary and mandibular alveolar ridges.
A
B
Fig. 1-35 Exostosis. A, Secondarily ulcerated palatal
exostosis. B, Radiograph shows an ovoid radiopacity distal to
the molar.
Fig. 1-36 Reactive subpontine exostosis. Nodular growth
of bone beneath the pontic of a posterior mandibular bridge. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 21
pathosis. Sometimes the exostosis must be removed if
it repeatedly has been exposed to trauma or has become
ulcerated and painful. In addition, surgical removal
may be required to accommodate a dental prosthesis
or to allow for proper ﬂap adaptation during periodon-
tal surgery. Reactive subpontine exostoses may need to
be removed if they interfere with oral hygiene or are
associated with adjacent periodontal disease.
TORUS PALATINUS
The torus palatinus is a common exostosis that occurs
in the midline of the vault of the hard palate. The
pathogenesis of these tori has long been debated, with
arguments centering on genetic versus environmental
factors, such as masticatory stress. Some authorities
have suggested that the torus palatinus is inherited as
an autosomal dominant trait. However, others believe
that the development of this lesion is multifactorial,
including both genetic and environmental inﬂuences.
In this model, patients are affected by a variety of
hereditary and local environmental factors. If enough
of these factors are present, then a “threshold” is
surpassed and the trait (torus palatinus) will be
expressed.
CLINICAL AND RADIOGRAPHIC
FEATURES
The torus palatinus presents as a bony hard mass that
arises along the midline suture of the hard palate (Figs.
1-37 to 1-39). Tori sometimes are classiﬁed according
to their morphologic appearance:
●The ﬂat torus has a broad base and a slightly convex,
smooth surface. It extends symmetrically onto both
sides of the midline raphe.
●The spindle torus has a midline ridge along the
palatal raphe. A median groove is sometimes
present.
●The nodular torus arises as multiple protuberances,
each with an individual base. These protuberances
may coalesce, forming grooves between them.
●The lobular torus is also a lobulated mass, but it
rises from a single base. Lobular tori can be either
sessile or pedunculated.
Most palatal tori are small, measuring less than 2 cm
in diameter; however, they can slowly increase in size
throughout life, sometimes to the extent that they ﬁll
the entire palatal vault. Most tori cause no symptoms,
but in some cases the thin overlying mucosa may
become ulcerated secondary to trauma.
The torus palatinus does not usually appear on
routine dental radiographs. Rarely it may be seen as a
radiopacity on periapical ﬁlms if the ﬁlm is placed
behind the torus when the radiograph is taken.
The prevalence of palatal tori has varied widely in a
number of population studies, ranging from 9% to 60%.
Fig. 1-37 Torus palatinus. Midline bony nodule of the
palatal vault.
Fig. 1-38 Torus palatinus. Large, lobulated palatal mass.
Fig. 1-39 Torus palatinus. Asymmetric, lobulated bony
mass. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

22 ORAL AND MAXILLOFACIAL PATHOLOGY
Some of this variation may be due to the criteria used
to make the diagnosis and also may be based on
whether the study was conducted on live patients or
skulls. There appear to be signiﬁcant racial differences,
however, with a higher prevalence in Asian and Inuit
(i.e., Eskimo) populations. In the United States, most
studies have shown a prevalence of 20% to 35%, with
little difference between whites and blacks. Almost all
studies from around the world have shown a pro-
nounced female-to-male ratio of 2:1. The prevalence
peaks during early adult life, tapering off in later years.
This ﬁnding supports the theory that tori are dynamic
lesions that are related, in part, to environmental
factors; in later life, some may undergo resorption
remodeling in response to decreased functional
stresses.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the torus shows a mass of
dense, lamellar, cortical bone. An inner zone of tra-
becular bone sometimes is seen.
TREATMENT AND PROGNOSIS
Most palatal tori can be diagnosed clinically based on
their characteristic appearance; therefore biopsy rarely
is necessary. In edentulous patients, the torus may
need to be removed surgically to accommodate a
denture base. Surgical removal may also be indicated
for palatal tori that become repeatedly ulcerated or
that interfere with oral function.
TORUS MANDIBULARIS
The torus mandibularis is a common exostosis that
develops along the lingual aspect of the mandible. As
with torus palatinus, the cause of mandibular tori is
probably multifactorial, including both genetic and
environmental inﬂuences.
CLINICAL AND RADIOGRAPHIC
FEATURES
The mandibular torus presents as a bony protuberance
along the lingual aspect of the mandible above the
mylohyoid line in the region of the premolars (Fig.
1-40). Bilateral involvement occurs in more than 90%
of cases. Most mandibular tori occur as single nodules,
although multiple lobules paralleling the teeth are not
unusual. Patients often are unaware of their presence
unless the overlying mucosa becomes ulcerated sec-
ondary to trauma. In rare instances, bilateral tori may
become so large that they almost meet in the midline
(Fig. 1-41). A large mandibular torus may appear on
periapical radiographs as a radiopacity superimposed
on the roots of the teeth (Fig. 1-42), especially on ante-
rior ﬁlms. Mandibular tori are easily visualized on
occlusal radiographs (Fig. 1-43).
Most studies indicate that the torus mandibularis is
not as common as the torus palatinus; the prevalence
ranges from 5% to 40%. Like the torus palatinus, the
mandibular torus appears to be more common in
Asians and the Inuit. The prevalence in the United
States ranges from 7% to 10%, with little difference
between blacks and whites. A slight male predilection
has been noted.
The prevalence of mandibular torus peaks in early
adult life, tapering slightly in later years. In addition,
the prevalence has been correlated with both bruxism
and the number of teeth remaining present. These
ﬁndings support the theory that the torus mandibularis
Fig. 1-40 Torus mandibularis. Bilateral lobulated bony
protuberances of the mandibular lingual alveolar ridge.
Fig. 1-41 Torus mandibularis. Massive “kissing” tori meet
in the midline. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 23
is multifactorial in development and responds to func-
tional stresses.
HISTOPATHOLOGIC FEATURES
The histopathologic appearance of the torus mandibu-
laris is similar to that of other exostoses, consisting pri-
marily of a nodular mass of dense, cortical lamellar
bone (Fig. 1-44). An inner zone of trabecular bone with
associated fatty marrow sometimes is visible.
TREATMENT AND PROGNOSIS
Most mandibular tori are easily diagnosed clinically,
and no treatment is necessary. However, surgical
removal may be required to accommodate a lower full
or partial denture. Occasionally, tori may recur if teeth
are still present in the area.
EAGLE SYNDROME (STYLOHYOID
SYNDROME; CAROTID ARTERY
SYNDROME; STYLALGIA)
The styloid process is a slender bony projection that
originates from the inferior aspect of the temporal
bone, anterior and medial to the stylomastoid foramen.
It is connected to the lesser cornu of the hyoid bone by
the stylohyoid ligament. The external and internal
carotid arteries lie on either side. Elongation of the
styloid process or mineralization of the stylohyoid liga-
ment complex is not unusual, having been reported in
18% to 40% of the population in some radiographic
reviews. Such mineralization is usually bilateral, but it
may affect only one side. Most cases are asymptomatic;
however, a small number of such patients experience
symptoms of Eagle syndrome, caused by impinge-
ment or compression of adjacent nerves or blood
vessels.
CLINICAL AND RADIOGRAPHIC
FEATURES
Eagle syndrome most commonly affects adults. The
patient experiences vague facial pain, especially while
swallowing, turning the head, or opening the mouth.
Other symptoms may include dysphagia, dysphonia,
otalgia, headache, dizziness, and transient syncope.
Elongation of the styloid process or mineralization
of the stylohyoid ligament complex can be seen on
panoramic or lateral-jaw radiographs (Fig. 1-45). The
mineralized stylohyoid complex may be palpated in
the tonsillar fossa area, and pain often is elicited.
Classic Eagle syndrome occurs after a tonsillectomy.
Development of scar tissue in the area of a mineralized
stylohyoid complex then results in cervicopharyngeal
Fig. 1-42 Torus mandibularis. Torus is causing a
radiopacity that is superimposed over the roots of the
mandibular teeth.
Fig. 1-43 Torus mandibularis. Occlusal radiograph
showing bilateral mandibular tori.
Fig. 1-44 Torus mandibularis. Nodular mass of dense,
cortical bone. Some fatty marrow is visible at the base of the
specimen. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

24 ORAL AND MAXILLOFACIAL PATHOLOGY
pain in the region of cranial nerves V, VII, IX, and X,
especially during swallowing. Some authors reserve
the term Eagle syndrome only for those cases in which
the ossiﬁcation of the stylohyoid chain occurs as a
result of the tonsillectomy or other neck trauma.
A second form of this condition unrelated to tonsil-
lectomy is sometimes known as carotid artery syn-
drome or stylohyoid syndrome. The elongated,
mineralized complex is thought to impinge on the
internal or external carotid arteries and associated
sympathetic nerve ﬁbers. The patient may complain of
pain in the neck when turning the head, and this pain
may radiate to other sites in the head or neck.
Traumatic Eagle syndrome also has been reported,
in which symptoms develop after fracture of a mineral-
ized stylohyoid ligament.
TREATMENT AND PROGNOSIS
Treatment of Eagle syndrome depends on the severity
of the symptoms. For mild cases, no treatment may be
necessary (except reassurance of the patient). Local
injection of corticosteroids sometimes provides relief.
In more severe cases, partial surgical excision of the
elongated styloid process or mineralized stylohyoid
ligament is required. Usually, this is accomplished via
an intraoral approach, although an extraoral approach
also can be used. The prognosis is good.
STAFNE DEFECT (STAFNE BONE CYST;
LINGUAL MANDIBULAR SALIVARY
GLAND DEPRESSION; LATENT BONE
CYST; STATIC BONE CYST; STATIC
BONE DEFECT; LINGUAL CORTICAL
MANDIBULAR DEFECT)
In 1942, Stafne described a series of asymptomatic
radiolucent lesions located near the angle of the man-
dible. Subsequent reports of similar lesions have shown
that this condition represents a focal concavity of the
cortical bone on the lingual surface of the mandible. In
most cases, biopsy has revealed histologically normal
salivary gland tissue, suggesting that these lesions rep-
resent developmental defects containing a portion of
the submandibular gland. However, a few of these
defects have been reported to be devoid of contents or
to contain muscle, ﬁbrous connective tissue, blood
vessels, fat, or lymphoid tissue.
Similar lingual cortical defects also have been noted
more anteriorly in the mandible, in the area of the
incisor, canine, or premolar teeth. These rare defects
have been related to the sublingual gland or to aber-
rant salivary gland tissue. In addition, one report has
implicated the parotid gland as the cause of an appar-
ent cortical defect in the upper mandibular ramus.
Therefore, all of the major salivary glands appear to be
capable of causing such cortical concavities.
In rare examples, the radiolucent defect has been
reported to be totally surrounded by intact bone. Such
cases might be explained by entrapment of embryonic
salivary gland tissue within the jawbone.
CLINICAL AND RADIOGRAPHIC
FEATURES
The classic Stafne defect presents as an asymptomatic
radiolucency below the mandibular canal in the poste-
rior mandible, between the molar teeth and the angle
of the mandible (Fig. 1-46). The lesion is typically well
circumscribed and has a sclerotic border. Sometimes
the defect may interrupt the continuity of the inferior
border of the mandible, with a palpable notch observed
clinically in this area. Most Stafne defects are unilat-
eral, although bilateral cases may be seen. Anterior
lingual salivary defects associated with the sublingual
gland present as well-deﬁned radiolucencies that may
appear superimposed over the apices of the anterior
teeth (Figs. 1-47 and 1-48).
Posterior Stafne defects are not rare, having been
reported in 0.3% of panoramic radiographs. A striking
male predilection is observed, with 80% to 90% of all
cases seen in men.
Although the defect is believed to be developmental
in nature, it does not appear to be present from birth.
Fig. 1-45 Eagle syndrome. Mineralization of the stylohyoid
ligament is visible posterior to the mandibular ramus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 25
Most cases have been reported in middle-aged and
older adults, with children rarely affected; this implies
that the lesion usually “develops” at a later age. Stafne
defects typically remain stable in size; hence the name
static bone cyst. In a few cases, however, the lesion
has increased in size over time (Fig. 1-49). This also
indicates that these lesions are not congenital.
The diagnosis can usually be made on a clinical basis
by the typical radiographic location and lack of symp-
toms. If the clinical diagnosis is in doubt, then it can be
conﬁrmed by CT scans, MRI, or sialography. CT scans
and MRIs show a well-deﬁned concavity on the lingual
surface of the mandible. Sialograms may be able to
demonstrate the presence of salivary gland tissue in the
area of the defect.
HISTOPATHOLOGIC FEATURES
Because of the typical radiographic appearance, biopsy
is usually not necessary to establish the diagnosis of
Stafne defects of the posterior mandible. If biopsy is
performed, normal submandibular gland tissue is
usually seen. However, some defects are devoid of
tissue or contain muscle, blood vessels, fat, connective
tissue, or lymphoid tissue. In cases reported to be
devoid of contents, it is possible that the gland was
simply displaced at the time of biopsy.
TREATMENT AND PROGNOSIS
No treatment is necessary for patients with Stafne
defects of the posterior mandible, and the prognosis is
excellent. Because anterior lingual salivary defects may
be difﬁcult to recognize, biopsy may be necessary to
rule out other pathologic lesions.
Developmental Cysts
By deﬁnition, a cyst is a pathologic cavity (often ﬂuid-
ﬁlled) that is lined by epithelium. A number of differ-
ent developmental cysts of the head and neck have
been described. Some of these have been considered
historically as “ﬁssural” cysts because they were thought
Fig. 1-46 Stafne defect. Radiolucency of the posterior
mandible below the mandibular canal.
Fig. 1-47 Stafne defect. Anterior radiolucent lesion of the
body of the mandible associated with the sublingual gland.
Fig. 1-48 Stafne defect. Lingual surface of the mandible
showing an anterior cortical defect caused by the sublingual
gland. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

26 ORAL AND MAXILLOFACIAL PATHOLOGY
to arise from epithelium entrapped along embryonal
lines of fusion. However, the concept of a ﬁssural origin
for many of these cysts has been questioned in more
recent years. In many instances the exact pathogenesis of
these lesions is still uncertain. Regardless of their origin,
once cysts develop in the oral and maxillofacial region,
they tend to slowly increase in size, possibly in response
to a slightly elevated hydrostatic luminal pressure.
PALATAL CYSTS OF THE
NEWBORN (EPSTEIN’S PEARLS;
BOHN’S NODULES)
Small developmental cysts are a common ﬁnding on
the palate of newborn infants. Researchers have theo-
rized that these “inclusion” cysts may arise in one of
two ways. First, as the palatal shelves meet and fuse in
the midline during embryonic life to form the second-
ary palate, small islands of epithelium may become
entrapped below the surface along the median palatal
raphe and form cysts. Second, these cysts may arise
from epithelial remnants derived from the develop-
ment of the minor salivary glands of the palate.
As originally described, Epstein’s pearls occur
along the median palatal raphe and presumably arise
from epithelium entrapped along the line of fusion.
Bohn’s nodules are scattered over the hard palate,
often near the soft palate junction and are believed to
be derived from the minor salivary glands. However,
these two terms have been used almost interchange-
ably in the literature and also have often been used to
describe gingival cysts of the newborn (see page 691),
similar-appearing lesions of dental lamina origin.
Therefore, the term palatal cysts of the newborn
may be preferable to help distinguish them from gin-
gival cysts of the newborn. In addition, because these
cysts are most common near the midline at the junc-
tion of the hard and soft palates, it is usually difﬁcult to
ascertain clinically whether they are arising from epi-
thelium entrapped by fusion of the palate or from the
developing minor salivary glands.
CLINICAL FEATURES
Palatal cysts of the newborn are quite common and
have been reported in as many as 65% to 85% of neo-
nates. The cysts are small, 1- to 3-mm, white or yellow-
white papules that appear most often along the midline
near the junction of the hard and soft palates (Fig.
1-50). Occasionally, they may occur in a more anterior
location along the raphe or on the posterior palate
lateral to the midline. Frequently a cluster of two to
six cysts is observed, although the lesions also can
occur singly.
A
C
B
Fig. 1-49 Stafne defect. A, Ill-deﬁned radiolucency near the angle of the mandible.
B, Appearance of the same defect several years later showing enlargement of the lesion.
C, Computed tomography (CT) image of the same lesion showing a left lingual cortical defect
(arrow). (Courtesy of Dr. Carroll Gallagher.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 27
HISTOPATHOLOGIC FEATURES
Microscopic examination reveals keratin-ﬁlled cysts
that are lined by stratiﬁed squamous epithelium. Some-
times these cysts demonstrate a communication with
the mucosal surface.
TREATMENT AND PROGNOSIS
Palatal cysts of the newborn are innocuous lesions, and
no treatment is required. They are self-healing and
rarely observable several weeks after birth. Presum-
ably the epithelium degenerates, or the cysts rupture
onto the mucosal surface and eliminate their keratin
contents.
NASOLABIAL CYST (NASOALVEOLAR
CYST; KLESTADT CYST)
The nasolabial cyst is a rare developmental cyst that
occurs in the upper lip lateral to the midline. The
pathogenesis is uncertain, although there are two major
theories. One theory considers the nasolabial cyst to
be a “ﬁssural” cyst arising from epithelial remnants
entrapped along the line of fusion of the maxillary,
medial nasal, and lateral nasal processes. A second
theory suggests that these cysts develop from misplaced
epithelium of the nasolacrimal duct because of their
similar location and histologic appearance.
CLINICAL AND RADIOGRAPHIC
FEATURES
The nasolabial cyst usually appears as a swelling of the
upper lip lateral to the midline, resulting in elevation
of the ala of the nose. The enlargement often elevates
the mucosa of the nasal vestibule and obliterates the
maxillary mucolabial fold (Fig. 1-51). On occasion, this
expansion may result in nasal obstruction or may inter-
fere with the wearing of a denture. Pain is uncommon
unless the lesion is secondarily infected. The cyst may
rupture spontaneously and may drain into the oral
cavity or nose.
Nasolabial cysts are most commonly seen in adults,
with a peak prevalence in the fourth and ﬁfth decades
of life. A signiﬁcant predilection exists for women, with
a female-to-male ratio of 3:1. Approximately 10% of the
reported cases have been bilateral.
Because the nasolabial cyst arises in soft tissues, in
most cases no radiographic changes are seen. Occa-
sionally, pressure resorption of the underlying bone
may occur.
HISTOPATHOLOGIC FEATURES
The nasolabial cyst is characteristically lined by pseu-
dostratiﬁed columnar epithelium, often demonstrat-
ing goblet cells and cilia (Fig. 1-52). Areas of cuboidal
Fig. 1-50 Epstein’s pearls. Small keratin-ﬁlled cysts at the
junction of the hard and soft palates. (Courtesy of Tristan Neville.)
A B
Fig. 1-51 Nasolabial cyst. A, Enlargement of the left upper lip with elevation of the ala of
the nose. B, Intraoral swelling ﬁlls the maxillary labial fold. (Courtesy of Dr. Jim Weir.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

28 ORAL AND MAXILLOFACIAL PATHOLOGY
epithelium and squamous metaplasia are not unusual.
Apocrine changes also have been reported. The cyst
wall is composed of ﬁbrous connective tissue with adja-
cent skeletal muscle. Inﬂammation may be seen if the
lesion is secondarily infected.
TREATMENT AND PROGNOSIS
Complete surgical excision of the cyst via an intraoral
approach has been the treatment of choice. Because
the lesion is often close to the ﬂoor of the nose, it is
sometimes necessary to sacriﬁce a portion of the nasal
mucosa to ensure total removal. Recurrence is rare.
Recently an alternative transnasal approach has been
suggested that allows endoscopic marsupialization of
the cystic cavity.
“GLOBULOMAXILLARY CYST”
As originally described, the “globulomaxillary cyst”
was purported to be a ﬁssural cyst that arose from epi-
thelium entrapped during fusion of the globular portion
of the medial nasal process with the maxillary process.
This concept has been questioned, however, because
the globular portion of the medial nasal process is pri-
marily united with the maxillary process and a fusion
does not occur. Therefore, epithelial entrapment should
not occur during embryologic development of this
area.
Virtually all cysts in the globulomaxillary region
(between the lateral incisor and canine teeth) can be
explained on an odontogenic basis. Many are lined by
inﬂamed stratiﬁed squamous epithelium and are con-
sistent with periapical cysts (see page 130). Some
exhibit speciﬁc histopathologic features of an odonto-
genic keratocyst (see page 683) or developmental
lateral periodontal cyst (see page 692). Researchers
have also theorized that some of these lesions may arise
from inﬂammation of the reduced enamel epithelium
at the time of eruption of the teeth.
On rare occasions, cysts in the globulomaxillary area
may be lined by pseudostratiﬁed, ciliated, columnar
epithelium. Such cases may lend credence to the ﬁs-
sural theory of origin. However, this epithelium may
be explained by the close proximity of the sinus lining.
In addition, respiratory epithelium also has been
reported in periapical cysts, dentigerous cysts, and
glandular odontogenic cysts found in other locations.
Because a ﬁssural cyst in this region probably does
not exist, the term globulomaxillary cyst should no longer
be used. When a radiolucency between the maxillary
lateral incisor and canine is encountered, the clinician
should ﬁrst consider an odontogenic origin for the
lesion.
NASOPALATINE DUCT CYST
(INCISIVE CANAL CYST)
The nasopalatine duct cyst is the most common non-
odontogenic cyst of the oral cavity, occurring in about
1% of the population. The cyst is believed to arise from
remnants of the nasopalatine duct, an embryologic
structure connecting the oral and nasal cavities in the
area of the incisive canal.
In the 7-week-old fetus, the developing palate con-
sists of the primary palate, which is formed by the
fusion of the medial nasal processes. Behind the
primary palate, downgrowth of the nasal septum pro-
duces two communications between the oral and nasal
cavities, the primitive nasal choanae. Formation of the
secondary palate begins around the eighth intrauter-
ine week, with downward growth of the medial parts
of the maxillary processes (palatine processes) to a
location on either side of the tongue.
As the mandible develops and the tongue drops
down, these palatine processes grow horizontally,
fusing with the nasal septum in the midline and with
the primary palate along their anterior aspect. Two
passageways persist in the midline between the primary
and secondary palates (the incisive canals). Also
formed by this fusion and found within the incisive
canals are epithelial structures—the nasopalatine
ducts. These ducts normally degenerate in humans but
may leave epithelial remnants behind in the incisive
canals.
The incisive canals begin on the ﬂoor of the nasal
cavity on either side of the nasal septum, coursing
downward and forward to exit the palatal bone via a
common foramen in the area of the incisive papilla. In
addition to the nasopalatine ducts, these canals contain
the nasopalatine nerve plus anastomosing branches of
the descending palatine and sphenopalatine arteries.
Fig. 1-52 Nasolabial cyst. Pseudostratiﬁed columnar
epithelial lining. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 29
Occasionally, two smaller foramina carrying the naso-
palatine nerves—the canals of Scarpa—are found
within the incisive foramen.
In some mammals the nasopalatine ducts remain
patent and provide communication between the oral
and nasal cavities. On rare occasions, patent or par-
tially patent nasopalatine ducts may be encountered in
humans. In mammals the nasopalatine ducts may com-
municate with the vomer-nasal organ of Jacobson,
acting as an accessory olfactory organ. However, in
humans, Jacobson’s organ usually recedes in uterine
life to become a vestigial structure.
Researchers have suggested that the nasopalatine
duct cyst may arise from the epithelium of Jacobson’s
organ, but this appears highly unlikely. Trauma or
infection of the duct and mucous retention of adjacent
minor salivary glands also have been mentioned as
possible etiologic factors, but the role of each has been
questioned. Although the pathogenesis of this lesion is
still uncertain, the lesion most likely represents a spon-
taneous cystic degeneration of remnants of the naso-
palatine duct.
CLINICAL AND RADIOGRAPHIC
FEATURES
The nasopalatine duct cyst may develop at almost any
age but is most common in the fourth to sixth decades
of life. In spite of its being a “developmental” cyst, the
nasopalatine duct cyst is rarely seen during the ﬁrst
decade. Most studies have shown a male predilection.
The most common presenting symptoms include
swelling of the anterior palate, drainage, and pain (Fig.
1-53). Patients sometimes relate a long history of these
symptoms, probably because of their intermittent
nature. However, many lesions are asymptomatic and
are discovered on routine radiographs. Rarely a large
cyst may produce a “through-and-through” ﬂuctuant
expansion involving the anterior palate and labial alve-
olar mucosa.
Radiographs usually demonstrate a well-circum-
scribed radiolucency in or near the midline of the ante-
rior maxilla, between and apical to the central incisor
teeth (Figs. 1-54 and 1-55). Root resorption is rarely
noted. The lesion most often is round or oval with a
sclerotic border. Some cysts may have an inverted pear
shape, presumably because of resistance of adjacent
tooth roots. Other examples may show a classic heart
shape as a result of superimposition of the nasal spine
or because they are notched by the nasal septum.
The radiographic diameter of nasopalatine duct
cysts can range from small lesions, less than 6 mm, to
destructive lesions as large as 6 cm. However, most
cysts are in the range of 1.0 to 2.5 cm, with an average
diameter of 1.5 to 1.7 cm. It may be difﬁcult to distin-
guish a small nasopalatine duct cyst from a large inci-
sive foramen. It is generally accepted that a diameter
of 6 mm is the upper limit of normal size for the inci-
sive foramen. Therefore, a radiolucency that is 6 mm
or smaller in this area is usually considered a normal
foramen unless other clinical signs or symptoms are
present.
In rare instances, a nasopalatine duct cyst may
develop in the soft tissues of the incisive papilla area
without any bony involvement. Such lesions often are
Fig. 1-53 Nasopalatine duct cyst. Fluctuant swelling of the
anterior hard palate.
Fig. 1-54 Nasopalatine duct cyst. Well-circumscribed
radiolucency between and apical to the roots of the maxillary
central incisors. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

30 ORAL AND MAXILLOFACIAL PATHOLOGY
called cysts of the incisive papilla. These cysts fre-
quently demonstrate bluish discoloration as a result of
the ﬂuid contents in the cyst lumen (Fig. 1-56).
HISTOPATHOLOGIC FEATURES
The epithelial lining of nasopalatine duct cysts is highly
variable (Figs. 1-57 and 1-58). It may be composed of
the following:
● Stratiﬁed squamous epithelium
● Pseudostratiﬁed columnar epithelium
●Simple columnar epithelium
●Simple cuboidal epithelium
Frequently, more than one epithelial type is found
in the same cyst. Stratiﬁed squamous epithelium is
most common, present in at least three fourths of all
cysts. Pseudostratiﬁed columnar epithelium has been
reported in from one third to three fourths of all cases.
Simple cuboidal and columnar epithelium are discov-
ered less frequently.
Cilia and goblet cells may be found in association
with columnar linings. The type of epithelium may be
related to the vertical position of the cyst within the
incisive canal. Cysts developing within the superior
aspect of the canal near the nasal cavity are more likely
to demonstrate respiratory epithelium; those in an infe-
rior position near the oral cavity are more likely to
exhibit squamous epithelium.
The contents of the cyst wall can be a helpful diag-
nostic aid. Because the nasopalatine duct cyst arises
within the incisive canal, moderate-sized nerves and
small muscular arteries and veins are usually found in
Fig. 1-55 Nasopalatine duct cyst. Large destructive cyst of
the palate.
Fig. 1-56 Cyst of the incisive papilla. Swelling of the
incisive papilla.
Fig. 1-57 Nasopalatine duct cyst. Cystic lining showing
transition from pseudostratiﬁed columnar to stratiﬁed
squamous epithelium.
Fig. 1-58 Nasopalatine duct cyst. Flattened cuboidal
epithelial lining. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 31
the wall of the cyst (Fig. 1-59). Small mucous glands
have been reported in as many as one third of cases.
Occasionally, the clinician may see small islands of
hyaline cartilage. Frequently, an inﬂammatory response
is noted in the cyst wall and may range from mild to
heavy. This inﬂammation is usually chronic in nature
and is composed of lymphocytes, plasma cells, and his-
tiocytes. Associated acute inﬂammatory cells (neutro-
phils) sometimes may be seen.
TREATMENT AND PROGNOSIS
Nasopalatine duct cysts are treated by surgical enucle-
ation. Biopsy is recommended because the lesion is not
diagnostic radiographically; other benign and malig-
nant lesions have been known to mimic the nasopala-
tine duct cyst. The lesion is best approached with a
palatal ﬂap that is reﬂected after an incision is made
along the lingual gingival margin of the anterior maxil-
lary teeth. Recurrence is rare. Malignant transforma-
tion has been reported in a couple of cases, but this is
an extremely rare complication.
MEDIAN PALATAL (PALATINE) CYST
The median palatal cyst is a rare ﬁssural cyst that theo-
retically develops from epithelium entrapped along
the embryonic line of fusion of the lateral palatal
shelves of the maxilla. This cyst may be difﬁcult to dis-
tinguish from a nasopalatine duct cyst. In fact, most
“median palatal cysts” may represent posteriorly posi-
tioned nasopalatine duct cysts. Because the nasopala-
tine ducts course posteriorly and superiorly as they
extend from the incisive canal to the nasal cavity, a
nasopalatine duct cyst that arises from posterior rem-
nants of this duct near the nasal cavity might be mis-
taken for a median palatal cyst. On the other hand, if
a true median palatal cyst were to develop toward the
anterior portion of the hard palate, then it could easily
be mistaken for a nasopalatine duct cyst.
CLINICAL AND RADIOGRAPHIC
FEATURES
The median palatal cyst presents as a ﬁrm or ﬂuctuant
swelling of the midline of the hard palate posterior to
the palatine papilla. The lesion appears most frequently
in young adults. Often it is asymptomatic, but some
patients complain of pain or expansion. The average
size of this cyst is 2 × 2 cm, but sometimes it can
become quite large. Occlusal radiographs demonstrate
a well-circumscribed radiolucency in the midline of
the hard palate (Fig. 1-60). Occasional reported cases
have been associated with divergence of the central
incisors, although it may be difﬁcult to rule out a naso-
palatine duct cyst in these instances.
To differentiate the median palatal cyst from other
cystic lesions of the maxilla, Gingell and associates sug-
gested the following diagnostic criteria:
●Grossly appears symmetrical along the midline of
the hard palate
●Located posterior to the palatine papilla
●Appears ovoid or circular radiographically
●Not intimately associated with a nonvital tooth
Fig. 1-59 Nasopalatine duct cyst. Cyst wall showing blood
vessels, nerve bundles, and minor salivary glands.
Fig. 1-60 Median palatal cyst. Well-circumscribed
radiolucency apical to the maxillary incisors in the midline.
At surgery the lesion was unrelated to the incisive canal.
(Courtesy of Dr. Timothy Armanini.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

32 ORAL AND MAXILLOFACIAL PATHOLOGY
●Does not communicate with the incisive canal
●Shows no microscopic evidence of large neurovas-
cular bundles, hyaline cartilage, or minor salivary
glands in the cyst wall
It must be stressed that a true median palatal cyst
should exhibit clinical enlargement of the palate. A
midline radiolucency without clinical evidence of
expansion is probably a nasopalatine duct cyst.
HISTOPATHOLOGIC FEATURES
Microscopic examination shows a cyst that is usually
lined by stratiﬁed squamous epithelium. Areas of cili-
ated pseudostratiﬁed columnar epithelium have been
reported in some cases. Chronic inﬂammation may be
present in the cyst wall.
TREATMENT AND PROGNOSIS
The median palatal cyst is treated by surgical removal.
Recurrence should not be expected.
“MEDIAN MANDIBULAR CYST”
The “median mandibular cyst” is a controversial
lesion of questionable existence. Theoretically, it rep-
resents a ﬁssural cyst in the anterior midline of the
mandible that develops from epithelium entrapped
during fusion of the halves of the mandible during
embryonic life. However, the mandible actually devel-
ops as a single bilobed proliferation of mesenchyme
with a central isthmus in the midline. As the mandible
grows, this isthmus is eliminated. Therefore, because
no fusion of epithelium-lined processes occurs, entrap-
ment of epithelium should not be possible.
Because respiratory prosoplasia is not uncommon in
odontogenic cysts, it appears likely that most (if not all)
of these midline cysts are of odontogenic origin. Many
purported cases would be classiﬁed today as examples
of the glandular odontogenic cyst (see page 697), which
has a propensity for occurrence in the midline mandib-
ular region. Others could be classiﬁed as periapical cysts,
odontogenic keratocysts, or lateral periodontal cysts. Because
a ﬁssural cyst in this region probably does not exist, the
term median mandibular cyst should no longer be used.
FOLLICULAR CYSTS OF THE SKIN
Follicular cysts of the skin are common keratin-ﬁlled
lesions that arise from one or more portions of the hair
follicle. The most common type, which is derived from
the follicular infundibulum, is known as an epider-
moid or infundibular cyst. These cysts often arise
after localized inﬂammation of the hair follicle and
probably represent a nonneoplastic proliferation of the
infundibular epithelium resulting from the healing
process. The term sebaceous cyst sometimes is used
mistakenly as a synonym for both the epidermoid cyst
and another cyst of the scalp known as a pilar, tricho-
lemmal, or isthmus-catagen cyst. However, because
both the epidermoid cyst and pilar cyst are derived
from the hair follicle rather than the sebaceous gland,
the term sebaceous cyst should be avoided.
Keratin-ﬁlled cysts of the skin may occasionally arise
after traumatic implantation of epithelium, although
such lesions may be difﬁcult to distinguish from an
infundibular cyst. Rarely, such epidermal inclusion
(implantation) cysts also can develop in the mouth.
These small inclusion cysts should be distinguished
from oral epidermoid cysts that occur in the midline
ﬂoor of mouth region and represent the minimal mani-
festation of the teratoma-dermoid cyst-epidermoid cyst
spectrum (see page 33).
CLINICAL FEATURES
Epidermoid (infundibular) cysts account for approxi-
mately 80% of follicular cysts of the skin and are most
common in the acne-prone areas of the head, neck, and
back. They are unusual before puberty unless they are
associated with Gardner syndrome (see page 651).
Young adults are more likely to have cysts on the face,
whereas older adults are more likely to have cysts on
the back. Males are affected more frequently than
females.
Epidermoid cysts present as nodular, ﬂuctuant sub-
cutaneous lesions that may or may not be associated
with inﬂammation (Figs. 1-61 and 1-62). If a nonin-
ﬂamed lesion presents in an area of thin skin, such as
the earlobe, then it may be white or yellow.
Pilar (tricholemmal) cysts comprise approximately
10% to 15% of skin cysts, occurring most frequently on
Fig. 1-61 Epidermoid cyst. Fluctuant nodule at the lateral
edge of the eyebrow. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 33
the scalp (Fig. 1-63). They are twice as common in
women as in men. The lesion is usually movable and
shells out easily.
HISTOPATHOLOGIC FEATURES
Microscopic examination of an epidermoid cyst reveals
a cavity that is lined by stratiﬁed squamous epithelium
resembling epidermis (Fig. 1-64). A well-developed
granular cell layer is seen, and the lumen is ﬁlled with
degenerating orthokeratin. Not infrequently, the epi-
thelial lining will be disrupted. When this occurs,
a prominent granulomatous inﬂammatory reaction,
including multinucleated giant cells, can be present in
the cyst wall because the exposed keratin is recognized
as a foreign material.
The pilar cyst is also lined by stratiﬁed squamous
epithelium, although a granular cell layer is usually
absent or greatly diminished (Fig. 1-65). The keratino-
cytes remain large in the upper epithelial layers with
an abrupt transition to dense, compact keratin that ﬁlls
the cyst lumen.
TREATMENT AND PROGNOSIS
Epidermoid and pilar cysts are usually treated by con-
servative surgical excision, and recurrence is uncom-
mon. Malignant transformation has been reported but
is exceedingly rare.
DERMOID CYST
The dermoid cyst is an uncommon developmental
cystic malformation. The cyst is lined by epidermis-like
epithelium and contains dermal adnexal structures in
the cyst wall. It is generally classiﬁed as a benign cystic
form of teratoma.
Fig. 1-62 Epidermoid cyst. Infant with a mass in the upper
lip.
Fig. 1-63 Pilar cyst. Nodular mass on the scalp.
A B
Fig. 1-64 Epidermoid cyst. A, Low-power view showing a keratin-ﬁlled cystic cavity.
B, High-power view showing stratiﬁed squamous epithelial lining with orthokeratin production. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

34 ORAL AND MAXILLOFACIAL PATHOLOGY
By deﬁnition, a true teratoma is a developmental
tumor composed of tissue from all three germ layers:
(1) ectoderm, (2) mesoderm, and (3) endoderm. Such
tumors are believed to arise from germ cells or
entrapped totipotent blastomeres, which can produce
derivatives of all three germ layers.
Teratomatous malformations have a spectrum of
complexity. In their most complex form, these lesions
produce multiple types of tissue that are arranged in a
disorganized fashion. These “complex” teratomas are
most common in the ovaries or testes and can be benign
or malignant. Occasionally, ovarian teratomas (or “der-
moids”) produce well-formed teeth, or even partially
complete jaws. Complex teratomas of the oral cavity
are rare and are usually congenital in nature. When
they occur, they usually extend through a cleft palate
from the pituitary area via Rathke’s pouch. Cervical
teratomas also have been reported.
The term teratoid cyst has been used to describe a
cystic form of teratoma that contains a variety of germ
layer derivatives:
1.Skin appendages, including hair follicles, seba-
ceous glands, and sweat glands
2.Connective tissue elements, such as muscle,
blood vessels, and bone
3.Endodermal structures, such as gastrointestinal
lining
Rarely, oral cysts may be lined entirely by gastroin-
testinal epithelium. These heterotopic oral gastroin-
testinal cysts (enterocystomas, enteric duplication
cysts) are usually considered to be choristomas, or his-
tologically normal tissue found in an abnormal loca-
tion. However, these lesions probably can be included
under the broad umbrella of teratomatous lesions,
especially because they are occasionally found in com-
bination with dermoid cysts.
Dermoid cysts are simpler in structure than complex
teratomas or teratoid cysts. Although they do not
contain tissue from all three germ layers, they probably
represent a forme fruste of a teratoma. Similar cysts of
the oral cavity can be seen that are lined by epidermis-
like epithelium, but they contain no dermal append-
ages in the cyst wall. These lesions have been called
epidermoid cysts and represent the simplest expres-
sion of the teratoma spectrum. These intraoral epider-
moid cysts should not be confused with the more
common epidermoid cyst of the skin (see page 32),
a nonteratomatous lesion that arises from the hair
follicle.
CLINICAL AND RADIOGRAPHIC
FEATURES
Dermoid cysts most commonly occur in the midline of
the ﬂoor of the mouth (Fig. 1-66), although occasion-
ally they are displaced laterally or develop in other
locations. If the cyst develops above the geniohyoid
muscle, then a sublingual swelling may displace the
tongue toward the roof of the mouth and create difﬁ-
culty in eating, speaking, or even breathing. Cysts that
occur below the geniohyoid muscle often produce a
submental swelling, with a “double-chin” appearance.
Oral dermoid cysts can vary in size from a few mil-
limeters to 12 cm in diameter. They are most common
in children and young adults; 15% of reported cases
have been congenital. The lesion is usually slow growing
and painless, presenting as a doughy or rubbery mass
that frequently retains pitting after application of pres-
Fig. 1-65 Pilar cyst. Medium-power view showing an
abrupt transition between the stratiﬁed squamous epithelial
lining and compact keratin without the presence of a
transitional granular cell layer.
Fig. 1-66 Dermoid cyst. Fluctuant midline swelling in the
ﬂoor of the mouth. (From Budnick SD: Handbook of pediatric oral
pathology, Chicago, 1981, Year Book Medical.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 35
sure. Secondary infection can occur, and the lesion
may drain intraorally or onto the skin. MRIs, CT scans,
or contrast medium radiographs may be helpful in
delineating the extent of the lesion.
HISTOPATHOLOGIC FEATURES
Dermoid cysts are lined by orthokeratinized stratiﬁed
squamous epithelium, with a prominent granular cell
layer. Abundant keratin often is found within the cyst
lumen. On rare occasions, areas of respiratory epithe-
lium can be seen. The cyst wall is composed of ﬁbrous
connective tissue that contains one or more skin
appendages, such as sebaceous glands, hair follicles, or
sweat glands (Fig. 1-67).
TREATMENT AND PROGNOSIS
Dermoid cysts are treated by surgical removal. Those
located above the geniohyoid muscle can be removed
by an intraoral incision, and those below the geniohyoid
muscle may require an extraoral approach. Recurrence
is uncommon. Malignant transformation into squamous
cell carcinoma has been reported only rarely.
THYROGLOSSAL DUCT CYST
(THYROGLOSSAL TRACT CYST)
The thyroid gland begins its development at the end of
the third week of embryonic life as a proliferation of
endodermal cells from the ventral ﬂoor of the pharynx,
between the tuberculum impar and copula of the
developing tongue—a point that later becomes the
foramen cecum. This thyroid anlage descends into
the neck as a bilobed diverticulum anterior to the
developing hyoid bone and reaches its deﬁnitive level
below the thyroid cartilage by the seventh embryonic
week. Along this path of descent, an epithelial tract or
duct is formed, maintaining an attachment to the base
of the tongue. This thyroglossal duct becomes inti-
mately associated with the developing hyoid bone. As
the hyoid matures and rotates to its adult position, the
thyroglossal duct passes in front and beneath the hyoid,
looping upward and behind it before curving down-
ward again into the lower neck. The caudal segment of
this duct often persists, forming the pyramidal lobe of
the thyroid gland.
The thyroglossal duct epithelium normally under-
goes atrophy and is obliterated. However, remnants of
this epithelium may persist and give rise to cysts along
this tract known as thyroglossal duct cysts. The
impetus for cystic degeneration is uncertain. Inﬂam-
mation is the most frequently suggested stimulus, espe-
cially from adjacent lymphoid tissue that may react to
draining infections of the head and neck. Retention of
secretions within the duct is another possible factor. In
addition, there are several reports of familial occur-
rence of such cysts.
CLINICAL FEATURES
Thyroglossal duct cysts classically develop in the
midline and may occur anywhere from the foramen
cecum area of the tongue to the suprasternal notch.
Suprahyoid cysts may be submental in location. In 60%
to 80% of cases, the cyst develops below the hyoid bone.
Intralingual cysts are rare. Cysts that develop in the
area of the thyroid cartilage often are deﬂected lateral
to the midline because of the sharp anterior margin of
the thyroid cartilage.
Thyroglossal duct cysts may develop at any age, but
they are most commonly diagnosed in the ﬁrst two
decades of life; about 50% of cases occur before the age
of 20. There is no sex predilection. The cyst usually
presents as a painless, ﬂuctuant, movable swelling
unless it is complicated by secondary infection (Fig.
1-68). Lesions that develop at the base of the tongue
may cause laryngeal obstruction. Most thyroglossal
duct cysts are smaller than 3 cm in diameter, but
occasional cysts may reach 10 cm in size. If the cyst
maintains an attachment to the hyoid bone or tongue,
it will move vertically during swallowing or protru-
sion of the tongue. Fistulous tracts to the skin or
mucosa develop in as many as one third of cases,
usually from rupture of an infected cyst or as a sequela
of surgery.
Fig. 1-67 Dermoid cyst. Squamous epithelial lining (top),
with hair follicle (F), sebaceous glands (S) in the cyst wall. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

36 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Thyroglossal duct cysts are usually lined by columnar
or stratiﬁed squamous epithelium, although occasion-
ally, cuboidal or even small intestine epithelium may
be documented (Fig. 1-69). Sometimes a mixture of
epithelial types is present. Thyroid tissue may occur in
the cyst wall, but this is not a constant ﬁnding.
TREATMENT AND PROGNOSIS
Thyroglossal duct cysts are best treated by a Sistrunk
procedure. In this operation the cyst is removed in
addition to the midline segment of the hyoid bone and
a generous portion of muscular tissue along the entire
thyroglossal tract. The recurrence rate associated with
this procedure is less than 10%. A much higher recur-
rence rate can be expected with less aggressive
surgery.
Carcinoma arising in a thyroglossal duct cyst is a
rare complication that occurs in approximately 1% of
cases. Most of these have been papillary thyroid adeno-
carcinomas. Fortunately, metastases from thyroglossal
carcinoma are rare, and the prognosis for people with
these tumors is good.
BRANCHIAL CLEFT CYST (CERVICAL
LYMPHOEPITHELIAL CYST)
The branchial cleft cyst, a developmental cyst of the
lateral neck, has a disputed pathogenesis. The classic
theory holds that the cyst develops from remnants of
the branchial clefts because it occurs in the area of the
embryonic gill arch apparatus. A second theory consid-
ers that it arises from cystic changes in parotid gland
epithelium that becomes entrapped in the upper cervi-
cal lymph nodes during embryonic life. However,
immunohistochemical analysis supports the classic
branchial cleft theory of pathogenesis for this lesion.
About 95% of these cysts are believed to arise from the
second branchial arch, with the remaining 5% originat-
ing from the ﬁrst, third, and fourth branchial arches.
CLINICAL FEATURES
The branchial cleft cyst most commonly occurs in the
upper lateral neck along the anterior border of the
sternocleidomastoid muscle (Figs. 1-70 and 1-71). It
most frequently affects young adults between the ages
of 20 and 40. Clinically, the cyst appears as a soft,
ﬂuctuant mass that can range from 1 to 10 cm in diam-
eter. Associated tenderness or pain sometimes may
occur with secondary infection. Occasionally, the lesion
becomes evident after an upper respiratory tract infec-
tion or trauma. Some lesions appear as sinuses or
ﬁstulae that may produce a mucoid discharge onto
the skin. Two thirds of branchial cleft cysts occur on
the left side of the neck, and one third are found on the
right side. In rare instances, bilateral cysts may
develop.
Although one theory suggests that these cysts are
derived from parotid epithelium that becomes
entrapped within lymph node tissue, lymphoepithelial
cysts are uncommon within the parotid gland itself. In
recent years, however, increased numbers of parotid
Fig. 1-68 Thyroglossal duct cyst. Swelling (arrow) of the
anterior midline of the neck. (Courtesy of Dr. Philip Sprinkle.)
Fig. 1-69 Thyroglossal duct cyst. Cyst (top) lined by
stratiﬁed squamous epithelium. Thyroid follicles can be seen
in the cyst wall (bottom). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 37
lymphoepithelial cysts have been reported in patients
with HIV infection. These are probably related to
intraparotid lymphadenopathy associated with HIV
infection.
HISTOPATHOLOGIC FEATURES
More than 90% of branchial cleft cysts are lined by
stratiﬁed squamous epithelium that may or may not be
keratinized (Fig. 1-72). Some cysts demonstrate respi-
ratory epithelium. The wall of the cyst typically con-
tains lymphoid tissue, often demonstrating germinal
center formation. However, occasional cysts have been
reported without lymphoid tissue.
TREATMENT AND PROGNOSIS
The branchial cleft cyst is treated by surgical removal.
The lesion almost never recurs.
Rare examples of malignant transformation in these
cysts have been reported. Although such an occurrence
is theoretically possible, most suspected cases actually
represent cystic metastases from previously undetected
carcinomas of the head and neck region, especially
from the base of tongue, lingual tonsil, or palatine
tonsil. When evaluating patients with cystic neck
masses, ﬁne-needle aspiration biopsy can be helpful to
rule out the possibility of malignancy before surgery.
ORAL LYMPHOEPITHELIAL CYST
The oral lymphoepithelial cyst is an uncommon
lesion of the mouth that develops within oral lymphoid
tissue. It is microscopically similar to the branchial
cleft cyst (cervical lymphoepithelial cyst) but much
smaller in size.
Lymphoid tissue is normally found in the oral cavity
and pharynx, principally consisting of Waldeyer’s
ring, which includes the palatine tonsils, lingual tonsils,
and pharyngeal adenoids. In addition, accessory oral
tonsils or lymphoid aggregates may occur in the ﬂoor
of the mouth, ventral surface of the tongue, and soft
palate.
Oral lymphoid tissue has a close relationship with
the overlying mucosal epithelium. This epithelium
demonstrates invaginations into the tonsillar tissue,
resulting in blind pouches or tonsillar crypts that may
ﬁll up with keratin debris. The tonsillar crypt may
Fig. 1-70 Cervical lymphoepithelial cyst. Fluctuant
swelling of the lateral neck.
Fig. 1-71 Cervical lymphoepithelial cyst. Imaging study of
the same cyst depicted in Figure 1-70, showing a well-
circumscribed lesion of the lateral neck (arrows).
Fig. 1-72 Cervical lymphoepithelial cyst. Medium-
powered view showing a cyst lined by stratiﬁed squamous
epithelium. Note the lymphoid tissue in the cyst wall. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

38 ORAL AND MAXILLOFACIAL PATHOLOGY
become obstructed or pinched off from the surface,
producing a keratin-ﬁlled cyst within the lymphoid
tissue just below the mucosal surface. It also is possible
that oral lymphoepithelial cysts may develop from sali-
vary or surface mucosal epithelium that becomes
enclaved in lymphoid tissue during embryogenesis. It
even has been suggested that these cysts may arise
from the excretory ducts of the sublingual gland or
minor salivary glands, and that the associated lymphoid
tissue represents a secondary immune response.
CLINICAL FEATURES
The oral lymphoepithelial cyst presents as a small sub-
mucosal mass that is usually less than 1 cm in diameter;
rarely will the lesion be greater than 1.5 cm (Figs. 1-73
and 1-74). The cyst may feel ﬁrm or soft to palpation,
and the overlying mucosa is smooth and nonulcerated.
The lesion is typically white or yellow and often con-
tains creamy or cheesy keratinous material in the
lumen. The cyst is usually asymptomatic, although
occasionally, patients may complain of swelling or
drainage. Pain is rare but may occur secondary to
trauma.
Oral lymphoepithelial cysts may develop in people
of almost any age, but they are most common in young
adults. The most frequent location is the ﬂoor of
the mouth, with at least half of all cases found there.
The ventral surface and posterior lateral border of the
tongue are the next most common sites. These cysts
also may develop in the area of the palatine tonsil or
soft palate. All of these locations represent sites of
normal or accessory oral lymphoid tissue.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the oral lymphoepithelial
cyst demonstrates a cystic cavity that is lined by strati-
ﬁed squamous epithelium without rete ridges (Fig.
1-75). This epithelium is typically parakeratinized,
with desquamated epithelial cells seen ﬁlling the cyst
lumen. In rare instances the epithelial lining also may
contain mucous cells. Occasional cysts may communi-
cate with the overlying mucosal surface.
The most striking feature is the presence of lym-
phoid tissue in the cyst wall. In most instances, this
lymphoid tissue encircles the cyst, but sometimes it
involves only a portion of the cyst wall. Germinal
centers are usually, but not always, present.
TREATMENT AND PROGNOSIS
The oral lymphoepithelial cyst is usually treated with
surgical excision and should not recur. Because the
lesion is typically asymptomatic and innocuous, biopsy
may not always be necessary if the lesion is distinctive
enough to make the diagnosis on a clinical basis.
Other Rare Developmental
Anomalies
HEMIHYPERPLASIA
(HEMIHYPERTROPHY)
Hemihyperplasia is a rare developmental anomaly
characterized by asymmetric overgrowth of one or
more body parts. Although the condition is known
more commonly as hemihypertrophy, it actually rep-
resents a hyperplasia of the tissues rather than a hyper-
trophy. Hemihyperplasia can be an isolated ﬁnding,
but it also may be associated with a variety of malfor-
mation syndromes (Box 1-3).
Fig. 1-73 Oral lymphoepithelial cyst. Small yellow-white
nodule of the tonsillar fossa.
Fig. 1-74 Oral lymphoepithelial cyst. Small white nodule
of the posterior lateral border of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 39
ﬁned to one side of the face, the term hemifacial
hyperplasia (or hemifacial hypertrophy) may apply.
The condition can occasionally be crossed, involving
different areas on both sides of the body. Hemihyper-
plasia shows a 2:1 female-to-male predilection, and it
occurs more often on the right side of the body.
Asymmetry often is noted at birth, although in some
cases the condition may not become evident until later
in childhood (Fig. 1-76). The enlargement becomes
more accentuated with age, especially at puberty. This
disproportionate growth continues until the patient’s
overall growth ceases, resulting in permanent
asymmetry.
The changes may involve all the tissues on the
affected side, including the underlying bone. Often the
skin is thickened and may demonstrate increased pig-
mentation, hypertrichosis, telangiectasias, or nevus
ﬂammeus. About 20% of those affected are mentally
retarded. One of the most signiﬁcant features is an
increased prevalence of abdominal tumors, especially
Wilms’ tumor, adrenal cortical carcinoma, and hepa-
toblastoma. These tumors have been reported in 5.9%
of patients with isolated hemihyperplasia, and they do
not necessarily occur on the same side as the somatic
enlargement.
Unilateral macroglossia, featuring prominent
tongue papillae, is common. Enlargement of other oral
soft tissues and bone can occur. The mandibular canal
may be increased in size on radiographs. The crowns
of the teeth on the affected side, especially the perma-
nent cuspids, premolars, and ﬁrst molars, can be larger.
Premature development of these teeth, along with pre-
cocious eruption, may be obvious. The roots also may
be larger, but some reports have described root resorp-
tion. Malocclusion with open bite is not unusual.
A B
Fig. 1-75 Oral lymphoepithelial cyst. A, Low-power view showing a keratin-ﬁlled cyst
below the mucosal surface. Lymphoid tissue is present in the cyst wall. B, High-power view
showing lymphoid tissue adjacent to the cystic lining.
Box 1-3
Malformation Syndromes Associated
with Hemihyperplasia
● Beckwith-Wiedemann syndrome
● Neuroﬁbromatosis
● Klippel-Trénaunay-Weber syndrome
● Proteus syndrome
● McCune-Albright syndrome
●Epidermal nevus syndrome
● Triploid/diploid mixoploidy
● Langer-Giedion syndrome
●Multiple exostoses syndrome
● Maffucci syndrome
● Ollier syndrome
●Segmental odontomaxillary dysplasia
Almost all cases of isolated hemihyperplasia are spo-
radic. A number of possible etiologic factors have been
suggested, but the cause remains obscure. Various
theories include vascular or lymphatic abnormalities,
central nervous system disturbances, endocrine
dysfunctions, and aberrant twinning mechanisms.
Occasionally, chromosomal anomalies have been
documented.
CLINICAL AND RADIOGRAPHIC
FEATURES
In a person with hemihyperplasia, one entire side of
the body (complex hemihyperplasia) may be affected
or the enlargement may be limited to a single limb
(simple hemihyperplasia). If the enlargement is con- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

40 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Microscopic examination shows an increase in thick-
ness of the epithelium, with hyperplasia of the underly-
ing connective tissues.
TREATMENT AND PROGNOSIS
A complete workup should be undertaken to rule out
other possible causes of unilateral growth, such as
Beckwith-Wiedemann syndrome, Proteus syndrome,
and neuroﬁbromatosis type I (see page 529), which
can exhibit hemihyperplasia. During childhood, peri-
odic ultrasound examination should be performed to
rule out development of abdominal tumors. After the
patient’s growth has ceased, cosmetic surgery can be
performed, including soft tissue debulking, face lifts,
and orthognathic surgery. Orthodontic therapy is also
frequently needed.
PROGRESSIVE HEMIFACIAL ATROPHY
(PROGRESSIVE FACIAL HEMIATROPHY;
ROMBERG SYNDROME; PARRY-
ROMBERG SYNDROME)
Progressive hemifacial atrophy is an uncommon
and poorly understood degenerative condition charac-
terized by atrophic changes affecting one side of the
face. The cause of these changes remains obscure.
Speculation has considered trophic malfunction of
the cervical sympathetic nervous system. A history of
trauma has been documented in some cases, although
a number of recent reports have considered Borrelia
spp. infection (Lyme disease) in the cause. Usually, the
condition is sporadic, but a few familial cases have
been reported, suggesting a possible hereditary inﬂu-
ence. Progressive hemifacial atrophy exhibits many
features similar to a localized form of scleroderma
(see page 798), indicating a close relationship between
these two disorders.
CLINICAL AND RADIOGRAPHIC
FEATURES
The onset of the syndrome is usually during the ﬁrst
two decades of life. The condition begins as atrophy of
the skin and subcutaneous structures in a localized
area of the face (Fig. 1-77). This atrophy progresses at
a variable rate and affects the dermatome of one or
more branches of the trigeminal nerve. Hypoplasia of
the underlying bone also may occur. Osseous hypopla-
sia is more common when the condition begins during
the ﬁrst decade. Occasionally, bilateral facial atrophy
may occur, or the condition may affect one side of
the entire body. Females are affected more often than
males.
A
B
C
Fig. 1-76 Hemihyperplasia. A, Enlargement of the right side of the face. B, Same patient
with associated enlargement of the right half of the tongue. C, Panoramic radiograph of the
same patient showing enlargement of the mandible and teeth on the right side. (Courtesy of
Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 41
The overlying skin often exhibits dark pigmentation.
Some patients have a sharp line of demarcation, resem-
bling a large linear scar, between normal and abnor-
mal skin near the midline of the forehead, known
as linear scleroderma “en coup de sabre” (i.e., “strike of
the sword”). Ocular involvement is common, and the
most frequent manifestation is enophthalmos because
of loss of periorbital fat. Local alopecia may occur.
Occasionally, trigeminal neuralgia, facial paresthe-
sia, migraine, or epilepsy may develop. MRI studies
may reveal a variety of central nervous system
abnormalities.
The mouth and nose are deviated toward the affected
side. Atrophy of the upper lip may expose the maxillary
teeth. Unilateral atrophy of the tongue also can occur.
Unilateral posterior open bite often develops as a result
of mandibular hypoplasia and delayed eruption of the
teeth. The teeth on the affected side may exhibit deﬁ-
cient root development or root resorption.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the affected skin reveals
atrophy of the epidermis and a variable perivascular
inﬁltrate of lymphocytes and monocytes. In cases
showing clinical features of linear scleroderma, dermal
ﬁbrosis can be seen. Degenerative changes in the vas-
cular endothelium can be identiﬁed with electron
microscopy.
TREATMENT AND PROGNOSIS
The atrophy typically progresses slowly for several
years, and then becomes stable. Plastic surgery may be
tried to correct the cosmetic deformity, and orthodon-
tic therapy may be helpful to treat any associated
malocclusion.
SEGMENTAL ODONTOMAXILLARY
DYSPLASIA (HEMIMAXILLOFACIAL
DYSPLASIA)
Segmental odontomaxillary dysplasia is a recently
recognized developmental disorder that affects the jaw
and (sometimes) the overlying facial tissues. The cause
is unknown. Clinically, it is frequently mistaken for
craniofacial ﬁbrous dysplasia or hemifacial hyperpla-
sia, but it represents a distinct and separate entity.
CLINICAL AND RADIOGRAPHIC
FEATURES
Segmental odontomaxillary dysplasia is usually discov-
ered during childhood and is characterized by pain-
less, unilateral enlargement of the maxillary bone,
along with ﬁbrous hyperplasia of the overlying gingival
soft tissues (Fig. 1-78). One or both developing maxil-
lary premolars frequently are missing, and the primary
teeth in the affected area may be hypoplastic or show
enamel defects. Radiographic examination reveals
thickened trabeculae that often are vertically oriented,
which results in a relatively radiopaque, granular
appearance. The maxillary sinus may be smaller on the
affected side. Several cases have been associated with
hypertrichosis or rough erythema of the overlying
facial skin. One patient was described with a Becker’s
nevus (hypertrichosis and hyperpigmentation) of the
ipsilateral face and neck.
HISTOPATHOLOGIC FEATURES
The gingival soft tissues may show nonspeciﬁc ﬁbrosis.
The affected maxillary bone consists of irregular tra-
beculae with a woven appearance. This bone shows
numerous resting and reversal lines, but it lacks signiﬁ-
cant osteoblastic and osteoclastic activity. Deciduous
teeth in the involved area may exhibit irregular den-
tinal tubules, a focally deﬁcient odontoblastic layer,
and external resorption.
TREATMENT AND PROGNOSIS
Because segmental odontomaxillary dysplasia has been
recognized only recently as a distinct entity, not much
is known about its natural evolution. Once diagnosed,
Fig. 1-77 Progressive hemifacial atrophy. Young girl with
right-sided facial atrophy. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

42 ORAL AND MAXILLOFACIAL PATHOLOGY
the condition seems to remain stable and may not
require surgical intervention. However, orthodontic
therapy and orthognathic surgery may be considered
in some cases.
CROUZON SYNDROME
(CRANIOFACIAL DYSOSTOSIS)
Crouzon syndrome is one of a rare group of syn-
dromes characterized by craniosynostosis, or prema-
ture closing of the cranial sutures. It is believed to be
caused by one of a variety of mutations of the ﬁbroblast
growth factor receptor 2 (FGFR2) gene on chromo-
some 10q26. The condition occurs in about 1 of every
65,000 births and is inherited as an autosomal domi-
nant trait. A signiﬁcant number of cases, however, rep-
resent new mutations, often apparently related to
increased paternal age.
CLINICAL AND RADIOGRAPHIC
FEATURES
Crouzon syndrome exhibits a wide variability in expres-
sion. The premature sutural closing leads to cranial
malformations, such as brachycephaly (short head),
scaphocephaly (boat-shaped head), or trigonoceph-
aly (triangle-shaped head). The most severely affected
patients can demonstrate a “cloverleaf” skull (kleeblatt-
A B
C
Fig. 1-78 Segmental odontomaxillary dysplasia. A, Unilateral enlargement of the maxilla
and overlying gingival soft tissues. B, Periapical radiograph showing coarse trabecular pattern
with absence of the ﬁrst premolar. C, Panoramic radiograph showing irregular bone pattern of
the left maxilla expanding into the maxillary sinus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 43
schädel deformity). The orbits are shallow, resulting
in characteristic ocular proptosis (Fig. 1-79). Visual
impairment or total blindness and a hearing deﬁcit
may occur. Some patients report headaches, attribut-
able to increased intracranial pressure. Marked mental
deﬁciency is rarely seen. Skull radiographs typically
show increased digital markings (i.e., “beaten-metal”
pattern).
The maxilla is underdeveloped, resulting in midface
hypoplasia. Often the maxillary teeth are crowded, and
occlusal disharmony usually occurs. Cleft lip and cleft
palate are rare, but lateral palatal swellings may
produce a midline maxillary pseudocleft.
TREATMENT AND PROGNOSIS
The clinical defects of Crouzon syndrome can be
treated surgically, but multiple procedures may be nec-
essary. Early craniectomy often is needed to alleviate
the raised intracranial pressure. Frontoorbital advance-
ment can be performed to correct the ocular defects,
with midfacial advancement used to correct the maxil-
lary hypoplasia.
APERT SYNDROME
(ACROCEPHALOSYNDACTYLY)
Like Crouzon syndrome, Apert syndrome is a rare
condition that is characterized by craniosynostosis. It
occurs in about 1 of every 65,000 births and is caused
by one of two point mutations in the ﬁbroblast growth
factor receptor 2 (FGFR2) gene, which is located on
chromosome 10q26. Although it is inherited as an
autosomal dominant trait, most cases represent spo-
radic new mutations, which are thought to be exclu-
sively of paternal origin and often associated with
increased paternal age.
CLINICAL AND RADIOGRAPHIC
FEATURES
Craniosynostosis typically produces acrobrachyceph-
aly (tower skull); severe cases may demonstrate the
kleeblattschädel deformity (cloverleaf skull). The occiput
is ﬂattened, and a tall appearance to the forehead is
noted. Ocular proptosis is a characteristic ﬁnding,
along with hypertelorism and downward- slanting
lateral palpebral ﬁssures (Fig. 1-80). Visual loss can
result from the following:
●Chronic exposure of the unprotected eyes
●Increased intracranial pressure
●Compression of the optic nerves
Skull ﬁlms may demonstrate digital impressions
similar to those of Crouzon syndrome (Fig. 1-81).
The middle third of the face is signiﬁcantly retruded
and hypoplastic, resulting in a relative mandibular
prognathism. The reduced size of the nasopharynx and
narrowing of the posterior choanae can lead to respira-
tory distress in the young child. To compensate for this,
most infants become mouth breathers, contributing
to an “open-mouth” appearance. Sleep apnea may
A B
Fig. 1-79 Crouzon syndrome. Ocular proptosis and midface hypoplasia. (Courtesy of Dr. Robert
Gorlin.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

44 ORAL AND MAXILLOFACIAL PATHOLOGY
the teeth. Shovel-shaped incisors have been reported
in one third of patients.
TREATMENT AND PROGNOSIS
The cosmetic and functional defects of Apert syndrome
can be treated by an interdisciplinary approach using
multiple surgical procedures. Craniectomy often is
performed during the ﬁrst year of life to treat the cra-
niosynostosis. Frontofacial advancement and midface
advancement can be done later to correct the proptosis
and midface hypoplasia. Coordinated orthodontic
Fig. 1-80 Apert syndrome. Midface hypoplasia and ocular
proptosis.
Fig. 1-81 Apert syndrome. Radiograph showing “tower
skull,” midface hypoplasia, and digital markings. Similar
digital impressions are apparent in people with Crouzon
syndrome. (Courtesy of Dr. Robert Gorlin.)
develop. Middle-ear infections are common, as is con-
ductive hearing loss.
Characteristic limb defects help distinguish Apert
syndrome from other craniosynostosis syndromes.
Syndactyly of the second, third, and fourth digits of the
hands and feet always is observed (Fig. 1-82). Associ-
ated synonychia also may occur. The ﬁrst and ﬁfth
digits may be separate or joined to the middle digits.
Synostosis of adjacent phalanges may be observed on
radiographs. The average height of affected patients is
below that of the general population.
Mental retardation is common in a large proportion
of patients with Apert syndrome. An unusual acnelike
eruption develops in most of the patients and involves
the forearms.
Speciﬁc oral manifestations include a trapezoid-
shaped appearance to the lips when they are relaxed,
resulting from the midface hypoplasia and mouth
breathing. Three fourths of all patients exhibit either a
cleft of the soft palate or a biﬁd uvula. The maxillary
hypoplasia leads to a V-shaped arch and crowding of
the teeth. Class III malocclusion typically occurs and
may be associated with anterior open bite plus anterior
and posterior crossbite. Swellings are observed along
the lateral hard palate from the accumulation of
glycosaminoglycans, especially hyaluronic acid (Fig.
1-83). These swellings often enlarge with age to
produce a pseudocleft of the hard palate. Gingival
thickening may be associated with delayed eruption of
Fig. 1-82 Apert syndrome. Syndactyly of the hand. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 45
therapy often is necessary to bring unerupted teeth
into place and to improve occlusion. Surgery also can
be used to separate the fused ﬁngers.
MANDIBULOFACIAL DYSOSTOSIS
(TREACHER COLLINS SYNDROME;
FRANCESCHETTI-ZWAHLEN-KLEIN
SYNDROME)
Mandibulofacial dysostosis is a rare syndrome that
is characterized primarily by defects of structures
derived from the ﬁrst and second branchial arches. It
is inherited as an autosomal dominant trait and occurs
in around 1 of every 25,000 to 50,000 live births. The
condition has variable expressivity, and the severity of
the clinical features often tends to be greater in subse-
quent generations of the same family. Approximately
60% of cases represent new mutations, and these often
are associated with increased paternal age. The gene
for mandibulofacial dysostosis (treacle or TCOF1) has
been mapped to chromosome 5q32-q33.1.
CLINICAL AND RADIOGRAPHIC
FEATURES
Individuals with mandibulofacial dysostosis exhibit a
characteristic facies (Fig. 1-84). The zygomas are hypo-
plastic, resulting in a narrow face with depressed
cheeks and downward-slanting palpebral ﬁssures. In
75% of patients, a coloboma, or notch, occurs on the
outer portion of the lower eyelid. Approximately half
of the patients have no eyelashes medial to the colo-
boma. Often the sideburns show a tongue-shaped
extension toward the cheek.
The ears may demonstrate a number of anomalies.
The pinnae often are deformed or misplaced, and extra
ear tags may be seen. Ossicle defects or absence of the
external auditory canal can cause conductive hearing
loss.
The mandible is underdeveloped, resulting in a
markedly retruded chin. Radiographs often demon-
strate hypoplasia of the condylar and coronoid
Fig. 1-83 Apert syndrome. Abnormal shape of the maxilla,
with swellings of the posterior lateral hard palate, resulting in
pseudocleft formation.
A B
Fig. 1-84 Mandibulofacial dysostosis. Patient exhibits a hypoplastic mandible, downward-
slanting palpebral ﬁssures, and ear deformities. (Courtesy of Dr. Tom Brock.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

46 ORAL AND MAXILLOFACIAL PATHOLOGY
processes, with prominent antegonial notching. The
mouth is downturned, and about 15% of patients have
lateral facial clefting (see page 2) that produces macro-
stomia. Cleft palate is seen in about one third of cases.
The parotid glands may be hypoplastic or may be totally
absent (see page 453).
A number of infants may experience respiratory and
feeding difﬁculties because of hypoplasia of the naso-
pharynx, oropharynx, and hypopharynx. Choanal
atresia is a common ﬁnding, and the larynx and trachea
are often narrow. Combined with the mandibular
hypoplasia and resultant improper tongue position,
these defects can lead to the infant’s death from respi-
ratory complications.
TREATMENT AND PROGNOSIS
Patients with mild forms of mandibulofacial dysostosis
may not require treatment. In more severe cases the
clinical appearance can be improved with cosmetic
surgery. Because of the extent of facial reconstruction
required, multiple surgical procedures are usually nec-
essary. Individual operations may be needed for the
eyes, zygomas, jaws, ears, and nose. Combined orth-
odontic therapy is needed along with the orthognathic
surgery.
BIBLIOGRAPHY
Orofacial Clefts
Avery JK, Chiego DJ Jr: Development of the face and palate.
In Essentials of oral histology and embryology: a clinical approach,
ed 3, pp 51-61, St Louis, 2006, Mosby.
Berkovitz BK, Holland GR, Moxham BJ: Development of the face
and development of the palate. In Oral anatomy, histology and
embryology, ed 3, pp 269-283, St Louis, 2002, Mosby.
Carinci F, Pezzetti F, Scapoli L et al: Recent developments in
orofacial cleft genetics, J Craniofac Surg 14:130-143, 2003.
Derijcke A, Eerens A, Carels C: The incidence of oral clefts: a
review, Br J Oral Maxillofac Surg 34:488-494, 1996.
Eppley BL, van Aalst JA, Robey A et al: The spectrum of orofacial
clefting, Plast Reconstr Surg 115:101e-114e, 2005.
Evans CA: Orthodontic treatment for patients with clefts, Clin
Plast Surg 31:271-290, 2004.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Orofacial clefting
syndromes: general aspects. In Syndromes of the head and neck,
ed 4, pp 850-876, New York, 2001, Oxford University Press.
Gosain AK, Conley SF, Marks S et al: Submucous cleft palate:
diagnostic methods and outcomes of surgical treatment, Plast
Reconstr Surg 97:1497-1509, 1996.
Harada K, Sato M, Omura K: Long-term maxillomandibular skel-
etal and dental changes in children with cleft lip and palate
after maxillary distraction, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 102:292-299, 2006.
Krapels IP, Vermeij-Keers C, Müller M et al: Nutrition and genes
in the development of orofacial clefting, Nutr Rev 64:280-
288, 2006.
Marazita ML, Mooney MP: Current concepts in the embryology
and genetics of cleft lip and cleft palate, Clin Plast Surg 31:125-
140, 2004.
Millard DR Jr, Latham RA: Improved primary surgical and dental
treatment of clefts, Plast Reconstr Surg 86:856-871, 1990.
Murray JC: Gene/environment causes of cleft lip and/or palate,
Clin Genet 61:248-256, 2002.
Rintala A, Leisti J, Liesmaa M et al: Oblique facial clefts, Scand J
Plast Reconstr Surg 14:291-297, 1980.
Shprintzen RJ: Pierre Robin, micrognathia, and airway obstruc-
tion: the dependency of treatment on accurate diagnosis, Int
Anesthesiol Clin 26:64-71, 1988.
St-Hilaire H, Buchbinder D: Maxillofacial pathology and man-
agement of Pierre Robin sequence, Otolaryngol Clin North Am
33:1241-1256, 2000.
Stoll C, Alembik Y, Dott B et al: Associated malformations in
cases with oral clefts, Cleft Palate Craniofac J 37:41-47, 2000.
Ten Cate AR, Nanci A: Embryology of the head, face, and oral
cavity. In Nanci A: Ten Cate’s oral histology: development, struc-
ture, and function, ed 6, pp 30-53, St Louis, 2003, Mosby.
Thornton JB, Nimer S, Howard PS: The incidence, classiﬁcation,
etiology, and embryology of oral clefts, Semin Orthod 2:162-
168, 1996.
van den Elzen AP, Semmekrot BA, Bongers EM et al: Diagnosis
and treatment of the Pierre Robin sequence: results of a ret-
rospective clinical study and review of the literature, Eur J
Pediatr 160:47-53, 2001.
Vanderas AP: Incidence of cleft lip, cleft palate, and cleft lip and
palate among races: a review, Cleft Palate J 24:216-225,
1987.
Weinberg SM, Neiswanger K, Martin RA et al: The Pittsburgh
oral-facial cleft study: expanding the cleft phenotype. Back-
ground and justiﬁcation, Cleft Palate Craniofac J 43:7-20,
2006.
Commissural Lip Pits
Baker BR: Pits of the lip commissures in caucasoid males, Oral
Surg Oral Med Oral Pathol 21:56-60, 1966.
Everett FG, Wescott WB: Commissural lip pits, Oral Surg Oral
Med Oral Pathol 14:202-209, 1961.
Gorsky M, Buchner A, Cohen C: Commissural lip pits in Israeli
Jews of different ethnic origin, Community Dent Oral Epidemiol
13:195-196, 1985.
Paramedian Lip Pits
Burdick AB, Bixler D, Puckett CL: Genetic analysis in families
with van der Woude syndrome, J Craniofac Genet Dev Biol
5:181-208, 1985.
Cervenka J, Gorlin RJ, Anderson VE: The syndrome of pits of the
lower lip and cleft lip and/or palate: genetic considerations,
Am J Hum Genet 19:416-432, 1967.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Popliteal pterygium
syndrome (facio-genito-popliteal syndrome). In Syndromes of
the head and neck, ed 4, pp 775-778, New York, 2001, Oxford
University Press.
Kondo S, Schutte BC, Richardson RJ et al: Mutations in IRF6
cause Van der Woude and popliteal pterygium syndromes,
Nat Genet 32:285-289, 2002.
Matsumoto N, Niikawa N: Kabuki make-up syndrome: a review,
Am J Med Genet C Semin Med Genet 117:57-65, 2003.
Onofre MA, Brosco HB, Brosco JU et al: Congenital ﬁstulae of
the lower lip in van der Woude syndrome: a histomorpho-
logical study, Cleft Palate Craniofac J 36:79-85, 1999.
Onofre MA, Brosco HB, Taga R: Relationship between lower-lip
ﬁstulae and cleft lip and/or palate in van der Woude syn-
drome, Cleft Palate Craniofac J 34:261-265, 1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 47
Rizos M, Spyropoulos MN: Van der Woude syndrome: a review.
Cardinal signs, epidemiology, associated features, differential
diagnosis, expressivity, genetic counseling and treatment, Eur
J Orthod 26:17-24, 2004.
Schutte BC, Basart AM, Watanabe Y et al: Microdeletions at
chromosome bands 1q32-q41 as a cause of van der Woude
syndrome, Am J Med Genet 84:145-150, 1999.
Shotelersuk V, Punyashthiti R, Srivuthana S et al: Kabuki syn-
drome: report of six Thai children and further phenotypic
and genetic delineation, Am J Med Genet 110:384-390,
2002.
Double Lip
Barnett ML, Bosshardt LL, Morgan AF: Double lip and double lip
with blepharochalasis (Ascher’s syndrome), Oral Surg Oral
Med Oral Pathol 34:727-733, 1972.
Eski M, Nisanci M, Atkas A et al: Congenital double lip: review
of 5 cases, Br J Oral Maxillofac Surg 45:68-70, 2007.
Gomez-Duaso AJ, Seoane J, Vazquez-Garcia J et al: Ascher syn-
drome: report of two cases, J Oral Maxillofac Surg 55:88-90,
1997.
Kenny KF, Hreha JP, Dent CD: Bilateral redundant mucosal
tissue of the upper lip, J Am Dent Assoc 120:193-194,
1990.
Fordyce Granules
Daley TD: Pathology of intraoral sebaceous glands, J Oral Pathol
Med 22:241-245, 1993.
Fordyce JA: A peculiar affection of the mucous membrane of the
lips and oral cavity, J Cutan Genito-Urin Dis 14:413-419,
1896.
Halperin V, Kolas S, Jefferis KR et al: The occurrence of Fordyce
spots, benign migratory glossitis, median rhomboid glossitis,
and ﬁssured tongue in 2,478 dental patients, Oral Surg Oral
Med Oral Pathol 6:1072-1077, 1953.
Miles AEW: Sebaceous glands in the lip and cheek mucosa of
man, Br Dent J 105:235-248, 1958.
Sewerin I: The sebaceous glands in the vermilion border of the
lips and in the oral mucosa of man, Acta Odontol Scand
33(suppl 68):13-226, 1975.
Sewerin I, Prætorius F: Keratin-ﬁlled pseudocysts of ducts of
sebaceous glands in the vermilion border of the lip, J Oral
Pathol 3:279-283, 1974.
Leukoedema
Archard HO, Carlson KP, Stanley HR: Leukoedema of the human
oral mucosa, Oral Surg Oral Med Oral Pathol 25:717-728,
1968.
Axéll T, Henricsson V: Leukoedema—an epidemiologic study
with special reference to the inﬂuence of tobacco habits, Com-
munity Dent Oral Epidemiol 9:142-146, 1981.
Durocher RT, Thalman R, Fiore-Donno G: Leukoedema of the
oral mucosa, J Am Dent Assoc 85:1105-1109, 1972.
Martin JL: Leukoedema: an epidemiological study in white and
African Americans, J Tenn Dent Assoc 77:18-21, 1997.
Martin JL, Crump EP: Leukoedema of the buccal mucosa in
Negro children and youth, Oral Surg Oral Med Oral Pathol
34:49-58, 1972.
Sandstead HR, Lowe JW: Leukoedema and keratosis in relation
to leukoplakia of the buccal mucosa in man, J Natl Cancer Inst
14:423-437, 1953.
van Wyk CW, Ambrosio SC: Leukoedema: ultrastructural and
histochemical observations, J Oral Pathol 12:319-329, 1983.
Microglossia
Dunham ME, Austin TL: Congenital aglossia and situs inversus,
Int J Pediatr Otorhinolaryngol 19:163-168, 1990.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Oromandibular-limb
hypogenesis syndromes. In Syndromes of the head and neck, ed
4, pp 822-826, New York, 2001, Oxford University Press.
Hall BD: Aglossla-adactylia, Birth Defects Orig Artic Ser 7:233-
236, 1971.
Shah RM: Palatomandibular and maxillo-mandibular fusion,
partial aglossia and cleft palate in a human embryo: report of
a case, Teratology 15:261-272, 1977.
Yasuda Y, Kitai N, Fujii Y et al: Report of a patient with hypoglos-
sia-hypodactylia syndrome and a review of the literature, Cleft
Palate Craniofac J 40:196-202, 2003.
Macroglossia
Cohen MM Jr: Beckwith-Wiedemann syndrome: historical, clini-
copathological, and etiopathogenetic perspectives, Pediatr
Dev Pathol 8:287-304, 2005.
Engström W, Lindham S, Schoﬁeld P: Wiedemann-Beckwith
syndrome, Eur J Pediatr 147:450-457, 1988.
Maturo SC, Mair EA: Submucosal minimally invasive lingual
excision: an effective, novel surgery for pediatric tongue base
reduction, Ann Otol Rhinol Laryngol 115:624-630, 2006.
Morgan WE, Friedman EM, Duncan NO et al: Surgical manage-
ment of macroglossia in children, Arch Otolaryngol Head Neck
Surg 122:326-329, 1996.
Myer CM III, Hotaling AJ, Reilly JS: The diagnosis and treatment
of macroglossia in children, Ear Nose Throat J 65:444-448,
1986.
Rimell FL, Shapiro AM, Shoemaker DL et al: Head and neck
manifestations of Beckwith-Wiedemann syndrome, Otolaryn-
gol Head Neck Surg 113:262-265, 1995.
Siddiqui A, Pensler JM: The efﬁcacy of tongue resection in treat-
ment of symptomatic macroglossia in the child, Ann Plast Surg
25:14-17, 1990.
Vogel JE, Mulliken JB, Kaban LB: Macroglossia: a review of the
condition and a new classiﬁcation, Plast Reconstr Surg 78:715-
723, 1986.
Wang J, Goodger NM, Pogrel MA: The role of tongue reduction,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:269-273,
2003.
Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann
syndrome, Am J Med Genet C Semin Med Genet 137:12-23,
2005.
Wolford LM, Cottrell DA: Diagnosis of macroglossia and indica-
tions for reduction glossectomy, Am J Orthod Dentofac Orthop
110:170-177, 1996.
Ankyloglossia
Dollberg S, Botzer E, Grunis E et al: Immediate nipple pain relief
after frenotomy in breast-fed infants with ankyloglossia: a
randomized, prospective study, J Pediatr Surg 41:1598-1600,
2006.
Ewart NP: A lingual mucogingival problem associated with anky-
loglossia: a case report, N Z Dent J 86:16-17, 1990.
Flinck A, Paludan A, Matsson L et al: Oral ﬁndings in a group
of newborn Swedish children, Int J Paediatr Dent 4:67-73,
1994.
Hall DMB, Renfrew MJ: Tongue tie, Arch Dis Child 90:1211-
1215, 2005.
Lalakea ML, Messner AH: Ankyloglossia: does it matter? Pediatr
Clin N Am 50:381-397, 2003.
Lalakea ML, Messner AH: Ankyloglossia: the adolescent and
adult perspective, Otolaryngol Head Neck Surg 128:746-752,
2003.
Mukai S, Mukai C, Asaoka K: Ankyloglossia with deviation of the
epiglottis and larynx, Ann Otol Rhinol Laryngol 100:3-20,
1991. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

48 ORAL AND MAXILLOFACIAL PATHOLOGY
Mukai S, Mukai C, Asaoka K: Congenital ankyloglossia with
deviation of the epiglottis and larynx: symptoms and respira-
tory function in adults, Ann Otol Rhinol Laryngol 102:620-624,
1993.
Lingual Thyroid
Batsakis JG, El-Naggar AK, Luna MA: Thyroid gland ectopias,
Ann Otol Rhinol Laryngol 105:996-1000, 1996.
Baughman RA: Lingual thyroid and lingual thyroglossal tract
remnants: a clinical and histopathologic study with review of
the literature, Oral Surg Oral Med Oral Pathol 34:781-799,
1972.
Chanin LR, Greenberg LM: Pediatric upper airway obstruction
due to ectopic thyroid: classiﬁcation and case reports, Laryn-
goscope 98:422-427, 1988.
Diaz-Arias AA, Bickel JT, Loy TS et al: Follicular carcinoma with
clear cell change arising in lingual thyroid, Oral Surg Oral Med
Oral Pathol 74:206-211, 1992.
Kalan A, Tariq M: Lingual thyroid gland: clinical evaluation and
comprehensive management, Ear Nose Throat J 78:340-341,
345-349, 1999.
Massine RE, Durning SJ, Koroscil TM: Lingual thyroid carci-
noma: a case report and review of the literature, Thyroid
11:1191-1196, 2001.
Montgomery ML: Lingual thyroid: a comprehensive review, West
J Surg Obstet Gynecol 43:661-669, 1935; 44:54-62, 122-128,
189-195, 237-247, 303-309, 373-379, 442-446, 1936.
Prasad KC, Bhat V: Surgical management of lingual thyroid: a
report of four cases, J Oral Maxillofac Surg 58:223-227,
2000.
Williams JD, Sclafani AP, Slupchinskij O et al: Evaluation and
management of the lingual thyroid gland, Ann Otol Rhinol
Laryngol 105:312-316, 1996.
Fissured Tongue
Bouquot JE, Gundlach KKH: Odd tongues: the prevalence of
common tongue lesions in 23,616 white Americans over 35
years of age, Quintessence Int 17:719-730, 1986.
Eidelman E, Chosack A, Cohen T: Scrotal tongue and geographic
tongue: polygenic and associated traits, Oral Surg Oral Med
Oral Pathol 42:591-596, 1976.
Halperin V, Kolas S, Jefferis KR: The occurrence of Fordyce
spots, benign migratory glossitis, median rhomboid glossitis,
and ﬁssured tongue in 2,478 dental patients, Oral Surg Oral
Med Oral Pathol 6:1072-1077, 1953.
Jainkittivong A, Aneksuk V, Langlais RP: Oral mucosal
conditions in elderly dental patients, Oral Dis 8:218-223,
2002.
Kullaa-Mikkonen A: Familial study of ﬁssured tongue, Scand J
Dent Res 96:366-375, 1988.
Kullaa-Mikkonen A, Sorvari T: Lingua ﬁssurata: a clinical, stereo-
microscopic and histopathological study, Int J Oral Maxillofac
Surg 15:525-533, 1986.
Yarom N, Cantony U, Gorsky M: Prevalence of ﬁssured tongue,
geographic tongue and median rhomboid glossitis among
Israeli adults of different ethnic origins, Dermatology 209:88-
94, 2004.
Hairy Tongue
Bouquot JE, Gundlach KKH: Odd tongues: the prevalence of
common tongue lesions in 23,616 white Americans over 35
years of age, Quintessence Int 17:719-730, 1986.
Celis A, Little JW: Clinical study of hairy tongue in hospital
patients, J Oral Med 21:139-145, 1966.
Danser MM, Mantilla Gómez S, Van der Weijden GA: Tongue
coating and tongue brushing: a literature review, Int J Dent
Hygiene 1:151-158, 2003.
Farman AG: Hairy tongue (lingua villosa), J Oral Med 32:85-91,
1977.
Gómez SM, Danser MM, Sipos PM et al: Tongue coating and
salivary bacterial counts in healthy/gingivitis subjects
and periodontitis patients, J Clin Periodontol 28:970-978,
2001.
Manabe M, Lim HW, Winzer M et al: Architectural organization
of ﬁliform papillae in normal and black hairy tongue epithe-
lium, Arch Dermatol 135:177-181, 1999.
Sarti GM, Haddy RI, Schaffer D et al: Black hairy tongue, Am
Fam Physician 41:1751-1755, 1990.
Standish SM, Moorman WC: Treatment of hairy tongue with
podophyllin resin, J Am Dent Assoc 68:535-540, 1964.
Varicosities
Ettinger RL, Manderson RD: A clinical study of sublingual
varices, Oral Surg Oral Med Oral Pathol 38:540-545, 1974.
Jainkittivong A, Aneksuk V, Langlais RP: Oral mucosal
conditions in elderly dental patients, Oral Dis 8:218-223,
2002.
Kleinman HZ: Lingual varicosities, Oral Surg Oral Med Oral Pathol
23:546-548, 1967.
Southam JC, Ettinger RL: A histologic study of sublingual varices,
Oral Surg Oral Med Oral Pathol 38:879-886, 1974.
Weathers DR, Fine RM: Thrombosed varix of oral cavity, Arch
Dermatol 104:427-430, 1971.
Caliber-Persistent Artery
Jaspers MT: Oral caliber-persistent artery: unusual presentations
of unusual lesions, Oral Surg Oral Med Oral Pathol 74:631-633,
1992.
Lovas JG, Goodday RH: Clinical diagnosis of caliber-persistent
labial artery of the lower lip, Oral Surg Oral Med Oral Pathol
76:480-483, 1993.
Lovas JGL, Rodu B, Hammond HL et al: Caliber-persistent labial
artery: a common vascular anomaly, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 86:308-312, 1998.
Miko T, Adler P, Endes P: Simulated cancer of the lower lip
attributed to a “caliber persistent” artery, J Oral Pathol 9:137-
144, 1980.
Lateral Soft Palate Fistulas
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Fistulas of lateral soft
palate and associated anomalies. In Syndromes of the head and
neck, ed 4, p 1160, New York, 2001, Oxford University
Press.
Miller AS, Brookreson KR, Brody BA: Lateral soft-palate ﬁstula:
report of a case, Arch Otolaryngol 91:200, 1970.
Coronoid Hyperplasia
Gerbino G, Bianchi SD, Bernardi M et al: Hyperplasia of the
mandibular coronoid process: long-term follow-up after coro-
noidotomy, J Craniomaxillofac Surg 25:169-173, 1997.
Giacomuzzi D: Bilateral enlargement of the mandibular coro-
noid processes: review of the literature and report of case, J
Oral Maxillofac Surg 44:728-731, 1986.
Hall RE, Orbach S, Landesberg R: Bilateral hyperplasia of the
mandibular coronoid processes: a report of two cases, Oral
Surg Oral Med Oral Pathol 67:141-145, 1989.
Izumi M, Isobe M, Toyama M et al: Computed tomographic fea-
tures of bilateral coronoid process hyperplasia with special
emphasis on patients without interference between the
process and the zygomatic bone, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 99:93-100, 2005.
McLoughlin PM, Hopper C, Bowley NB: Hyperplasia of the man-
dibular coronoid process: an analysis of 31 cases and a review
of the literature, J Oral Maxillofac Surg 53:250-255, 1995. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 49
Tucker MR, Guilford WB, Howard CW: Coronoid process
hyperplasia causing restricted opening and facial asymmetry,
Oral Surg Oral Med Oral Pathol 58:130-132, 1984.
Condylar Hyperplasia
Bruce RA, Hayward JR: Condylar hyperplasia and mandibular
asymmetry: a review, J Oral Surg 26:281-290, 1968.
Eslami B, Behnia H, Javadi H et al: Histopathologic comparison
of normal and hyperplastic condyles, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 96:711-717, 2003.
Gray RJM, Horner K, Testa HJ et al: Condylar hyperplasia: cor-
relation of histological and scintigraphic features, Dentomaxil-
lofac Radiol 23:103-107, 1994.
Iannetti G, Cascone P, Belli E et al: Condylar hyperplasia: cepha-
lometric study, treatment planning, and surgical correction
(our experience), Oral Surg Oral Med Oral Pathol 68:673-681,
1989.
Motamedi MHK: Treatment of condylar hyperplasia of the man-
dible using unilateral ramus osteotomies, J Oral Maxillofac
Surg 54:1161-1169, 1996.
Obwegeser HL, Makek MS: Hemimandibular hyperplasia-hemi-
mandibular elongation, J Maxillofac Surg 14:183-208, 1986.
Slootweg PJ, Müller H: Condylar hyperplasia: a clinico-patho-
logical analysis of 22 cases, J Maxillofac Surg 14:209-214,
1986.
Condylar Hypoplasia
Arun T, Kayhan F, Kiziltan M: Treatment of condylar hypoplasia
with distraction osteogenesis: a case report, Angle Orthod
72:371-376, 2002.
Berger SS, Stewart RE: Mandibular hypoplasia secondary to peri-
natal trauma: report of case, J Oral Surg 35:578-582, 1977.
Jerrell RG, Fuselier B, Mahan P: Acquired condylar hypoplasia:
report of case, ASDC J Dent Child 58:147-153, 1991.
Sapp JP, Cherrick HM: Pathological aspects of developmental,
inﬂammatory, and neoplastic disease. In Sarnat BG, Laskin
DM: The temporomandibular joint: a biological basis for clinical
practice, ed 4, pp 150-151, Philadelphia, 1991, WB
Saunders.
Svensson B, Larsson Å, Adell R: The mandibular condyle in juve-
nile chronic arthritis patients with mandibular hypoplasia. A
clinical and histological study, Int J Oral Maxillofac Surg
30:306-312, 2001.
Biﬁd Condyle
Antoniades K, Hadjipetrou L, Antoniades V et al: Bilateral biﬁd
mandibular condyle, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 97:535-538, 2004.
Cowan DF, Ferguson MM: Biﬁd mandibular condyle, Dentomax-
illofac Radiol 26:70-73, 1997.
Gundlach KKH, Fuhrmann A, Beckmann-Van der Ven G: The
double-headed mandibular condyle, Oral Surg Oral Med Oral
Pathol 64:249-253, 1987.
Loh FC, Yeo JF: Biﬁd mandibular condyle, Oral Surg Oral Med
Oral Pathol 69:24-27, 1990.
Stefanou EP, Fanourakis IG, Vlastos K et al: Bilateral biﬁd man-
dibular condyles. Report of four cases, Dentomaxillofac Radiol
27:186-188, 1998.
Szentpétery A, Kocsis G, Marcsik A: The problem of the biﬁd
mandibular condyle, J Oral Maxillofac Surg 48:1254-1257,
1990.
Exostoses
Antoniades DZ, Belazi M, Papanayiotou P: Concurrence of torus
palatinus with palatal and buccal exostoses. Case report and
review of the literature, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 85:552-557, 1998.
Blakemore JR, Eller DJ, Tomaro AJ: Maxillary exostoses: surgical
management of an unusual case, Oral Surg Oral Med Oral
Pathol 40:200-204, 1975.
Bouquot JE, Gundlach KKH: Oral exophytic lesions in 23,616
white Americans over 35 years of age, Oral Surg Oral Med Oral
Pathol 62:284-291, 1986.
Frazier KB, Baker PS, Abdelsayed R et al: A case report of sub-
pontic osseous hyperplasia in the maxillary arch, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 89:73-76, 2000.
Hegtvedt AK, Terry BC, Burkes EJ et al: Skin graft vestibuloplasty
exostosis: a report of two cases, Oral Surg Oral Med Oral Pathol
69:149-152, 1990.
Jainkittivong A, Langlais RP: Buccal and palatal exostoses: preva-
lence and concurrence with tori, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 90:48-53, 2000.
Morton TH Jr, Natkin E: Hyperostosis and ﬁxed partial denture
pontics: report of 16 patients and review of literature, J Pros-
thet Dent 64:539-547, 1990.
Pack ARC, Gaudie WM, Jennings AM: Bony exostosis as a
sequela to free gingival grafting: two case reports, J Periodontol
62:269-271, 1991.
Sonnier KE, Horning GM, Cohen ME: Palatal tubercles, palatal
tori, and mandibular tori: prevalence and anatomical features
in a U.S. population, J Periodontol 70:329-336, 1999.
Wasson DJ, Rapley JW, Cronin RJ: Subpontic osseous hyperpla-
sia: a literature review, J Prosthet Dent 66:638-641, 1991.
Torus Palatinus and Torus Mandibularis
Al Quran FA, Al-Dwairi ZN: Torus palatinus and torus mandibu-
laris in edentulous patients, J Contemp Dent Pract 7:112-119,
2006.
Eggen S: Torus mandibularis: an estimation of the degree of
genetic determination, Acta Odontol Scand 47:409-415,
1989.
Eggen S, Natvig B: Relationship between torus mandibularis
and number of present teeth, Scand J Dent Res 94:233-240,
1986.
Eggen S, Natvig B: Variation in torus mandibularis prevalence in
Norway: a statistical analysis using logistic regression, Com-
munity Dent Oral Epidemiol 19:32-35, 1991.
Gorsky M, Bukai A, Shohat M: Genetic inﬂuence on the
prevalence of torus palatinus, Am J Med Genet 75:138-140,
1998.
Haugen LK: Palatine and mandibular tori: a morphologic study
in the current Norwegian population, Acta Odontol Scand
50:65-77, 1992.
Kerdpon D, Sirirungrojying S: A clinical study of oral tori in
southern Thailand: prevalence and the relation to parafunc-
tional activity, Eur J Oral Sci 107:9-13, 1999.
Kolas S, Halperin V, Jefferis K et al: The occurrence of torus
palatinus and torus mandibularis in 2,478 dental patients,
Oral Surg Oral Med Oral Pathol 6:1134-1141, 1953.
Reichart PA, Neuhaus F, Sookasem M: Prevalence of torus pala-
tinus and torus mandibularis in Germans and Thai, Commu-
nity Dent Oral Epidemiol 16:61-64, 1988.
Suzuki M, Sakai T: A familial study of torus palatinus and torus
mandibularis, Am J Phys Anthropol 18:263-272, 1960.
Eagle Syndrome
Bafaqeeh SA: Eagle syndrome: classic and carotid artery types,
J Otolaryngol 29:88-94, 2000.
Blatchford SJ, Coulthard SW: Eagle’s syndrome: an atypical
cause of dysphonia, Ear Nose Throat J 68:48-51, 1989.
Camarda AJ, Deschamps C, Forest D: I. Stylohyoid chain ossiﬁ-
cation: a discussion of etiology, Oral Surg Oral Med Oral Pathol
67:508-514, 1989. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

50 ORAL AND MAXILLOFACIAL PATHOLOGY
Camarda AJ, Deschamps C, Forest D: II. Stylohyoid chain ossiﬁ-
cation: a discussion of etiology, Oral Surg Oral Med Oral Pathol
67:515-520, 1989.
Correll RW, Jensen JL, Taylor JB et al: Mineralization of the sty-
lohyoid-stylomandibular ligament complex: a radiographic
incidence study, Oral Surg Oral Med Oral Pathol 48:286-291,
1979.
Eagle WW: Elongated styloid processes: report of two cases, Arch
Otolaryngol 25:584-587, 1937.
Montalbetti L, Ferrandi D, Pergami P et al: Elongated styloid
process and Eagle’s syndrome, Cephalalgia 15:80-93, 1995.
Rechtweg JS, Wax MK: Eagle’s syndrome: a review, Am J Otolar-
yngol 19:316-321, 1998.
Smith RG, Cherry JE: Traumatic Eagle’s syndrome: report of a
case and review of the literature, J Oral Maxillofac Surg 46:606-
609, 1988.
Stafne Defect
Apruzzese D, Longoni S: Stafne cyst in an anterior location, J Oral
Maxillofac Surg 57:333-338, 1999.
Ariji E, Fujiwara N, Tabata O et al: Stafne’s bone cavity: classiﬁca-
tion based on outline and content determined by computed
tomography, Oral Surg Oral Med Oral Pathol 76:375-380,
1993.
Barker GR: A radiolucency of the ascending ramus of the man-
dible associated with invested parotid salivary gland material
and analogous with a Stafne bone cavity, Br J Oral Maxillofac
Surg 26:81-84, 1988.
Bouquot JE, Gnepp DR, Dardick I et al: Intraosseous salivary
tissue: jawbone examples of choristomas, hamartomas,
embryonic rests, and inﬂammatory entrapment: another
histogenetic source for intraosseous adenocarcinoma, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 90:205-217,
2000.
Branstetter BF, Weissman JL, Kaplan SB: Imaging of a Stafne
bone cavity: what MR adds and why a new name is needed,
AJNR Am J Neuroradiol 20:587, 1999.
Buchner A, Carpenter WM, Merrell PW et al: Anterior lingual
mandibular salivary gland defect. Evaluation of twenty-four
cases, Oral Surg Oral Med Oral Pathol 71:131-136, 1991.
Correll RW, Jensen JL, Rhyne RR: Lingual cortical mandibular
defects: a radiographic incidence study, Oral Surg Oral Med
Oral Pathol 50:287-291, 1980.
de Courten A, Küffer R, Samson J et al: Anterior lingual man-
dibular salivary gland defect (Stafne defect) presenting as a
residual cyst, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
94:460-464, 2002.
Miller AS, Winnick M: Salivary gland inclusion in the anterior
mandible: report of a case with a review of the literature on
aberrant salivary gland tissue and neoplasms, Oral Surg Oral
Med Oral Pathol 31:790-797, 1971.
Oikarinen VJ, Wolf J, Julku M: A stereosialographic study of
developmental mandibular bone defects (Stafne’s idiopathic
bone cavities), Int J Oral Surg 4:51-54, 1975.
Stafne EC: Bone cavities situated near the angle of the mandible,
J Am Dent Assoc 29:1969-1972, 1942.
Palatal Cysts of the Newborn
Burke GW Jr, Feagans WM, Elzay RP et al: Some aspects of the
origin and fate of midpalatal cysts in human fetuses, J Dent
Res 45:159-164, 1966.
Cataldo E, Berkman MD: Cysts of the oral mucosa in newborns,
Am J Dis Child 116:44-48, 1968.
Donley CL, Nelson, LP: Comparison of palatal and alveolar cysts
of the newborn in premature and full term infants, Pediatr
Dent 22:321-324, 2000.
Flinck A, Paludan A, Matsson L et al: Oral ﬁndings in a group of
newborn Swedish children, Int J Paediatr Dent 4:67-73,
1994.
Fromm A: Epstein’s pearls, Bohn’s nodules and inclusion-cysts of
the oral cavity, J Dent Child 34:275-287, 1967.
Jorgenson RJ, Shapiro SD, Salinas CF et al: Intraoral ﬁndings and
anomalies in neonates, Pediatrics 69:577-582, 1982.
Liu MH, Huang WH: Oral abnormalities in Taiwanese new-
borns, J Dent Child 71:118-120, 2004.
Monteleone L, McLellan MS: Epstein’s pearls (Bohn’s nodules) of
the palate, J Oral Surg 22:301-304, 1964.
Moreillon MC, Schroeder HE: Numerical frequency of epithelial
abnormalities, particularly microkeratocysts, in the develop-
ing human oral mucosa, Oral Surg Oral Med Oral Pathol 53:44-
55, 1982.
Nasolabial Cyst
Allard RHB: Nasolabial cyst: review of the literature and report
of 7 cases, Int J Oral Surg 11:351-359, 1982.
Choi JH, Cho JH, Kang HJ et al: Nasolabial cyst: a retrospective
analysis of 18 cases, Ear Nose Throat J 81:94-96, 2002.
Kuriloff DB: The nasolabial cyst—nasal hamartoma, Otolaryngol
Head Neck Surg 96:268-272, 1987.
López-Ríos F, Lassaletta-Atienza L, Domingo-Carrasco C et al:
Nasolabial cyst. Report of a case with extensive apocrine
change, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
84:404-406, 1997.
Roed-Petersen B: Nasolabial cysts: a presentation of ﬁve patients
with a review of the literature, Br J Oral Surg 7:84-95,
1969.
Su C-Y, Chien C-Y, Hwang C-F: A new transnasal approach to
endoscopic marsupialization of the nasolabial cyst, Laryngo-
scope 109:1116-1118, 1999.
Vasconcelos RF, Souza PE, Mesquita RA: Retrospective analysis
of 15 cases of nasolabial cyst, Quintessence Int 30:629-632,
1999
“Globulomaxillary Cyst”
Christ TF: The globulomaxillary cyst: an embryologic misconcep-
tion, Oral Surg Oral Med Oral Pathol 30:515-526, 1970.
D’Silva NJ, Anderson L: Globulomaxillary cyst revisited, Oral
Surg Oral Med Oral Pathol 76:182-184, 1993.
Ferenczy K: The relationship of globulomaxillary cysts to the
fusion of embryonal processes and to cleft palates, Oral Surg
Oral Med Oral Pathol 11:1388-1393, 1958.
Little JW, Jakobsen J: Origin of the globulomaxillary cyst, J Oral
Surg 31:188-195, 1973.
Steiner DR: A lesion of endodontic origin misdiagnosed as a
globulomaxillary cyst, J Endod 25:277-281, 1999.
Vedtofte P, Holmstrup P: Inﬂammatory paradental cysts in the
globulomaxillary region, J Oral Pathol Med 18:125-127,
1989.
Wysocki GP: The differential diagnosis of globulomaxillary
radiolucencies, Oral Surg Oral Med Oral Pathol 51:281-286,
1981.
Wysocki GP, Goldblatt LI: The so-called “globulomaxillary
cyst” is extinct, Oral Surg Oral Med Oral Pathol 76:185-186,
1993.
Nasopalatine Duct Cyst
Abrams AM, Howell FV, Bullock WK: Nasopalatine cysts, Oral
Surg Oral Med Oral Pathol 16:306-332, 1963.
Allard RHB, van der Kwast WAM, van der Waal I: Nasopalatine
duct cyst: review of the literature and report of 22 cases, Int
J Oral Surg 10:447-461, 1981.
Anneroth G, Hall G, Stuge U: Nasopalatine duct cyst, Int J Oral
Maxillofac Surg 15:572-580, 1986. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 51
Brown FH, Houston GD, Lubow RM et al: Cyst of the incisive
(palatine) papilla: report of a case, J Periodontol 58:274-275,
1987.
Chapple IL, Ord RA: Patent nasopalatine ducts: four case pre-
sentations and review of the literature, Oral Surg Oral Med
Oral Pathol 69:554-558, 1990.
Hisatomi M, Asaumi J, Konouchi H et al: MR imaging of naso-
palatine duct cysts, Eur J Radiol 39:73-76, 2001.
Swanson KS, Kaugars GE, Gunsolley JC: Nasopalatine duct cyst:
an analysis of 334 cases, J Oral Maxillofac Surg 49:268-271,
1991.
Takagi R, Ohashi Y, Suzuki M: Squamous cell carcinoma in
the maxilla probably originating from a nasopalatine
duct cyst: report of case, J Oral Maxillofac Surg 54:112-115,
1996.
Vasconcelos RF, de Aguiar MF, Castro WH et al: Retrospective
analysis of 31 cases of nasopalatine duct cyst, Oral Dis 5:325-
328, 1999.
Median Palatal Cyst
Courage GR, North AF, Hansen LS: Median palatine cysts, Oral
Surg Oral Med Oral Pathol 37:745-753, 1974.
Donnelly JC, Koudelka BM, Hartwell GR: Median palatal cyst, J
Endod 12:546-549, 1986.
Gingell JC, Levy BA, DePaola LG: Median palatine cyst, J Oral
Maxillofac Surg 43:47-51, 1985.
Gordon NC, Swann NP, Hansen LS: Median palatine cyst and
maxillary antral osteoma: report of an unusual case, J Oral
Surg 38:361-365, 1980.
“Median Mandibular Cyst”
Gardner DG: An evaluation of reported cases of median man-
dibular cysts, Oral Surg Oral Med Oral Pathol 65:208-213,
1988.
Soskolne WA, Shteyer A: Median mandibular cyst, Oral Surg Oral
Med Oral Pathol 44:84-88, 1977.
White DK, Lucas RM, Miller AS: Median mandibular cyst: review
of the literature and report of two cases, J Oral Surg 33:372-
375, 1975.
Epidermoid Cyst
Boatman BW, Headington JT: Epidermoid and tricholemmal
cysts. In Demis DJ: Clinical dermatology, chapter 4-57,
Philadelphia, 1996, Lippincott-Raven.
Golden BA, Zide MF: Cutaneous cysts of the head and neck, J
Oral Maxillofac Surg 63:1613-1619, 2005.
Kligman AM: The myth of the sebaceous cyst, Arch Dermatol
89:253-256, 1964.
López-Ríos F, Rodríguez-Peralto JL, Castaño E et al: Squamous
cell carcinoma arising in a cutaneous epidermal cyst, Am J
Dermatopathol 21:174-177, 1999.
Maize JC, Burgdorf WHC, Hurt MA et al: Follicular cysts. In
Cutaneous pathology, pp 540-541, Philadelphia, 1998,
Churchill Livingstone.
McGavran MH, Binnington B: Keratinous cysts of the skin, Arch
Dermatol 94:499-508, 1966.
Rajayogeswaran V, Eveson JW: Epidermoid cyst of the buccal
mucosa, Oral Surg Oral Med Oral Pathol 67:181-184, 1989.
Dermoid Cyst
Arcand P, Granger J, Brochu P: Congenital dermoid cyst of the
oral cavity with gastric choristoma, J Otolaryngol 17:219-222,
1988.
Crivelini MM, Soubhia AM, Biazolla ÉR et al: Heterotopic gas-
trointestinal cyst partially lined with dermoid cyst epithe-
lium, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
91:686-688, 2001.
Edwards PC, Lustrin L, Valderrama E: Dermoid cysts of the
tongue: report of ﬁve cases and review of the literature,
Pediatr Dev Pathol 6:531-535, 2003.
King RC, Smith BR, Burk JL: Dermoid cyst in the ﬂoor of the
mouth. Review of the literature and case reports, Oral Surg
Oral Med Oral Pathol 78:567-576, 1994.
Lipsett J, Sparnon AL, Byard RW: Embryogenesis of enterocys-
tomas-enteric duplication cysts of the tongue, Oral Surg Oral
Med Oral Pathol 75:626-630, 1993.
Meyer I: Dermoid cysts (dermoids) of the ﬂoor of the mouth, Oral
Surg Oral Med Oral Pathol 8:1149-1164, 1955.
Said-Al-Naief N, Fantasia JE, Sciubba JJ et al: Heterotopic oral
gastrointestinal cyst. Report of 2 cases and review of the lit-
erature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
88:80-86, 1999.
Shigematsu H, Dobashi A, Suzuki S et al: Delayed recurrence of
teratoid cyst 17 years after enucleation, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 92:539-542, 2001.
Thyroglossal Duct Cyst
Allard RHB: The thyroglossal cyst, Head Neck Surg 5:134-146,
1982.
Brousseau VJ, Solares CA, Xu M et al: Thyroglossal duct cysts:
presentation and management in children versus adults, Int
J Pediatr Otorhinolaryngol 67:1285-1290, 2003.
Dedivitis RA, Camargo DL, Peixoto GL et al: Thyroglossal duct:
a review of 55 cases, J Am Coll Surg 194:274-277, 2002.
Fernandez JF, Ordoñez NG, Schultz NA et al: Thyroglossal duct
carcinoma, Surgery 110:928-935, 1991.
Katz AD, Hachigian M: Thyroglossal duct cysts: a thirty-year
experience with emphasis on occurrence in older patients,
Am J Surg 155:741-744, 1988.
Kuint J, Horowitz Z, Kugel C et al: Laryngeal obstruction caused
by lingual thyroglossal duct cyst presenting at birth, Am J
Perinatol 14:353-356, 1997.
Patel SG, Escrig M, Shaha AR et al: Management of well-differ-
entiated thyroid carcinoma presenting within a thyroglossal
duct cyst, J Surg Oncol 79:134-139, 2002.
Plaza CP, López ME, Carrasco CE et al: Management of well-dif-
ferentiated thyroglossal remnant thyroid carcinoma: time to
close the debate? Report of ﬁve new cases and proposal of a
deﬁnitive algorithm for treatment, Ann Surg Oncol 13:745-
752, 2006.
Schader I, Robertson S, Maoate K et al: Hereditary thyroglossal
duct cysts, Pediatr Surg Int 21:593-594, 2005.
Branchial Cleft Cyst
Bhaskar SN, Bernier JL: Histogenesis of branchial cysts: a report
of 468 cases, Am J Pathol 35:407-423, 1959.
Elliott JN, Oertel YC: Lymphoepithelial cysts of the salivary
glands, Am J Clin Pathol 93:39-43, 1990.
Foss RD, Warnock GR, Clark WB et al: Malignant cyst of
the lateral aspect of the neck: branchial cleft carcinoma or
metastasis? Oral Surg Oral Med Oral Pathol 71:214-217,
1991.
Goldenberg D, Sciubba J, Koch WM: Cystic metastasis from
head and neck squamous cell cancer: a distinct disease
variant? Head Neck 28:633-638, 2006.
Kadhim AL, Sheahan P, Colreavy MP et al: Pearls and pitfalls in
the management of branchial cyst, J Laryngol Otol 118:946-
950, 2004.
Little JW, Rickles NH: The histogenesis of the branchial cyst, Am
J Pathol 50:533-547, 1967.
Mandel L, Reich R: HIV parotid gland lymphoepithelial cysts:
review and case reports, Oral Surg Oral Med Oral Pathol 74:
273-278, 1992. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

52 ORAL AND MAXILLOFACIAL PATHOLOGY
Regauer S, Gogg-Kamerer M, Braun H et al: Lateral neck
cysts—the branchial theory revisited, APMIS 105:623-630,
1997.
Skouteris CA, Patterson GT, Sotereanos GC: Benign cervical
lymphoepithelial cyst: report of cases, J Oral Maxillofac Surg
47:1106-1112, 1989.
Thompson LD, Heffner DK: The clinical importance of cystic
squamous cell carcinomas in the neck: a study of 136 cases,
Cancer 82:944-956, 1998.
Oral Lymphoepithelial Cyst
Bhaskar SN: Lymphoepithelial cysts of the oral cavity: report of
twenty-four cases, Oral Surg Oral Med Oral Pathol 21:120-128,
1966.
Buchner A, Hansen LS: Lymphoepithelial cysts of the oral cavity,
Oral Surg Oral Med Oral Pathol 50:441-449, 1980.
Chaudhry AP, Yamane GM, Scharlock SE et al: A clinico-patho-
logical study of intraoral lymphoepithelial cysts, J Oral Med
39:79-84, 1984.
Giunta J, Cataldo E: Lymphoepithelial cysts of the oral mucosa,
Oral Surg Oral Med Oral Pathol 35:77-84, 1973.
Hemihyperplasia
Ballock RT, Wiesner GL, Myers MT et al: Hemihypertrophy.
Concepts and controversies, J Bone Joint Surg 79:1731-1738,
1997.
Bell RA, McTigue DJ: Complex congenital hemihypertrophy:
a case report and literature review, J Pedod 8:300-313,
1984.
Dalal AB, Phadke SR, Pradhan M et al: Hemihyperplasia syn-
dromes, Indian J Pediatr 73:609-615, 2006.
Elliott M, Bayly R, Cole T et al: Clinical features and natural
history of Beckwith-Wiedemann syndrome: presentation of
74 new cases, Clin Genet 46:168-174, 1994.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Hemihyperplasia
(hemihypertrophy). In Syndromes of the head and neck, ed 4, pp
405-408, New York, 2001, Oxford University Press.
Horswell BB, Holmes AD, Barnett JS et al: Primary hemihyper-
trophy of the face: review and report of two cases, J Oral
Maxillofac Surg 45:217-222, 1987.
Hoyme HE, Seaver LH, Jones KL et al: Isolated hemihyperplasia
(hemihypertrophy): report of a prospective multicenter study
of the incidence of neoplasia and review, Am J Med Genet
79:274-278, 1998.
Progressive Hemifacial Atrophy
Abele DC, Bedingﬁeld RB, Chandler FW et al: Progressive facial
hemiatrophy (Parry-Romberg syndrome) and borreliosis, J
Am Acad Dermatol 22:531-533, 1990.
Blaszczyk M, Królicki L, Krasu M et al: Progressive facial hemi-
atrophy: central nervous system involvement and relation-
ship with scleroderma en coup de sabre, J Rheumatol
30:1997-2004, 2003.
Fayad S, Steffensen B: Root resorptions in a patient with hemi-
facial atrophy, J Endod 20:299-303, 1994.
Foster TD: The effects of hemifacial atrophy on dental growth,
Br Dent J 146:148-150, 1979.
Iñigo F, Rojo P, Ysunza A: Aesthetic treatment of Romberg’s
disease: experience with 35 cases, Br J Plast Surg 46:194-200,
1993.
Orozco-Covarrubias L, Guzmán-Meza A, Ridaura-Sanz C et al:
Scleroderma “en coup de sabre” and progressive facial hemi-
atrophy. Is it possible to differentiate them? J Eur Acad Derma-
tol Venereol 16:361-366, 2002.
Pensler JM, Murphy GF, Mulliken JB: Clinical and ultrastruc-
tural studies of Romberg’s hemifacial atrophy, Plast Reconstr
Surg 85:669-674, 1990.
Roddi R, Riggio E, Gilbert PM et al: Clinical evaluation of tech-
niques used in the surgical treatment of progressive hemifa-
cial atrophy, J Craniomaxillofac Surg 22:23-32, 1994.
Sommer A, Gambichler T, Bacharach-Buhles M et al: Clinical
and serological characteristics of progressive facial hemiatro-
phy: a case series of 12 patients, J Am Acad Dermatol 54:227-
223, 2006.
Segmental Odontomaxillary Dysplasia
Armstrong C, Napier SS, Boyd RC et al: Histopathology of the
teeth in segmental odontomaxillary dysplasia: new ﬁndings,
J Oral Pathol Med 33:246-248, 2004.
Becktor KB, Reibel J, Vedel B et al: Segmental odontomaxillary
dysplasia: clinical, radiological and histological aspects of four
cases, Oral Dis 8:106-110, 2002.
Danforth RA, Melrose RJ, Abrams AM, et al: Segmental odonto-
maxillary dysplasia. Report of eight cases and comparison
with hemimaxillofacial dysplasia, Oral Surg Oral Med Oral
Pathol 70:81-85, 1990.
Jones AC, Ford MJ: Simultaneous occurrence of segmental odon-
tomaxillary dysplasia and Becker’s nevus, J Oral Maxillofac
Surg 57:1251-1254, 1999.
Miles DA, Lovas JL, Cohen MM Jr: Hemimaxillofacial dysplasia:
a newly recognized disorder of facial asymmetry, hypertri-
chosis of the facial skin, unilateral enlargement of the maxilla,
and hypoplastic teeth in two patients, Oral Surg Oral Med Oral
Pathol 64:445-448, 1987.
Packota GV, Pharoah MJ, Petrikowski CG: Radiographic fea-
tures of segmental odontomaxillary dysplasia. A study of 12
cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:577-
584, 1996.
Paticoff K, Marion RW, Shprintzen RJ et al: Hemimaxillofacial
dysplasia. A report of two new cases and further delineation
of the disorder, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 83:484-488, 1997.
Crouzon Syndrome
David DJ, Sheen R: Surgical correction of Crouzon syndrome,
Plast Reconstr Surg 85:344-354, 1990.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Crouzon syndrome
(craniofacial dysostosis). In Syndromes of the head and neck, ed
4, pp 658-659, New York, 2001, Oxford University Press.
Katzen JT, McCarthy JG: Syndromes involving craniosynostosis
and midface hypoplasia, Otolaryngol Clin North Am 33:1257-
1284, 2000.
Kreiborg S: Crouzon syndrome, Scand J Plast Reconstr Surg Suppl
18:1-198, 1981.
Mulliken JB, Steinberger D, Kunze S et al: Molecular diagnosis
of bilateral coronal synostosis, Plast Reconstr Surg 104:1603-
1615, 1999.
Posnick JC: The craniofacial dysostosis syndromes. Staging of
reconstruction and management of secondary deformities,
Clin Plast Surg 24:429-446, 1997.
Singer SL, Walpole I, Brogan WF et al: Dentofacial features of a
family with Crouzon syndrome. Case reports, Aust Dent J
42:11-17, 1997.
Apert Syndrome
Cohen MM Jr, Kreiborg S: A clinical study of the craniofacial
features in Apert syndrome, Int J Oral Maxillofac Surg 25:45-
53, 1996.
Ferraro NF: Dental, orthodontic, and oral/maxillofacial evalua-
tion and treatment in Apert syndrome, Clin Plast Surg 18:291-
307, 1991.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Apert syndrome
(acrocephalosyndactyly). In Syndromes of the head and neck, ed
4, pp 654-658, New York, 2001, Oxford University Press. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 1 DEVELOPMENTAL DEFECTS OF THE ORAL AND MAXILLOFACIAL REGION 53
Ibrahimi OA, Chiu ES, McCarthy JG et al: Understanding the
molecular basis of Apert syndrome, Plast Reconstr Surg
115:264-270, 2005.
Katzen JT, McCarthy JG: Syndromes involving craniosynostosis
and midface hypoplasia, Otolaryngol Clin North Am 33:1257-
1284, 2000.
Kreiborg S, Cohen MM Jr: The oral manifestations of Apert syn-
drome, J Craniofac Genet Dev Biol 12:41-48, 1992.
Marsh JL, Galic M, Vannier MW: Surgical correction of the cra-
niofacial dysmorphology of Apert syndrome, Clin Plast Surg
18:251-275, 1991.
Mulliken JB, Steinberger D, Kunze S et al: Molecular diagnosis
of bilateral coronal synostosis, Plast Reconstr Surg 104:1603-
1615, 1999.
Mandibulofacial Dysostosis
Fuente del Campo A, Martinez Elizondo M, Arnaud E: Treacher
Collins syndrome (mandibulofacial dysostosis), Clin Plast Surg
21:613-623, 1994.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Mandibulofacial dys-
ostosis (Treacher Collins syndrome, Franceschetti-Zwahlen-
Klein syndrome). In Syndromes of the head and neck, ed 4, pp
799-802, New York, 2001, Oxford University Press.
Marszalek B, Wójcicki P, Kobus K et al: Clinical features, treat-
ment and genetic background of Treacher Collins syndrome,
J Appl Genet 43:223-233, 2002.
Posnick JC: Treacher Collins syndrome: perspectives in evalua-
tion and treatment, J Oral Maxillofac Surg 55:1120-1133,
1997.
Posnick JC, Ruiz RL: Treacher Collins syndrome: current evalu-
ation, treatment, and future directions, Cleft Palate Craniofac J
37:434, 2000. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

54
2
Abnormalities of Teeth
CHAPTER OUTLINE
ENVIRONMENTAL ALTERATIONS OF TEETH
Environmental Effects on Tooth Structure
Development
Turner’s Hypoplasia
Molar Incisor Hypomineralization
Hypoplasia Caused by Antineoplastic Therapy
Dental Fluorosis
Syphilitic Hypoplasia
Postdevelopmental Loss of Tooth Structure
Tooth Wear
Attrition
Abrasion
Erosion
Abfraction
Internal and External Resorption
Environmental Discoloration of Teeth
Extrinsic Stains
Intrinsic Stains
Localized Disturbances in Eruption
Impaction
Ankylosis
DEVELOPMENTAL ALTERATIONS OF TEETH
Developmental Alterations in the Number of Teeth
Hypodontia
Hyperdontia
Developmental Alterations in the Size of Teeth
Microdontia
Macrodontia
Developmental Alterations in the Shape of Teeth
Gemination, Fusion, and Concrescence
Accessory Cusps
Cusp of Carabelli
Talon Cusp
Dens Evaginatus
Dens Invaginatus
Ectopic Enamel
Enamel Pearls
Cervical Enamel Extensions
Taurodontism
Hypercementosis
Dilaceration
Supernumerary Roots
Developmental Alterations in the Structure of Teeth
Amelogenesis Imperfecta
Hypoplastic Amelogenesis Imperfecta
Hypomaturation Amelogenesis Imperfecta
Hypocalciﬁed Amelogenesis Imperfecta
Amelogenesis Imperfecta with Taurodontism
Dentinogenesis Imperfecta
Dentin Dysplasia
Dentin Dysplasia Type I
Dentin Dysplasia Type II
Regional Odontodysplasia
in nature. Later parts of this chapter delineate the
idiopathic and hereditary alterations of teeth. Box
2-1 lists the major categories of tooth alteration
that can be affected by environmental inﬂuences.
In many cases the cause and effect are obvious; in
others the primary nature of the problem is less
distinct.
Environmental Alterations
of Teeth
The abnormalities of the teeth can be divided into
those that are inﬂuenced by environmental forces
and those that are idiopathic and appear hereditary `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 2 ABNORMALITIES OF TEETH 55
CLINICAL AND RADIOGRAPHIC
FEATURES
Almost all visible environmental enamel defects can be
classiﬁed into one of three patterns:
1. Hypoplasia
2. Diffuse opacities
3. Demarcated opacities
Subtle enamel defects can be masked by saliva,
plaque, or poor illumination. When attempting to
detect areas of altered enamel, the dentition should be
cleaned thoroughly; then it should be dried with gauze.
Dental operatory lights are an ideal light source (direct
sunlight should be avoided). Plaque-disclosing solution
can be used to highlight small defects. The altered
enamel may be localized or present on numerous teeth,
Box 2-1
Environmental Alterations of Teeth
●Developmental tooth defects
●Postdevelopmental structure loss
●Discolorations of teeth
●Localized disturbances in eruption
Box 2-2
Factors Associated with Enamel Defects
SYSTEMIC
●Birth-related trauma: Breech presentations, hypoxia,
multiple births, premature birth, prolonged labor
●Chemicals: Antineoplastic chemotherapy, ﬂuoride,
lead, tetracycline, thalidomide, vitamin D
●Chromosomal abnormalities: Trisomy 21
●Infections: Chicken pox, cytomegalovirus (CMV), gas-
trointestinal infections, measles, pneumonia, respira-
tory infections, rubella, syphilis, tetanus
●Inherited diseases: Amelo-cerebro-hypohidrotic syn-
drome, amelo-onycho-hypohidrotic syndrome, epi-
dermolysis bullosa, galactosemia,
mucopolysaccharidosis IV, Nance-Horan syndrome,
oculo-dento-osseous dysplasia, phenylketonuria,
pseudohypoparathyroidism, tricho-dento-osseous
syndrome, tuberous sclerosis, vitamin D–dependent
rickets
●Malnutrition: Generalized malnutrition, vitamin-D
deﬁciency, vitamin-A deﬁciency
●Metabolic disorders: Cardiac disease, celiac disease,
gastrointestinal malabsorption, gastrointestinal lym-
phangiectasia, hepatobiliary disease, hyperbilirubine-
mia, hypocalcemia, hypothyroidism,
hypoparathyroidism, maternal diabetes, renal
disease, toxemia of pregnancy
●Neurologic disorders: Cerebral palsy, mental retarda-
tion, sensorineural hearing defects
LOCAL
●Local acute mechanical trauma: Falls, gunshots, neo-
natal mechanical ventilation, ritual mutilation,
surgery, vehicular accidents
● Electrical burn
● Irradiation
●Local infection: Acute neonatal maxillitis, periapical
inﬂammatory disease
ENVIRONMENTAL EFFECTS ON TOOTH
STRUCTURE DEVELOPMENT
The ameloblasts in the developing tooth germ are
extremely sensitive to external stimuli, and many
factors can result in abnormalities in the enamel (Box
2-2). The primary hereditary abnormalities of the
enamel that are unrelated to other disorders are termed
amelogenesis imperfecta (see page 99).
Dental enamel is unique in that remodeling does
not occur after initial formation. Therefore, abnormali-
ties in enamel formation are etched permanently on
the tooth surface. The enamel develops in three major
stages: (1) matrix formation, (2) mineralization, and
(3) maturation. During matrix formation, the enamel
proteins are laid down. In the next phase, minerals are
deposited and the majority of the original proteins are
removed. During the ﬁnal maturation period, the
enamel undergoes ﬁnal mineralization and the rem-
nants of the original proteins are removed. In the early
stage of mineralization, the enamel is dull, white, and
relatively soft. During the late stage of maturation, the
ﬁnal hard translucent enamel replaces this diffuse
opaque enamel.
The timing of the ameloblastic damage has a great
effect on the location and appearance of the defect in
the enamel. The cause of the damage does not appear
to be of major importance, because many different
local and systemic stimuli can result in defects that
have similar clinical appearances. The ﬁnal enamel
represents a record of all signiﬁcant insults received
during tooth development. Deciduous enamel contains
a neonatal ring, and the rate of enamel apposition is
estimated to be 0.023 mm/day. Using this knowledge,
the clinician can accurately estimate the timing of an
insult to the deciduous teeth to within 1 week. In the
permanent dentition, the position of the enamel defects
provides a rough estimate of the time of damage;
however, available data on the chronology of tooth
development are derived from a relatively small sample
size, and the ranges of normal values are wide. In addi-
tion, gender and racial variations are not established
thoroughly. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

56 ORAL AND MAXILLOFACIAL PATHOLOGY
and all or part of the surfaces of each affected tooth may
be involved. Enamel hypoplasia occurs in the form of
pits, grooves, or larger areas of missing enamel. Diffuse
opacities of enamel appear as variations in the trans-
lucency of the enamel. The affected enamel is of normal
thickness; however, it has an increased white opacity
with no clear boundary with the adjacent normal
enamel. Demarcated opacities of enamel show areas
of decreased translucence, increased opacity, and a
sharp boundary with the adjacent enamel. The enamel
is of normal thickness, and the affected opacity may be
white, cream, yellow, or brown.
The crowns of the deciduous dentition begin to
develop at approximately the fourteenth week of gesta-
tion and continue until the child is 12 months of age.
Development of the crowns of the permanent denti-
tion occurs from approximately 6 months to 15 years
of age. The site of coronal damage correlates with the
area of ameloblastic activity at the time of the injury;
the affected enamel is restricted to the areas in which
secretory activity or active maturation of the enamel
matrix was occurring.
Environmental enamel abnormalities are extremely
common. In a review of more than 1500 children from
12 to 15 years of age in an industrialized nation, the
prevalence of enamel defects in the permanent denti-
tion was 68.4%. Within this group, 67.2% demonstrated
opacities, 14.6% revealed hypoplasia, and both patterns
were seen in 13.4% of the children. The average number
of affected teeth per individual was 3.6, with greater
than 10% of the children having 10 or more teeth
involved.
A common pattern is seen as a result of systemic
inﬂuences, such as exanthematous fevers, that occur
during the ﬁrst 2 years of life. Horizontal rows of pits
or diminished enamel are present on the anterior teeth
and ﬁrst molars (Figs. 2-1 and 2-2). The enamel loss is
bilaterally symmetric, and the location of the defects
correlates well with the developmental stage of the
affected teeth. A similar pattern of enamel defects can
be seen in the cuspids, bicuspids, and second molars
when the inciting event occurs around the age of 4 to
5 years (Fig. 2-3).
TURNER’S HYPOPLASIA
Another frequent pattern of enamel defects seen in
permanent teeth is caused by periapical inﬂammatory
disease of the overlying deciduous tooth. The altered
tooth is called a Turner’s tooth (after the clinician
whose publications allowed this problem to be widely
recognized). The appearance of the affected area varies
according to the timing and severity of the insult. The
enamel defects vary from focal areas of white, yellow,
or brown discoloration to extensive hypoplasia, which
can involve the entire crown. The process is noted most
frequently in the permanent bicuspids because of their
Fig. 2-1 Environmental enamel hypoplasia. Bilaterally
symmetrical pattern of horizontal enamel hypoplasia of the
anterior dentition. Maxillary central incisors have been
restored previously. (From Neville BW, Damm DD, White DK: Color
atlas of clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.)
Fig. 2-2 Environmental enamel hypoplasia. Same patient
as depicted in Fig. 2-1. Note the lack of enamel damage on
bicuspids. (From Neville BW, Damm DD, White DK: Color atlas of
clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.)
Fig. 2-3 Environmental enamel hypoplasia. Horizontal
enamel hypoplasia of the bicuspids and second molars. Note
sparing of the ﬁrst molars. (From Neville BW, Damm DD, White DK:
Color atlas of clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 57
relationship to the overlying deciduous molars (Figs.
2-4 and 2-5). Anterior teeth are involved less frequently
because crown formation is usually complete before
the development of any apical inﬂammatory disease in
the relatively caries-resistant anterior deciduous denti-
tion. Factors that determine the degree of damage to
the permanent tooth by the overlying infection include
the stage of tooth development, length of time the infec-
tion remains untreated, the virulence of the infective
organisms, and the host resistance to the infection.
In addition to classic Turner’s teeth, an increased
prevalence of demarcated opacities has been reported
in the permanent successors of carious primary teeth.
In one report, if the primary tooth developed caries,
the successor was twice as likely to demonstrate a cir-
cumscribed enamel defect. In addition, if the primary
tooth was extracted for any reason other than trauma,
then the prevalence of a demarcated enamel defect
increased ﬁvefold.
Traumatic injury to deciduous teeth also can cause
signiﬁcant alterations of the underlying dentition and
the formation of Turner’s teeth. This is not a rare occur-
rence; up to 45% of all children sustain injuries to their
primary teeth. In a prospective study of 114 children
with 255 traumatized primary teeth, 23% of the corre-
sponding permanent teeth demonstrated developmen-
tal disturbances. The maxillary central incisors are
affected in the majority of the cases; the maxillary
lateral incisors are altered less frequently (Fig. 2-6). In
several large reviews, the prevalence of involvement of
the posterior teeth or mandibular incisors was less than
10% of all cases.
The frequency of traumatic damage of the anterior
maxillary dentition is not surprising, considering the
common occurrence of trauma to the deciduous denti-
tion of the prominent anterior maxilla and the close
anatomic relationship between the developing tooth
bud and the apices of the overlying primary incisors.
As would be expected, the clinical appearance of the
alteration varies according to the timing and severity
of the damage.
Because of the position of the primary apices rela-
tive to the tooth bud, the facial surface of the maxillary
incisors is the location most frequently affected. Typi-
cally, the affected area appears as a zone of white or
yellowish-brown discoloration with or without an area
of horizontal enamel hypoplasia. The trauma also can
cause displacement of the already formed hard-tooth
Fig. 2-4 Turner’s hypoplasia. Extensive enamel hypoplasia
of mandibular ﬁrst bicuspid secondary to previous
inﬂammatory process associated with overlying ﬁrst
deciduous molar. (From Halstead CL, Blozis GG, Drinnan AJ et al:
Physical evaluation of the dental patient, St Louis, 1982, Mosby.)
Fig. 2-5 Turner’s hypoplasia. Radiograph of the same
tooth depicted in Fig. 2-4. Note the lack of signiﬁcant enamel
and irregularity of the dentin surface. (From Halstead CL, Blozis
GG, Drinnan AJ et al: Physical evaluation of the dental patient, St Louis,
1982, Mosby.)
Fig. 2-6 Turner’s hypoplasia. Extensive coronal hypoplasia
of permanent maxillary left central incisor secondary to
previous trauma to deciduous central incisor. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

58 ORAL AND MAXILLOFACIAL PATHOLOGY
substance in relation to the soft tissue of the remaining
developing tooth. This results in a bend of the tooth
known as dilaceration and can affect either the crown
or the root of a tooth (see page 97). Severe trauma early
in the development of the tooth can result in such dis-
organization of the bud that the resultant product may
resemble a complex odontoma (see page 724). Similar
levels of damage late in the formative process can lead
to partial or total arrest in root formation.
MOLAR INCISOR HYPOMINERALIZATION
Over the last two to three decades, a number of publica-
tions have described a unique pattern of defective enamel
that has been recognized most frequently in Northern
Europe, although the pathosis is not limited to that geo-
graphic region. In the past this disorder most likely went
undiagnosed because of the high prevalence of caries,
but with the dramatic reduction in caries, these tooth
changes have become more recognized.
Patients affected with molar incisor hypomineral-
ization have enamel defects of one or more ﬁrst per-
manent molars. The altered enamel may be white,
yellow, or brown, with a sharp demarcation between
the defective and surrounding normal enamel. Often,
the involved enamel is soft and porous with a resem-
blance to discolored chalk or old Dutch cheese (“cheese
molars”). Frequently, the incisors also are affected, but
the defects generally are much less severe.
The enamel of the affected molars is very fragile and
can chip easily. Often, affected molars are sensitive to
cold, warm, or mechanical trauma. Toothbrushing is
frequently painful, with a tendency for the children to
avoid brushing these teeth. As would be expected, the
lack of normal enamel and absence of appropriate
hygiene lead to rapid development of caries. During
attempts at dental therapy, these teeth often are highly
sensitive and very difﬁcult to anesthetize.
The cause of molar incisor hypomineralization is
unknown, but many investigators believe the condition
arises from a systemic inﬂuence during the ﬁrst years
of life, coinciding with the period of mineralization of
the affected dentition. A number of prevalence studies
have been performed with the results ranging from
3.6% to 25%.
HYPOPLASIA CAUSED BY
ANTINEOPLASTIC THERAPY
As modern medicine increases the prevalence of suc-
cessful therapy against childhood cancer, it has become
evident that a number of developmental alterations
arise secondary to use of therapeutic radiation or che-
motherapy. As would be expected, developing teeth
are affected most severely, with these therapies pro-
ducing clinically obvious alterations most commonly in
patients younger than 12 years and most extensively
in those younger than 5 years. The degree and severity
of the developmental alterations are related to the
patient’s age at treatment, the form of therapy, and the
dose and ﬁeld of radiation, if used.
Although both chemotherapeutic agents and radia-
tion therapy can be responsible for developmental
abnormalities, the most severe alterations are associ-
ated with radiation. Doses as low as 0.72 Gy are associ-
ated with mild developmental defects in both enamel
and dentin. As the dose escalates, so does the effect on
the developing dentition and jaws. Frequently noted
alterations include hypodontia, microdontia, radicular
hypoplasia, and enamel hypoplasia (Fig. 2-7). In addi-
tion, mandibular hypoplasia and a reduction of the
vertical development of the lower third of the face are
not rare. The mandibular hypoplasia may be the direct
effect of the radiation, reduced alveolar bone growth
secondary to impaired root development, or (possibly)
growth failure related to altered pituitary function
caused by cranial radiation. Chemotherapy alone
results in much less dramatic alterations but can
produce an increased number of enamel hypoplasias
and discolorations, slightly smaller tooth size, and occa-
sional radicular hypoplasia that is less severe than that
secondary to radiation.
DENTAL FLUOROSIS
The ingestion of excess amounts of ﬂuoride also can
result in signiﬁcant enamel defects known as dental
ﬂuorosis. In 1901, Dr. Frederick S. McKay suggested
the association between this altered enamel and an
agent in the Colorado Springs, Colorado, water supply
during investigation of the Colorado brown stain seen
in the teeth of many of his patients. In 1909, Dr. F.L.
Robertson noted a similar association in many of his
patients in Bauxite, Arkansas (the home of bauxite
Fig. 2-7 Hypoplasia caused by antineoplastic therapy.
Developmental radicular hypoplasia and microdontia caused
by radiation therapy. (From Neville BW, Damm DD, White DK: Color
atlas of clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 59
mines for aluminum). In 1930, H.V. Churchill, a
chemist in Bauxite who was employed by the Aluminum
Company of America, discovered high concentrations
of ﬂuoride (13.7 ppm) in the water and contacted
McKay for samples of the water in affected areas of Colo-
rado. McKay’s samples also demonstrated high levels of
ﬂuoride, and the ﬁnal part of the puzzle was solved.
Although the ﬂuoride produced an unusual and per-
manent dental stain, a resistance to caries also was
noted. In 1931 the National Institutes of Health hired
Dr. H. Trendley Dean to investigate the association
between ﬂuoride, the presence of dental ﬂuorosis, and
the prevalence of caries among children. Ultimately
this led to the ﬁrst water ﬂuoridation clinical trial in
Grand Rapids, Michigan. Because of the efforts of these
pioneers and the simultaneous work of many others, it
was discovered that ﬂuoride in the water at 1.0 ppm
reduced caries by 50% to 70%. Since 1962 ﬂuoridation
of drinking water is recommended, with the optimum
range being 0.7 to 1.2 ppm. The lower concentration
is recommended for warmer climates in which water
consumption is thought to be higher, but this distinc-
tion has been questioned because of an evolving indoor
lifestyle and the use of modern air-conditioning. In
1999 the United States Centers for Disease Control
and Prevention designated ﬂuoridation of drinking
water as one of the ten great public health achieve-
ments of the twentieth century in the United States.
Initially, ﬂuoride’s ability to reduce caries was
thought to be secondary to its incorporation into devel-
oping enamel, resulting in a stronger and more acid-
resistant ﬂuorapatite crystal. A number of more recent
studies have suggested that the posteruptive effects of
ﬂuoride may be of equal or even greater importance.
Researchers believe that continued exposure to topical
ﬂuoride contained in products such as toothpaste or
ﬂuoridated water inhibits demineralization, enhances
remineralization, and exhibits antibacterial effects. In
addition, they have suggested that preeruptive ﬂuoride
is most effective against pit and ﬁssure caries, whereas
smooth surface caries is affected most signiﬁcantly by
posteruptive exposure.
Consumption of optimally ﬂuoridated water has
been associated with a low prevalence of altered
enamel, which usually is mild in degree. However, an
increased prevalence of dental ﬂuorosis has been noted
in recent years. In addition, the relative caries reduc-
tion in ﬂuoridated communities has improved between
8% and 37%. This has been attributed to the diffusion
of ﬂuoride to nonﬂuoridated areas through bottling
and processing of foods and beverages with ﬂuoridated
water, as well as to the widespread use of ﬂuoride
toothpaste. Adult-strength ﬂuoride toothpastes, ﬂuo-
ride supplements, infant foods, soft drinks, fruit juices,
and industrial environmental emissions all represent
potential sources of ﬂuoride for children in their for-
mative years. Infant formulas also used to contain sig-
niﬁcant amounts of ﬂuoride; however, in 1979, U.S.
manufacturers voluntarily agreed to dramatically limit
ﬂuoride in infant formulas. Despite this, some investi-
gators have noted an increased prevalence of ﬂuorosis
continuing after 1979 in individuals who consumed
powdered, concentrated formula that was reconsti-
tuted with optimally ﬂuoridated water. To minimize
the chance of ﬂuorosis, the use of ready-to-feed formula
or reconstitution with low-ﬂuoride bottled water has
been recommended.
Because of this dissemination of ﬂuoride, the need
for supplements in nonﬂuoridated areas is declining.
In patients who use ﬂuoride toothpastes, the anticario-
genic beneﬁt of supplements is very small or nonexis-
tent and the risk of ﬂuorosis at the community level
becomes a certainty. Several investigators have recom-
mended strongly that children younger than 7 years of
age apply only a pea-sized amount of ﬂuoride tooth-
paste on the toothbrush and avoid swallowing. Because
young children tend to swallow almost all toothpaste
placed on their brush, parents should be warned to
avoid ﬂuoridated toothpaste in children younger than
2 years of age and perform oral hygiene with only a
toothbrush and water. In addition, ﬂuoride supple-
ments are recommended only in nonﬂuoridated areas
for children who are at high risk for rampant caries.
Finally, an effort is under way to alter the 1962 recom-
mendation and lower the optimum level of ﬂuoride in
the public water supply to 0.7 ppm.
Fluoride appears to create its signiﬁcant enamel
defects through retention of the amelogenin proteins
in the enamel structure, leading to the formation of
hypomineralized enamel. These alterations create a
permanent hypomaturation of the enamel in which an
increased surface and subsurface porosity of the enamel
is observed. This enamel structure alters the light
reﬂection and creates the appearance of white, chalky
areas. Most of the problems associated with dental ﬂuo-
rosis are aesthetic and concern the appearance of the
anterior teeth. Therefore, the critical period for clini-
cally signiﬁcant dental ﬂuorosis is during the second
and third years of life, when these teeth are forming.
The severity of dental ﬂuorosis is dose dependent,
with higher intakes of ﬂuoride during critical periods
of tooth development being associated with more
severe ﬂuorosis. The affected teeth are caries resistant,
and the altered tooth structure appears as areas of lus-
terless white opaque enamel that may have zones of
yellow to dark-brown discoloration (Figs. 2-8 and 2-9).
In the past, areas of moderate-to-severe enamel ﬂuoro-
sis were termed mottled enamel. True enamel hypo-
plasia is uncommon but can occur as deep, irregular,
and brownish pits. Because other factors can result in `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

60 ORAL AND MAXILLOFACIAL PATHOLOGY
a similar pattern of enamel damage, a deﬁnitive diag-
nosis requires that the defects be present in a bilater-
ally symmetric distribution, and evidence of prior
excessive ﬂuoride intake or elevated levels of ﬂuoride
in the enamel or other tissues should be found.
Recently, an increased prevalence of dental changes
similar to dental ﬂuorosis has been linked to amoxicil-
lin use during early infancy. Commonly affected teeth
include the permanent ﬁrst molars and maxillary
central incisors. The number of affected teeth appears
to correlate with the duration of use. Although the
mechanism of this alteration is unclear, the antibiotic
may reduce gene expression of selected matrix pro-
teins or reduce the activity of proteinases that hydro-
lyze matrix proteins. It also should be noted that one
of the etiologic theories suggested for molar incisor
hypomineralization (see page 58) is prior antibiotic
therapy.
SYPHILITIC HYPOPLASIA
Congenital syphilis (see page 190) results in a pattern
of enamel hypoplasia that is well known but currently
so rare that lengthy discussion is not warranted. Ante-
rior teeth altered by syphilis are termed Hutchinson’s
incisors and exhibit crowns that are shaped like
straight-edge screwdrivers, with the greatest circum-
ference present in the middle one third of the crown
and a constricted incisal edge. The middle portion of
the incisal edge often demonstrates a central hypoplas-
tic notch. Altered posterior teeth are termed mulberry
molars and demonstrate constricted occlusal tables
with a disorganized surface anatomy that resembles
the bumpy surface of a mulberry.
TREATMENT AND PROGNOSIS
Most defects in the enamel are cosmetic rather than
functional dental problems. Those affected by dental
ﬂuorosis often beneﬁt from surface microabrasion,
which produces a dramatic and permanent improve-
ment in the surface brown or yellow discoloration.
Improvement in the white surface markings usually
requires further restorative dentistry. Other types of
environmental enamel hypoplasia have been associ-
ated with an increased prevalence of caries, with one
study reporting more than twice the level in patients
with such enamel defects. The decreased caries resis-
tance is thought to be secondary to focal loss of enamel
or because of imperfect enamel. The areas most fre-
quently associated with an increased prevalence of
caries demonstrate full-thickness enamel defects. Aes-
thetically or functionally defective teeth can be restored
through a variety of cosmetically pleasing techniques,
such as the following:
●Acid-etched composite resin restorations
● Labial veneers
● Full crowns
POSTDEVELOPMENTAL LOSS OF
TOOTH STRUCTURE
Tooth structure can be lost after its formation by a
variety of inﬂuences beyond the obvious cases related
to caries or traumatic fractures. Destruction can begin
on the enamel surface of the crown through abrasion,
attrition, erosion, or abfraction. In addition, loss of
tooth structure can begin on the dentin or cemen-
tal surfaces of the teeth by external or internal
resorption.
TOOTH WEAR
Tooth wear, also termed tooth surface loss, is a normal
physiologic process that occurs with aging but must be
considered pathologic when the degree of destruction
creates functional, aesthetic, or dental sensitivity prob-
lems. Although the four causes of tooth wear (i.e., attri-
tion, abrasion, erosion, abfraction), often are
Fig. 2-9 Dental ﬂuorosis. White opaque alteration of the
bicuspids and second molars in a patient who also exhibits
discoloration of the teeth secondary to tetracycline use.
Patient moved to area of endemic ﬂuorosis at 3 years of age.
Fig. 2-8 Dental ﬂuorosis. Dentition exhibiting lusterless,
white, and opaque enamel. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 61
discussed as independent pathoses, most of these types
of tooth loss are the result of a combination of inﬂu-
ences. Many cases of attrition are accelerated by the
presence of abrasive materials in the mouth. Erosion or
abrasion often further damages areas of dentin exposed
by attrition or abfraction. Areas softened by erosion are
more susceptible to attrition, abrasion, and abfraction.
The clinician should appreciate that acquired environ-
mental loss of tooth structure often is multifactorial.
Most researchers agree that the reported prevalence
of tooth wear is increasing. This is explained partly by
a greater awareness among clinicians and by the adult
population retaining more natural teeth as they age. In
addition, younger individuals appear to exhibit an
increased tooth surface loss that many believe may be
caused by a more acidic diet (e.g., acidic soft drinks,
diet foods, fresh fruits).
Attrition is the loss of tooth structure caused by
tooth-to-tooth contact during occlusion and mastica-
tion. The term comes from the Latin verb attritum,
which refers to the action of rubbing against another
surface. Some degree of attrition is physiologic, and the
process becomes more noticeable with age. When the
amount of tooth loss is extensive and begins to affect
aesthetic appearance and function, the process must
be considered pathologic.
The following factors can accelerate tooth
destruction:
●Poor-quality or absent enamel (e.g., ﬂuorosis, envi-
ronmental or hereditary enamel hypoplasia, or
dentinogenesis imperfecta)
●Premature contacts (edge-to-edge occlusion)
●Intraoral abrasives, erosion, and grinding habits
Abrasion is the pathologic wearing away of tooth
structure or restoration secondary to the mechanical
action of an external agent. The term arises from the
Latin verb abrasum, which literally means to scrape off
and implies wear or partial removal through a mechan-
ical process. The most common cause of abrasion is
toothbrushing that combines abrasive toothpaste with
heavy pressure and a horizontal brushing stroke. Other
items frequently associated with dental abrasion
include pencils, toothpicks, pipe stems, and bobby pins
(hair grips). Chewing tobacco, cracking nuts and seeds,
biting ﬁngernails or thread, and using dental ﬂoss inap-
propriately also can cause clinically signiﬁcant abra-
sion. When tooth wear is accelerated by chewing an
abrasive substance between opposing teeth, the process
has been termed demastication and exhibits features
of both attrition and abrasion.
Erosion is the loss of tooth structure caused by a
nonbacterial chemical process. The term is derived
from the Latin verb erosum, which literally means to
corrode and implies gradual destruction of a surface by
a chemical or electrolytic process. Some investigators
have suggested that the term dental corrosion would be a
more appropriate designation for this process, but
review of modern dictionaries reveals both terms are
acceptable, with little need for a disruption in the long-
held nomenclature of tooth wear. Typically, the expo-
sure to an acid is to blame, but chelating agents are
occasionally the primary cause. Although saliva aids
remineralization and contains bicarbonate with a sig-
niﬁcant buffering ability, this effect can be overwhelmed
by xerostomia or excess acid. Causes for salivary gland
hypofunction include salivary gland aplasia, dehydra-
tion, therapeutic radiation, medications and systemic
conditions such as Sjögren syndrome, bulimia nervosa,
and diabetes. The acidic source often is foods or drinks,
but other causes include some medications (e.g., chew-
able vitamin C, aspirin tablets), swimming pools with
poorly monitored pH, chronic involuntary regurgita-
tion (e.g., hiatal hernia, esophagitis, chronic alcoholism,
pregnancy), voluntary regurgitation (e.g., psychologic
problems, bulimia, occupations that require low body
weight), and industrial environmental exposure.
Erosion from dental exposure to gastric secretions is
termed perimolysis. Because saliva has the ability
to remineralize tooth surfaces exposed to acid, it appears
that areas of erosive damage must have some abrasive
component that removes the softened enamel before
remineralization.
Agreement on the prevalence of dental erosion does
not exist. Some investigators believe erosion rarely is
responsible solely for loss of tooth structure, although
others list erosion as the leading cause of accelerated
tooth wear.
Abfraction refers to the loss of tooth structure from
occlusal stresses that create repeated tooth ﬂexure
with failure of enamel and dentin at a location away
from the point of loading. The term is derived from
the Latin words ab and fractio, which respectively
translate into away and breaking. Dentin is able to with-
stand greater tensile stress than enamel. When occlu-
sal forces are applied eccentrically to a tooth, the
tensile stress is concentrated at the cervical fulcrum,
leading to ﬂexure that may produce disruption in the
chemical bonds of the enamel crystals in the cervical
areas. Once damaged, the cracked enamel can be lost
or more easily removed by erosion or abrasion. Some
investigators have suggested that the placement of
occlusal restorations weakens the tooth’s ability to
resist the stresses of occlusion and predisposes to
future abfractive lesions.
Like erosion, agreement on the prevalence of abfrac-
tion does not exist. Some propose that abfraction causes
most cervical tooth loss; others believe that little evi-
dence exists to indicate that this sequence of events
actually occurs in the mouth. Some investigators have
suggested that the engineering models used to justify
abfraction have not taken into consideration the cush-
ioning provided by the surrounding bone and peri- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

62 ORAL AND MAXILLOFACIAL PATHOLOGY
odontium, which may dissipate occlusal forces acting
on a tooth. The pattern of cervical tooth loss tends to
occur at sites with diminished serous salivary ﬂow and
could be explained by the initial loss of salivary protec-
tion rather than excess occlusal forces. Involvement by
abfraction of the facial cervical areas of the anterior
maxillary dentition is very puzzling, because the ﬂexure
during function would occur on the palatal surface of
the tooth, not the facial surface. During function, inves-
tigators have found little evidence that strains in lingual
enamel and dentin are any different from those that
occur in facial sites; however, areas of focal cervical
tooth loss occur almost exclusively on the facial sur-
faces. Finally, review of skulls from ancient Australian
aborigines has revealed advanced tooth wear both
occlusally and interproximally; and despite evidence of
heavy occlusal loads, cervical defects were rare.
CLINICAL FEATURES
ATTRITION
Attrition can occur in both the deciduous and the
permanent dentitions. As would be expected, the sur-
faces predominantly affected are those that contact the
opposing dentition. Most frequently, the incisal and
occlusal surfaces are involved, in addition to the lingual
of the anterior maxillary teeth and the labial of the
anterior mandibular teeth. Large, ﬂat, smooth, and
shiny wear facets are found in a relationship that cor-
responds to the pattern of occlusion. The interproximal
contact points also are affected from the vertical
movement of the teeth during function. Over time, this
interproximal loss can result in a shortening of the arch
length. Pulp exposure and dentin sensitivity are rare
because of the slow loss of tooth structure and the
apposition of reparative secondary dentin within the
pulp chamber (Fig. 2-10).
Fig. 2-10 Attrition. Extensive loss of coronal tooth height
without pulp exposure in patient with anterior edge-to-edge
occlusion.
Fig. 2-11 Abrasion. Horizontal cervical notches on the
anterior mandibular dentition. Note visible pulp canals that
have been ﬁlled with tertiary dentin.
Fig. 2-12 Abrasion. Notching of the right central incisor
caused by improper use of bobby pins. The patient also
exhibits environmental enamel hypoplasia of the anterior
dentition. (Courtesy of Dr. Robert J. Gorlin.)
ABRASION
Abrasion has a variety of patterns, depending on the
cause. Toothbrush abrasion typically appears as hori-
zontal cervical notches on the buccal surface of exposed
radicular cementum and dentin (Fig. 2-11). The defects
usually have sharply deﬁned margins and a hard,
smooth surface. If acid also is present, then the lesions
will be more rounded and shallower. The degree of
loss is greatest on prominent teeth (i.e., cuspids, bicus-
pids, teeth adjacent to edentulous areas) and occasion-
ally is more advanced on the side of the arch opposite
the dominant hand. Thread biting or the use of pipes
or bobby pins usually produces rounded or V-shaped
notches in the incisal edges of anterior teeth (Figs. 2-12
and 2-13). The inappropriate use of dental ﬂoss or
toothpicks results in the loss of interproximal radicular
cementum and dentin. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 63
EROSION
In patients with erosion, the tooth loss does not
correlate with functional wear patterns or with those
typically associated with known abrasives. The pre-
dominant sites of tooth loss appear to correlate closely
with those areas not protected by the serous secretions
of the parotid and submandibular glands. The facial
and palatal surfaces of the maxillary anterior teeth and
the facial and occlusal surfaces of the mandibular pos-
terior teeth are affected most frequently. Involvement
of the lingual surfaces of the entire mandibular denti-
tion is uncommon, possibly because of the protective
buffering capacity of the submandibular serous saliva.
The classic pattern of dental erosion is the cupped
lesion in which a central depression of dentin is sur-
rounded by elevated enamel. Cupped areas are seen
on the occlusal cusp tips, incisal edges, and marginal
ridges (Fig. 2-14). In contrast to abrasion, erosion com-
monly affects the facial surfaces of the maxillary ante-
riors and appears as shallow spoon-shaped depressions
Fig. 2-13 Abrasion. Notching of the anterior dentition on
the right side caused by long-term use of tobacco pipe.
A B
Fig. 2-14 Erosion. Multiple cupped-out depressions
corresponding to the cusp tips.
Fig. 2-15 Erosion. Extensive loss of buccal and occlusal
tooth structure. Note that the amalgam margins are above
the surface of the dentin.
Fig. 2-16 Erosion. Occlusal view of the maxillary dentition
exhibiting concave dentin depressions surrounded by
elevated rims of enamel.
in the cervical portion of the crown. The posterior teeth
frequently exhibit extensive loss of the occlusal surface,
and the edges of metallic restorations subsequently
may be above the level of the tooth structure (Fig.
2-15). After a portion of the cuspal enamel has been
lost, the dentin is destroyed more rapidly than the
remaining enamel, often resulting in a concave depres-
sion of the dentin surrounded by an elevated rim of
enamel (Fig. 2-16). The more rapid dissolution of the
dentin can lead to undermined enamel that often is lost
easily by chipping. Occasionally, entire buccal cusps
are lost and replaced by ski slope–like depressions that
extend from the lingual cusp to the buccal cemento-
enamel junction (Fig. 2-17). When palatal surfaces are
affected, the exposed dentin has a concave surface and
shows a peripheral white line of enamel (Fig. 2-18).
Active erosion typically reveals a clean, unstained
surface, whereas inactive sites become stained and
discolored.
Focal facial tooth wear of the gingival portion has
been given the nonspeciﬁc term, noncarious cervical `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

64 ORAL AND MAXILLOFACIAL PATHOLOGY
lesions, in an attempt to emphasize the multifactorial
nature of the process. These cervical defects often are
seen in association with loss of occlusal tooth structure,
which has features of erosion, attrition, or both.
Erosion limited to the facial surfaces of the maxillary
anterior dentition often is associated with dietary
sources of acid. When the tooth loss is conﬁned to the
incisal portions of the anterior dentition of both arches,
an external environmental source is suggested. When
erosion is located on the palatal surfaces of the maxil-
lary anterior teeth and the occlusal surfaces of the pos-
terior teeth of both dentitions, regurgitation of gastric
secretions is a probable cause. The location of the tooth
structure loss may suggest the cause of the damage but
is not completely reliable.
ABFRACTION
Abfraction appears as wedge-shaped defects limited
to the cervical area of the teeth and may closely resem-
ble cervical abrasion or erosion. Clues to the diagnosis
include defects that are deep, narrow, and V-shaped
(which do not allow the toothbrush to contact the base
of the defect) and often affect a single tooth with adja-
cent unaffected teeth (Fig. 2-19). In addition, occa-
sional lesions are subgingival, a site typically protected
from abrasion and erosion. The lesions predominantly
affect bicuspids and molars, are seen almost exclusively
on the facial surface, and exhibit a much greater preva-
lence in those with bruxism.
In all forms of tooth wear, the process typically pro-
ceeds at a slow rate that allows deposition of tertiary
dentin and prevents pulp exposure, even when exten-
sive loss of tooth structure is present (see Fig. 2-11). In
some cases, and especially in the deciduous dentition,
the tooth loss can proceed at a more accelerated rate
that results in a near or frank exposure of the pulp. In
a large review of 448 patients with tooth wear, 11.6%
revealed near or direct pulp exposure. In addition,
hypersensitivity was the presenting symptom in about
one third of patients with tooth wear.
TREATMENT AND PROGNOSIS
Normal levels of attrition require no therapy, with inter-
vention reserved for those cases that create a pathologic
degree of tooth loss. The presence of advanced tooth
wear in the deciduous dentition appears to correlate
with subsequent tooth wear in adulthood, suggesting a
continuation of the causative inﬂuences. Early diagnosis
and intervention may assist in preserving the perma-
nent dentition. Before any deﬁnitive action, the clinician
must remember that tooth wear almost invariably has a
multifactorial cause. Failure to recognize the interrela-
tionships of these pathoses can lead to inappropriate
therapy and failure of any attempted repair. Interven-
tion should emphasize detailed diagnosis, preventive
measures, and long-term monitoring. Immediate
therapy should be directed toward resolution of tooth
sensitivity and pain, but identifying the causes of tooth
Fig. 2-18 Erosion. Palatal surfaces of the maxillary
dentition in which the exposed dentin exhibits a concave
surface and a peripheral white line of enamel. The patient
had bulimia.
Fig. 2-19 Abfraction. Deep and narrow enamel cervical
defects on the facial surface of the mandibular dentition.
(From Neville BW, Damm DD, White DK: Color atlas of clinical oral
pathology, ed 2, Hamilton, 1999, BC Decker.)
Fig. 2-17 Erosion. Extensive loss of enamel and dentin on
the buccal surface of the maxillary bicuspids. The patient had
sucked chronically on tamarinds (an acidic fruit). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 65
structure loss and protecting the remaining dentition
also are important goals.
In patients affected by dental erosion, preventive
interventions should attempt not only to reduce acid
exposure but also to improve the oral cavity’s ability to
resist the effects of acid. Upon exposure to an acid, the
saliva has the ability to achieve remineralization with
time, but teeth are vulnerable to abrasion before com-
pletion of this action. Investigators have recommended
a minimum 1-hour interval between acid exposure and
toothbrushing in an attempt to minimize abrasion of
the weakened enamel. Patients with erosion should
limit toothbrushing to once a day in the morning
because of the increased vulnerability of acid-etched
enamel to abrasion and attrition. Low-abrasive tooth-
paste and professional guidance to prevent inappropri-
ate, overzealous, or too frequent toothbrushing may
assist in reducing associated abrasion. Consumption of
buffering substances such as milk and cheese also is
thought to be beneﬁcial. Proper hydration is extremely
important to maintain sufﬁcient salivary ﬂow. A sus-
pected common cause of tooth loss is decreased sali-
vary ﬂow secondary to dehydration, often associated
with strenuous work or athletic activities and possibly
complicated by use of acidic soft drinks or sports bever-
ages in the place of water. Chewing gum has been
suggested as a method for decreasing dental erosion by
increasing salivary ﬂow after acid exposure, but others
have demonstrated that enamel softened by acid can
be damaged by the adjacent soft tissues during the
movements of chewing in this time of vulnerability.
Patients should be informed of the potential for loss of
tooth structure associated with the overuse of acidic
foods and drinks (e.g., wine, carbonated beverages,
foods pickled in acetic acid, and citrate-containing
fruits, fruit juices, and candies), chronic regurgitation,
and improper oral hygiene techniques. Mouth guards
and occlusal adjustment can be used to slow nocturnal
attrition and to protect the teeth from frequent expo-
sure to acid from regurgitation or industrial sources.
Dental sensitivity can be reduced through the use of
varnishes, mouthwashes, or toothpastes containing
strontium chloride, stannous ﬂuoride, or monoﬂuoro-
phosphate. If initially unsuccessful, these agents can be
combined with iontophoresis.
Active restorative therapy is premature in the pres-
ence of ongoing tooth wear and should be postponed
until the patient expresses strong aesthetic concerns,
exhibits dental sensitivity that is nonresponsive to con-
servative interventions, or demonstrates progressive
and uncontrollable wear. Once indicated, the minimum
treatment necessary to solve the problem should be
implemented. In lesions thought to represent abfrac-
tion, glass ionomer materials are recommended
because of their greater resilience that allows the mate-
rial to ﬂex with the tooth. In areas of abrasion, a mate-
rial with optimum resistance to the abrasive process
should be chosen. In isolated teeth that continue to lose
Class V restorations, continued abfraction is likely, and
occlusal trauma should be eliminated. Replacement of
lost posterior teeth and avoidance of edge-to-edge
occlusion limit the effects of attrition. Lost tooth struc-
ture can be restored with composite resins, veneers,
onlays, or full crowns. Restorative procedures that do
not involve signiﬁcant removal of remaining tooth
structure are preferable in patients demonstrating
extensive tooth wear.
The body may adapt to loss of tooth structure by
continual eruption of the teeth, appositional alveolar
bone deposition, and compensatory skeletal growth. If
the process of tooth loss is slow, the vertical dimension
often is maintained; in patients with rapid destruction,
a loss of facial length occurs. Restoration of extensive
loss of tooth structure is complex and should be per-
formed only after a complete evaluation of the dento-
alveolar complex.
INTERNAL AND EXTERNAL RESORPTION
In addition to loss of tooth structure that begins on the
exposed coronal surfaces, destruction of teeth also can
occur through resorption, which is accomplished by
cells located in the dental pulp (i.e., internal resorp-
tion) or in the periodontal ligament (PDL) (i.e., exter-
nal resorption). Internal resorption is a relatively rare
occurrence, and most cases develop after injury to
pulpal tissues, such as physical trauma or caries-related
pulpitis. The resorption can continue as long as vital
pulp tissue remains and may result in communication
of the pulp with the PDL.
By contrast, external resorption is extremely com-
mon; with close examination, all patients are most
likely to have root resorption on one or more teeth. In
one radiographic review of 13,263 teeth, all patients
showed evidence of root resorption, and 86.4% of the
examined teeth demonstrated external resorption,
with an average of 16 affected teeth per patient. Most
areas of resorption are mild and of no clinical signiﬁ-
cance, but 10% of patients exhibit unusual amounts of
external resorption.
The potential for resorption is inherent within the
periodontal tissue of each patient, and this individual
susceptibility to resorption is the most important factor
in the degree of resorption that will occur after a stimu-
lus. The factors reported to increase the severity of
external resorption are delineated in Box 2-3. Many
cases have been termed idiopathic because no factor
could be found to explain the accelerated resorption.
When pretreatment radiographs of a given patient
exhibit a degree of resorption beyond that which is
normally seen, the clinician should realize the poten-
tial risks involved in initiating procedures (e.g., ortho- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

66 ORAL AND MAXILLOFACIAL PATHOLOGY
dontics) that are known to be associated with an
increased risk of external resorption.
CLINICAL AND RADIOGRAPHIC
FEATURES
Resorption of dentin or cementum can occur at any site
that contacts vital soft tissue. Internal resorption is
usually asymptomatic and discovered through routine
radiographs. Pain may be reported if the process is
associated with signiﬁcant pulpal inﬂammation. Two
main patterns are seen: (1) inﬂammatory resorption
and (2) replacement or metaplastic resorption (Fig.
2-20). In inﬂammatory resorption, the resorbed dentin
is replaced by inﬂamed granulation tissue. Although
this pattern may involve any portion of the canal, the
cervical zone is affected most frequently (and the
pulpal inﬂammation is usually caused by bacterial
invasion). The resorption continues as long as vital pulp
remains; typically, the coronal pulp is necrotic, with the
apical portion remaining vital. The results of pulp
testing are variable. In this pattern the area of destruc-
tion usually appears as a uniform, well-circumscribed
symmetric radiolucent enlargement of the pulp
chamber or canal. When it affects the coronal pulp, the
crown can display a pink discoloration (pink tooth
of Mummery) as the vascular resorptive process
approaches the surface (Fig. 2-21). When it occurs in
the root, the original outline of the canal is lost and a
balloonlike radiographic dilation of the canal is seen
(Fig. 2-22). If the process continues, the destruction
eventually can perforate the lateral root surface, which
may be difﬁcult to distinguish from external root
resorption (Fig. 2-23). Although most cases are pro-
gressive, some cases are transient and usually arise in
traumatized teeth or those that have recently under-
gone orthodontic or periodontal therapy.
The remaining pattern of internal resorption is
termed replacement or metaplastic resorption. In this form,
portions of the pulpal dentinal walls are resorbed
and replaced with bone or cementum-like bone (see
Fig. 2-20). Radiographically, replacement resorption
appears as an enlargement of the canal, which is ﬁlled
with a material that is less radiodense than the sur-
rounding dentin. Because a central zone of the pulp is
replaced with bone, the radiographic appearance often
demonstrates partial obliteration of the canal. The
outline of destruction is less deﬁned than that seen in
inﬂammatory resorption.
By contrast, external resorption typically appears as
a “moth-eaten” loss of tooth structure in which the
radiolucency is less well deﬁned and demonstrates
variations in density (Figs. 2-24 to 2-27). If the lesion
overlies the pulp canal, then close examination dem-
onstrates the retention of the unaltered canal through
the area of the defect. Most cases involve the apical or
midportions of the root. External resorption can create
signiﬁcant defects in the crowns of teeth before erup-
tion (see Fig. 2-26). This pattern frequently is misdiag-
nosed as preeruptive caries and is thought by some
investigators to be caused by defects in the enamel
epithelium that allow connective tissue to come into
direct contact with the enamel.
In reimplanted avulsed teeth, extensive external
resorption of the root is extremely common without
Box 2-3
Factors Associated with
External Resorption
● Cysts
● Dental trauma
●Excessive mechanical forces (e.g., orthodontic
therapy)
●Excessive occlusal forces
●Grafting of alveolar clefts
● Hormonal imbalances
●Intracoronal bleaching of pulpless teeth
●Local involvement by herpes zoster
●Paget’s disease of bone
● Periodontal treatment
● Periradicular inﬂammation
●Pressure from impacted teeth
●Reimplantation of teeth
● Tumors
InflammatoryReplacement/
metaplastic
Internal resorption External resorption
Fig. 2-20 Tooth resorption. Illustration contrasting the
common patterns of internal and external tooth resorption.
Internal resorption will result in a radiolucent enlargement of
the pulp chamber or canal. In external resorption, the
radiolucency is superimposed on the pulp canal, which
should not be enlarged. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 67
rapid and appropriate intervention (see Fig. 2-25). If
the tooth remains outside of the socket without being
placed in a proper storage medium, then the PDL cells
will undergo necrosis. Without vital PDL cells, the sur-
rounding bone will view the tooth as a foreign object
and initiate resorption and replacement by bone.
External resorption occurring during orthodontics
does not appear to be affected signiﬁcantly by the
patient’s sex or age, the severity of malocclusion, or the
type of mechanics used during therapy. Although the
patient’s individual susceptibility has the strongest
inﬂuence, the single most important skeletodental pre-
dictor is the distance a tooth is moved during therapy.
The maxillary anterior teeth typically are the most
severely affected, particularly in patients who have
been treated with premolar extractions. Movement of
A
B
Fig. 2-21 Internal resorption (pink tooth of Mummery).
A, Pink discoloration of the maxillary central incisor.
B, Radiograph of same patient showing extensive resorption
of both maxillary central incisors.
Fig. 2-22 Internal resorption. Balloonlike enlargement of
the root canal.
Fig. 2-23 Internal resorption. The destruction has resulted
in perforation of the lateral root surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

68 ORAL AND MAXILLOFACIAL PATHOLOGY
teeth with an abnormal root shape such as dilaceration
also has been associated with an increased severity of
external resorption.
Occasionally, external resorption may begin in the
cervical area and extend from a small opening to
involve a large area of the dentin between the cemen-
tum and the pulp. The resorption can extend apically
into the pulp or coronally under the enamel and simu-
late the pink tooth seen in internal resorption. The
Fig. 2-24 External resorption. Extensive irregular
destruction of both roots of the mandibular second molar
associated with chronic periodontitis. (Courtesy of Dr. Tommy
Shimer.)
Fig. 2-25 External resorption. “Moth-eaten” radiolucent
alteration of the maxillary left central incisor. The tooth had
been reimplanted after traumatic avulsion. (Courtesy of Dr. Harry
Meyers.)
Fig. 2-26 External resorption. Extensive external
resorption of the crown of the impacted right maxillary
cuspid. Histopathologic examination revealed resorption
without bacterial contamination or caries.
Fig. 2-27 External resorption. Diffuse external resorption
of radicular dentin of maxillary dentition. This process arose
after initiation of orthodontics. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 69
cervical pattern of external resorption often is rapid
and has been termed invasive cervical resorption. In
some instances, several teeth may be involved, and an
underlying cause for the accelerated destruction may
not be obvious (multiple idiopathic root resorption)
(Fig. 2-28). The exact cause of this pattern of resorption
has been elusive, and it may result from a variety of
inﬂammatory, traumatic, or bacterial stimuli affecting
the clastic cells within the PDL. The process has been
noted after orthodontic therapy, orthognathic surgery,
other dentoalveolar surgery, root scaling or planing,
internal bleaching of endodontically treated teeth,
local trauma, bruxism, and tooth fracture. Other inves-
tigators believe this pattern of resorption can be trig-
gered by periodontal pathogens and have seen good
response to local mechanical débridement combined
with systemic antibiotics.
In addition to invasive cervical resorption, general-
ized and progressive external resorption also can affect
the apical portion of the roots. Although this pattern
can occur secondary to an endocrine disturbance or
one of a small number of systemic conditions, many of
these cases are idiopathic and difﬁcult to arrest.
If difﬁculty arises in distinguishing external from
internal resorption, then the mesial-buccal-distal rule
can be used through two radiographic exposures: one
perpendicular and one mesial (objects closer to the
source of radiation will shift distally). With this tech-
nique, the sites of external resorption appear to shift
away from the pulp canal when the radiographs are
compared. In addition, the radiographs can reveal
which side of the root is affected in cases of external
resorption.
HISTOPATHOLOGIC FEATURES
In patients with internal inﬂammatory resorption, the
pulp tissue in the area of destruction is vascular and
exhibits increased cellularity and collagenization.
Immediately adjacent to the dentinal wall are numer-
ous multinucleated dentinoclasts, which are histologi-
cally and functionally identical to osteoclasts (Fig.
2-29). An inﬂammatory inﬁltrate characterized by lym-
phocytes, histiocytes, and polymorphonuclear leuko-
cytes is not uncommon. In replacement resorption, the
normal pulp tissue is replaced by woven bone that
fuses with the adjacent dentin. External resorption is
similar in appearance, with numerous multinucleated
dentinoclasts located in the areas of structure loss.
Areas of resorption often are repaired through deposi-
tion of osteodentin. In large defects, external inﬂam-
matory resorption results in deposition of inﬂamed
granulation tissue, and areas of replacement with
woven bone may also be seen. Extensive bony re-
placement in areas of external resorption can lead
to ankylosis.
TREATMENT AND PROGNOSIS
The treatment of internal and external resorption
centers on the removal of all soft tissue from the sites
of dental destruction. Internal resorption can be
Fig. 2-28 Multiple idiopathic root resorption. Extensive
invasive cervical resorption of several anterior mandibular
teeth. (Courtesy of Dr. Keith Lemmerman.)
Fig. 2-29 Internal resorption. Resorption of the inner
dentinal wall of the pulp. Note cellular and vascular ﬁbrous
connective tissue, which exhibits an adjacent inﬂammatory
inﬁltrate and numerous dentinoclasts within resorptive
lacunae. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

70 ORAL AND MAXILLOFACIAL PATHOLOGY
stopped consistently if endodontic therapy successfully
removes all vital pulp tissue before the process perfo-
rates into the PDL. Once perforation occurs, therapy
becomes more difﬁcult and the prognosis is poor. In
such cases, initial placement of calcium hydroxide
paste occasionally may result in remineralization of the
site of perforation and stop the resorptive process. If
remineralization of cervical sites of perforation is not
successful, then surgical exposure and restoration of
the defect may halt the process. Extraction often is
necessary for radicular perforations that do not respond
to therapy.
The ﬁrst step in treating external resorption is the
identiﬁcation and elimination of any accelerating
factor. Apically located sites cannot be approached
without signiﬁcant damage created by attempts at
access. Those cases located in the cervical areas can be
treated by surgical exposure, removal of all soft tissue
from the defects, and restoration of the lost structure
of the tooth. Because the cells responsible for the
resorption are located within the PDL, endodontic
therapy is not effective in stopping the process. In one
report of generalized cervical resorption, therapy
directed against local periodontal pathogens (débride-
ment combined with systemic metronidazole and
amoxicillin) stopped the resorption and was associated
with an increased density of the adjacent crestal
bone.
For avulsed teeth, the best way to prevent resorption
is to maintain PDL vitality by immediate reimplanta-
tion or short-term use of a physiologic storage solution.
Teeth reimplanted with an open apex should be moni-
tored monthly; for teeth with a closed apex, endodontic
therapy is necessary. Avulsed teeth with an open apex
and nonvital PDL cells should not be implanted.
ENVIRONMENTAL DISCOLORATION
OF TEETH
The color of normal teeth varies and depends on the
shade, translucency, and thickness of the enamel.
Abnormal colorations may be extrinsic or intrinsic.
Extrinsic stains occur from surface accumulation of an
exogenous pigment and typically can be removed with
a surface treatment, whereas intrinsic discolorations
arise from an endogenous material that is incorporated
into the enamel or dentin and cannot be removed by
prophylaxis with toothpaste or pumice. Box 2-4 lists
the most frequently documented causes of tooth
discolorations.
Dental ﬂuorosis is discussed in the section on envi-
ronmental effects on the structural development of the
teeth (see page 58). The alterations associated with
amelogenesis imperfecta (see page 99) and dentino-
genesis imperfecta (see page 106) are presented later
in this chapter in the text devoted to primary develop-
mental alterations of the teeth.
CLINICAL FEATURES
EXTRINSIC STAINS
Bacterial stains are a common cause of surface stain-
ing of exposed enamel, dentin, and cementum. Chro-
mogenic bacteria can produce colorations that vary
from green or black-brown to orange. The discolor-
ation occurs most frequently in children and is usually
seen initially on the labial surface of the maxillary ante-
rior teeth in the gingival one third. In contrast to most
plaque-related discolorations, the black-brown stains
most likely are not primarily of bacterial origin but are
secondary to the formation of ferric sulﬁde from an
interaction between bacterial hydrogen sulﬁde and
iron in the saliva or gingival crevicular ﬂuid.
Extensive use of tobacco products, tea, or coffee
often results in signiﬁcant brown discoloration of the
surface enamel (Fig. 2-30). The tar within the tobacco
dissolves in the saliva and easily penetrates the pits and
ﬁssures of the enamel. Smokers (of tobacco or mari-
juana) most frequently exhibit involvement of the
lingual surface of the mandibular incisors; users of
smokeless tobacco often demonstrate involvement of
the enamel in the area of tobacco placement. Stains
from beverages also often involve the lingual surface of
the anterior teeth, but the stains are usually more wide-
spread and less intense. In addition, foods that contain
Box 2-4
Tooth Discolorations
EXTRINSIC
● Bacterial stains
● Iron
● Tobacco
●Foods and beverages
● Gingival hemorrhage
● Restorative materials
● Medications
INTRINSIC
● Amelogenesis imperfecta
● Dentinogenesis imperfecta
● Dental ﬂuorosis
● Erythropoietic porphyria
● Hyperbilirubinemia
● Ochronosis
● Trauma
●Localized red blood cell breakdown
● Medications `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 71
abundant chlorophyll can produce a green discolor-
ation of the enamel surface.
The green discoloration associated with chromo-
genic bacteria or the frequent consumption of chloro-
phyll-containing foods can resemble the pattern of
green staining seen secondary to gingival hemor-
rhage. As would be expected, this pattern of discolor-
ation occurs most frequently in patients with poor oral
hygiene and erythematous, hemorrhagic, and enlarged
gingiva. The color results from the breakdown of hemo-
globin into green biliverdin.
A large number of medications may result in
surface staining of the teeth. In the past, use of products
containing high amounts of iron or iodine was associ-
ated with signiﬁcant black pigmentation of the teeth.
Exposure to sulﬁdes, silver nitrate, or manganese can
cause stains that vary from gray to yellow to brown to
black. Copper or nickel may produce a green stain;
cadmium, essential oils, and co-amoxiclav may be asso-
ciated with a yellow to brown discoloration. Multiple
recent reports have documented a yellow-brown stain-
ing of teeth associated with doxycycline, which can be
removed by professional abrasive cleaning; the cause
of this discoloration is unclear.
More recently, the most frequently reported culprits
include stannous ﬂuoride and chlorhexidine. Fluo-
ride staining may be associated with the use of 8%
stannous ﬂuoride and is thought to be secondary to the
combination of the stannous (tin) ion with bacterial
sulﬁdes. This black stain occurs predominantly in
people with poor oral hygiene in areas of a tooth previ-
ously affected by early carious involvement. The labial
surfaces of anterior teeth and the occlusal surfaces
of posterior teeth are the most frequently affected.
Chlorhexidine is associated with a yellow-brown stain
that predominantly involves the interproximal surfaces
near the gingival margins. The degree of staining varies
with the concentration of the medication and the
patient’s susceptibility. Although an increased fre-
quency has been associated with the use of tannin-
containing beverages, such as tea and wine, effective
brushing and ﬂossing or frequent gum chewing can
minimize staining. Chlorhexidine is not alone in its
association with tooth staining; many oral antiseptics,
such as Listerine and sanguinarine, also may produce
similar changes.
INTRINSIC STAINS
Congenital erythropoietic porphyria (Günther dis-
ease) is an autosomal recessive disorder of porphyrin
metabolism that results in the increased synthesis and
excretion of porphyrins and their related precursors.
Signiﬁcant diffuse discoloration of the dentition is
noted as a result of the deposition of porphyrin in the
teeth (Fig. 2-31). Affected teeth demonstrate a marked
red-brown coloration that exhibits a red ﬂuorescence
when exposed to a Wood’s ultraviolet (UV) light. The
deciduous teeth demonstrate a more intense coloration
because porphyrin is present in the enamel and the
dentin; in the permanent teeth, only the dentin
is affected. Excess porphyrins also are present in the
urine, which may reveal a similar ﬂuorescence when
exposed to a Wood’s light.
Another autosomal recessive metabolic disorder,
alkaptonuria, is associated with a blue-black discolor-
ation termed ochronosis that occurs in connective tissue,
tendons, and cartilage. On rare occasions, a blue dis-
coloration of the dentition may be seen in patients who
also are affected with Parkinson’s disease.
Bilirubin is a breakdown product of red blood cells,
and excess levels can be released into the blood in a
number of conditions. The increased amount of
Fig. 2-30 Tobacco discoloration. Extrinsic brown stains of
the enamel on the lingual surfaces of the anterior mandibular
dentition secondary to long-term tobacco abuse.
Fig. 2-31 Erythropoietic porphyria–related discoloration.
Red-brown discoloration of the maxillary dentition. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

72 ORAL AND MAXILLOFACIAL PATHOLOGY
bilirubin can accumulate in the interstitial ﬂuid,
mucosa, serosa, and skin, resulting in a yellow-green
discoloration known as jaundice (see page 821).
During periods of hyperbilirubinemia, developing
teeth also may accumulate the pigment and become
stained intrinsically. In most cases the deciduous teeth
are affected as a result of hyperbilirubinemia during
the neonatal period. The two most common causes are
erythroblastosis fetalis and biliary atresia. Other
diseases that less frequently display intrinsic staining
of this type include the following:
● Premature birth
● ABO incompatibility
●Neonatal respiratory distress
● Signiﬁcant internal hemorrhage
● Congenital hypothyroidism
● Biliary hypoplasia
● Metabolic diseases (tyrosinemia, α1-antitrypsin
deﬁciency)
● Neonatal hepatitis
Erythroblastosis fetalis is a hemolytic anemia of
newborns secondary to a blood incompatibility (usually
Rh factor) between the mother and the fetus. Cur-
rently, this disorder is relatively uncommon because of
the use of antiantigen gamma globulin at delivery in
mothers with Rh-negative blood.
Biliary atresia is a sclerosing process of the biliary
tree and is the leading cause of death from hepatic
failure in children in North America. However,
many affected children live after successful liver
transplantation.
The extent of the dental changes correlates with the
period of hyperbilirubinemia, and most patients exhibit
involvement limited to the primary dentition. Occa-
sionally, the cusps of the permanent ﬁrst molars may
be affected. In addition to enamel hypoplasia, the
affected teeth frequently demonstrate a green discol-
oration (chlorodontia). The color is the result of the
deposition of biliverdin (the breakdown product of bili-
rubin that causes jaundice) and may vary from yellow
to deep shades of green (Fig. 2-32). The color of tooth
structure formed after the resolution of the hyperbili-
rubinemia appears normal. The teeth often demon-
strate a sharp dividing line, separating green portions
(formed during hyperbilirubinemia) from normal-
colored portions (formed after normal levels of biliru-
bin were restored).
Coronal discoloration is a frequent ﬁnding after
trauma, especially in the deciduous dentition. Post-
traumatic injuries may create pink, yellow, or dark-
gray discoloration. Temporary pink discoloration that
arises 1 to 3 weeks after trauma may represent local-
ized vascular damage and often returns to normal in 1
to 3 weeks. In these instances, periapical radiographs
are warranted to rule out internal resorption that may
produce a similar clinical presentation. A yellow dis-
coloration is indicative of pulpal obliteration, termed
calciﬁc metamorphosis, and is discussed more fully
in Chapter 3 (see page 123). The dark-gray discolor-
ation is long-term and occurs in teeth with signiﬁcant
pulpal pathosis in which blood degradation products
have diffused into the dentinal tubules. Endodontic
therapy initiated before or shortly after the total death
of the pulp often prevents the discoloration. The pulpal
necrosis may be aseptic and not associated with signiﬁ-
cant tenderness to percussion, mobility, or associated
periapical inﬂammatory disease. A related process sec-
ondary to localized red blood cell destruction also
can result in discoloration of the teeth. Occasionally,
during a postmortem examination, a pink discoloration
of teeth is found. The crowns and necks of the teeth are
affected most frequently, and the process is thought to
arise from hemoglobin breakdown within the necrotic
pulp tissue in patients in whom blood has accumulated
in the head.
A similar pink or red discoloration of the maxillary
incisors has been reported in living patients with le-
promatous leprosy (see page 198). Although contro-
versial, some investigators believe these teeth are
involved selectively because of the decreased tempera-
ture preferred by the causative organism. This process
is thought to be secondary to infection-related necrosis
and the rupture of numerous small blood vessels within
the pulp, with a secondary release of hemoglobin into
the adjacent dentinal tubules.
Dental restorative materials, especially amalgam,
can result in black-gray discolorations of teeth. This
most frequently arises in younger patients who pre-
sumably have more open dentinal tubules. Large Class
II proximal restorations of posterior teeth can pro-
duce discoloration of the overlying facial surface. In
Fig. 2-32 Hyperbilirubinemia-related discoloration.
Diffuse grayish-blue discoloration of the dentition. Cervical
portions are stained most intensely. (Courtesy of Dr. John Giunta.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 73
addition, deep lingual metallic restorations on anterior
incisors can signiﬁcantly stain underlying dentin and
produce visible grayish discoloration on the labial
surface. To help reduce the possibility of discoloration,
the clinician should not restore endodontically treated
anterior teeth with amalgam (Fig. 2-33).
Several different medications can become incorpo-
rated into the developing tooth and result in clinically
evident discoloration. The severity of the alterations is
dependent on the time of administration, the dose, and
the duration of the drug’s use. The most infamous is
tetracycline, with the affected teeth varying from
bright yellow to dark brown and, in UV light, showing
a bright-yellow ﬂuorescence (Fig. 2-34). After chronic
exposure to ambient light, the ﬂuorescent yellow dis-
coloration fades over months to years into a nonﬂuo-
rescent brown discoloration. Often the facial surfaces
of the anterior teeth will darken while the posterior
dentition and lingual surfaces remain a ﬂuorescent
yellow. The drug and its homologues can cross the
placental barrier; therefore, administration should, if
possible, be avoided during pregnancy and in children
up to 8 years of age. All homologues of tetracycline are
associated with discoloration and include chlortetracy-
cline (gray-brown discoloration) and demethylchlortet-
racycline and oxytetracycline (yellow).
One semisynthetic derivative of tetracycline, mino-
cycline hydrochloride, has been shown to produce
signiﬁcant discoloration of the dentition and also may
affect teeth that are fully developed. Minocycline is a
widely used medication for the treatment of acne and
also is occasionally prescribed to treat rheumatoid
arthritis. Its prevalence of use is increasing (and, pre-
sumably, so will the number of patients affected with
discolored teeth and bone).
Although the mechanism is unknown, minocycline
appears to bind preferentially to certain types of col-
lagenous tissues (e.g., dental pulp, dentin, bone, dermis).
Once in these tissues, oxidation occurs and may
produce the distinctive discoloration. Some investiga-
tors believe supplementation with ascorbic acid (an
antioxidant) can block formation of the discoloration.
No matter the cause, once the pulp tissues are stained,
the coloration can be seen through the overlying trans-
lucent dentin and enamel. The staining is not universal;
only 3% to 6% of long-term users become affected. In
those affected, the period of time before discoloration
becomes evident can range from just 1 month to several
years.
In susceptible individuals, minocycline creates dis-
coloration in the skin, oral mucosa (see page 318),
nails, sclera, conjunctiva, thyroid, bone, and teeth. Col-
oration of the bone occasionally results in a distinctive
blue-gray appearance of the palate, mandibular tori, or
anterior alveolar mucosa, which represents the black
bone showing through the thin, translucent oral mucosa
(see page 317). Several patterns of staining are noted
in the dentition. Fully erupted teeth typically reveal a
blue-gray discoloration of the incisal three fourths,
with the middle one third being maximally involved.
The exposed roots of erupted teeth demonstrate a dark-
green discoloration, although the roots of developing
teeth are stained dark black.
Another antibiotic, ciproﬂoxacin, is given intrave-
nously to infants for Klebsiella spp. infections. Although
less notable than tetracycline, this medication also has
been associated with intrinsic tooth staining, usually a
greenish discoloration.
TREATMENT AND PROGNOSIS
Careful polishing with ﬁne pumice can remove most
extrinsic stains on the teeth; typically, normal prophy-
laxis paste is insufﬁcient. Stubborn stains often are
Fig. 2-33 Amalgam discoloration. Green-gray
discoloration of mandibular central incisor, which had
endodontic access preparation restored with amalgam.
Fig. 2-34 Tetracycline-related discoloration. Diffuse
brownish discoloration of the permanent dentition. (Courtesy of
Dr. John Fantasia.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

74 ORAL AND MAXILLOFACIAL PATHOLOGY
resolved by mixing 3% hydrogen peroxide with the
pumice or by using bicarbonated spray solutions. The
use of jet prophylactic devices with a mild abrasive
is the most effective. Recurrence of the stains is not
uncommon unless the cause is reduced or eliminated.
Improving the level of oral hygiene often minimizes
the chance of recurrence.
Intrinsic discoloration is much more difﬁcult to
resolve because of the frequent extensive involvement
of the dentin. Suggested aesthetic remedies include
external bleaching of vital teeth, internal bleaching of
nonvital teeth, bonded restorations, composite build-
ups, laminate veneer crowns, and full crowns. The
treatment must be individualized to fulﬁll the unique
needs of each patient and his or her speciﬁc pattern of
discoloration.
LOCALIZED DISTURBANCES
IN ERUPTION
IMPACTION
Eruption is the continuous process of movement of a
tooth from its developmental location to its functional
location. Teeth that cease to erupt before emergence
are impacted. Some authors subdivide these non-
erupted teeth into those that are obstructed by a physi-
cal barrier (impacted) and those that appear to exhibit
a lack of eruptive force (embedded). In many cases a
tooth may appear to be embedded; however, on
removal a previously undetected overlying odonto-
genic hamartoma or neoplasm is discovered. There-
fore, it appears appropriate to classify all these teeth
as impacted.
CLINICAL AND RADIOGRAPHIC
FEATURES
Impaction of deciduous teeth is extremely rare; when
seen, it most commonly involves second molars (Fig.
2-35). Analysis of cases suggests that ankylosis plays a
major role in the pathogenesis. In the permanent denti-
tion, the most frequently impacted teeth are the man-
dibular third molar, followed by maxillary third molars
and maxillary cuspids. In decreasing order of fre-
quency, impaction also may occur with mandibular
premolars, mandibular canines, maxillary premolars,
maxillary central incisors, maxillary lateral incisors,
and mandibular second molars. First molars and max-
illary second molars are rarely affected.
Lack of eruption most frequently is caused by crowd-
ing and insufﬁcient maxillofacial development. Proce-
dures that create more space, such as removal of
bicuspids for orthodontic purposes, are associated with
a decreased prevalence of third molar impaction.
Impacted teeth are frequently diverted or angulated
and eventually lose their potential to erupt (on comple-
tion of root development). Other factors known to be
associated with impaction include the following:
●Overlying cysts or tumors
● Trauma
● Reconstructive surgery
●Thickened overlying bone or soft tissue
●A host of systemic disorders, diseases, and
syndromes
Impacted teeth may be partially erupted or com-
pletely encased within the bone (i.e., full bony impac-
tion). In addition, the impaction may be classiﬁed
according to the angulation of the tooth in relationship
to the remaining dentition: mesioangular, distoangular,
vertical, horizontal, or inverted. On occasion, a small
spicule of nonvital bone may be seen radiographically
or clinically overlying the crown of partially erupted
permanent posterior tooth (Fig. 2-36). The process is
termed an eruption sequestrum and occurs when the
osseous fragment becomes separated from the contigu-
ous bone during eruption of the associated tooth. On
occasion, mild sensitivity is noted in the area, espe-
cially during eating.
TREATMENT AND PROGNOSIS
The choices of treatment for impacted teeth include
the following:
● Long-term observation
●Orthodontically assisted eruption
● Transplantation
● Surgical removal
Fig. 2-35 Impaction of deciduous tooth. The right
secondary primary molar demonstrates delayed eruption and
enlarged pericoronal radiolucency. (Courtesy of Dr. G. Thomas
Kluemper.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 75
The presence of infection, nonrestorable carious
lesions, cysts, tumors, or destruction of adjacent tooth
and bone mandates extraction. Surgical removal of
impacted teeth is the procedure performed most fre-
quently by oral and maxillofacial surgeons. The choice
of therapy in asymptomatic cases is an area of hot
debate, and no immediate resolution is obvious. The
risks associated with nonintervention include the
following:
●Crowding of dentition
● Resorption, caries, and worsening of the peri-
odontal status of adjacent teeth (Fig. 2-37)
● Development of pathologic conditions, such as
infections, cysts, and tumors
The risks of intervention include the following:
●Transient or permanent sensory loss
● Alveolitis
● Trismus
● Infection
● Fracture
●Temporomandibular joint (TMJ) injury
● Periodontal injury
●Injury to adjacent teeth
Dental referral patterns provide a variety of per-
spectives of different dental practitioners. Many spe-
cialists (e.g., oral and maxillofacial surgeons, oral and
maxillofacial pathologists) see a large percentage of
signiﬁcant pathologic conditions associated with
impacted teeth compared with the experience of other
clinicians. Although pathology rarely is associated with
impacted teeth in children and young adults, numer-
ous reports have documented an increased prevalence
of problems in the later decades; therefore, any mean-
ingful prospective studies must be lifelong rather than
conﬁned to just a few years. One review of 2646 peri-
coronal lesions submitted to an active oral pathology
service revealed that 32.9% of cases had pathol-
ogically signiﬁcant lesions, with strong relationship
between increasing age and the prevalence of pericoro-
nal pathosis. In this 6-year review were six primary
squamous cell carcinomas arising from dentigerous
cysts in addition to numerous odontogenic keratocysts
and odontogenic tumors. Because of the frequent
occurrence of signiﬁcant pericoronal pathology, spe-
cialists often recommend extraction over close obser-
vation of impacted teeth.
The eruption sequestrum requires no therapy
and usually undergoes spontaneous resorption or
exfoliation.
ANKYLOSIS
Eruption continues after the emergence of the teeth
to compensate for masticatory wear and the growth of
the jaws. The cessation of eruption after emergence is
termed ankylosis and occurs from an anatomic fusion
of tooth cementum or dentin with the alveolar bone.
Although the areas of union may be too subtle to be
detected clinically and radiographically, histopatho-
logic examination will demonstrate fusion between the
affected tooth and the adjacent bone in almost all cases.
Other terms for this process within the literature
include infraocclusion, secondary retention, sub-
mergence, reimpaction, and reinclusion. Secondary
retention is an acceptable term but may be confused
with retained primary teeth, which maintain their emer-
gence. Submergence, reimpaction, and reinclusion connote
an active depression, and this is not the case.
The pathogenesis of ankylosis is unknown and may
be secondary to one of many factors. Disturbances
from changes in local metabolism, trauma, injury,
chemical or thermal irritation, local failure of bone
Fig. 2-36 Eruption sequestrum. A radiopaque fragment of
sequestrating bone can be seen overlying an impacted third
molar.
Fig. 2-37 Impaction-related tooth resorption.
Mesioangular impaction of the right mandibular third molar
associated with signiﬁcant resorption of the distal root of the
second molar. (Courtesy of Dr. Richard Brock.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

76 ORAL AND MAXILLOFACIAL PATHOLOGY
growth, and abnormal pressure from the tongue have
been suggested. The periodontal ligament (PDL) might
act as a barrier that prevents osteoblasts from applying
bone directly onto cementum. Ankylosis could arise
from a variety of factors that result in a deﬁciency of
this natural barrier. Such loss could arise from trauma
or a genetically decreased PDL gap. Other theories
point to a disturbance between normal root resorption
and hard tissue repair. Several investigators believe
genetic predisposition has a signiﬁcant inﬂuence and
point to monozygotic twins who demonstrate strikingly
similar patterns of ankylosis to support this hypothesis.
CLINICAL AND RADIOGRAPHIC
FEATURES
Ankylosis may occur at any age; however, clinically the
condition is most obvious if the fusion develops during
the ﬁrst two decades of life. Most patients reported in
the literature with obvious alterations in occlusion are
between the ages of 7 and 18 years, with a peak pre-
valence occurring in 8- to 9-year-old children. The
reported prevalence of clinically detectable ankylosis
in children varies from 1.3% to 8.9% and has been
reported to be as high as 44% in siblings of those
affected.
Although any tooth may be affected, the most com-
monly involved teeth in order of frequency are the
mandibular primary ﬁrst molar, the mandibular
primary second molar, the maxillary primary ﬁrst
molar, and the maxillary primary second molar. Anky-
losis of permanent teeth is uncommon. In the decidu-
ous dentition, mandibular teeth are affected 10 times
as often as the maxillary dentition. The occlusal plane
of the involved tooth is below that of the adjacent denti-
tion (infraocclusion) in a patient with a history of previ-
ous full occlusion (Fig. 2-38). A sharp, solid sound may
be noted on percussion of the involved tooth but can
be detected only when more than 20% of the root is
fused to the bone. Radiographically, absence of the
PDL space may be noted; however, the area of fusion
is often in the bifurcation and interradicular root
surface, making radiographic detection most difﬁcult
(Fig. 2-39).
Ankylosed teeth that are allowed to remain in posi-
tion can lead to a number of dental problems. The
adjacent teeth often incline toward the affected tooth,
frequently with the development of subsequent occlu-
sal and periodontal problems. In addition, the oppos-
ing teeth often exhibit overeruption. Occasionally, the
ankylosed tooth leads to a localized deﬁciency of the
alveolar ridge or impaction of the underlying perma-
nent tooth. An increased frequency of lateral open bite
and crossbite is seen.
TREATMENT AND PROGNOSIS
Because they are fused to the adjacent bone, ankylosed
teeth fail to respond to normal orthodontic forces, with
attempts to move the ankylosed tooth occasionally
resulting in intrusion of the anchor teeth. Recom-
mended therapy for ankylosis of primary molars is vari-
able and often is determined by the severity and timing
of the process. When an underlying permanent succes-
sor is present, extraction of the ankylosed primary
molar should not be performed until it becomes obvious
that exfoliation is not proceeding normally or adverse
occlusal changes are developing. After extraction of an
ankylosed molar, the permanent tooth will erupt spon-
taneously in the majority of cases. In permanent teeth
or primary teeth without underlying successors, pros-
thetic buildup can be placed to augment the occlusal
height. Severe cases in primary teeth are treated best
with extraction and space maintenance. Luxation of
Fig. 2-38 Ankylosis. Deciduous molar well below the
occlusal plane of the adjacent teeth.
Fig. 2-39 Ankylosis. Radiograph of an ankylosed deciduous
molar. Note the lack of periodontal ligament (PDL) space. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 77
affected permanent teeth may be attempted with
extraction forceps in an effort to break the ankylosis. It
is hoped that the subsequent inﬂammatory reaction
results in the formation of a new ﬁbrous ligament in
the area of previous fusion. In these cases, reevaluation
in 6 months is mandatory. Finally, several reports have
documented successful repositioning of an ankylosed
permanent tooth with a combination of orthodontics,
segmental osteotomy, and distraction osteogenesis.
Developmental Alterations
of Teeth
Numerous developmental alterations of teeth can
occur. Box 2-5 delineates the major reported altera-
tions, and the following text pertains to these entities.
These alterations may be primary or arise secondary to
environmental inﬂuences (e.g., concrescence, hyperce-
mentosis, dilaceration). For the sake of convenience,
both the primary and the environmental forms will be
discussed together.
DEVELOPMENTAL ALTERATIONS IN
THE NUMBER OF TEETH
Variations in the number of teeth that develop are
common. Several terms are useful in the discussion of
the numeric variations of teeth. Anodontia refers to a
total lack of tooth development. Hypodontia denotes
the lack of development of one or more teeth; oligo-
dontia (a subdivision of hypodontia) indicates the lack
of development of six or more teeth. Hyperdontia
is the development of an increased number of teeth,
and the additional teeth are termed supernumerary.
Terms such as partial anodontia are oxymorons and
should be avoided. In addition, these terms pertain to
teeth that failed to develop and should not be applied
to teeth that developed but are impacted or have been
removed.
Genetic control appears to exert a strong inﬂuence
on the development of teeth. Hypodontia and hyper-
dontia have been noted in patients with a variety of
syndromes (Boxes 2-6 and 2-7). In all of these syn-
dromes, an increased prevalence of hypodontia or
hyperdontia exists, but the strength of the association
varies. Furthermore, the actual genetic contribution to
the increased or decreased number of teeth may be
unclear in some of these conditions. In addition to
these syndromes, an increased prevalence of hypodon-
tia is noted in patients with nonsyndromic cleft lip (CL)
or cleft palate (CP).
Genetic inﬂuences still may affect nonsyndromic
numeric alterations of teeth, because more than 200
genes are known to play a role in odontogenesis.
Because of the complexity of the system, variations in
tooth number arise in a wide variety of patterns. A large
percentage of primary hypodontia cases appear to
be inherited in an autosomal dominant fashion, with
incomplete penetrance and variable expressivity,
whereas a minority of examples present an autosomal
recessive or sex-linked pattern. The environment is not
without its inﬂuence, with occasional examples sug-
gesting multifactorial inheritance. Several investigators
have reported variable expression of hypodontia in
monozygotic twins (conﬁrmed by DNA ﬁngerprinting).
This discordance conﬁrms the occasional multifacto-
rial nature of the process. Overall, hypodontia most
likely represents a variety of disorders caused by vari-
able genetic and epigenetic factors.
Research has identiﬁed a gene mutation in only a
small percentage of nonsyndromic hypodontia cases.
Although this list will continue to lengthen over time,
the currently implicated genes include the PAX9 gene,
the MSX1 gene, the AXIN2 gene, and He-Zhao deﬁ-
ciency, which is associated with an unknown gene
that maps to chromosome 10q11.2. Although variable
expressivity is common, most of these examples
Box 2-5
Developmental Alterations of Teeth
NUMBER
● Hypodontia
● Hyperdontia
SIZE
● Microdontia
● Macrodontia
SHAPE
● Gemination
● Fusion
● Concrescence
● Accessory cusps
● Dens invaginatus
● Ectopic enamel
● Taurodontism
● Hypercementosis
● Accessory roots
● Dilaceration
STRUCTURE
● Amelogenesis imperfecta
● Dentinogenesis imperfecta
●Dentin dysplasia type I
●Dentin dysplasia type II
● Regional odontodysplasia `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

78 ORAL AND MAXILLOFACIAL PATHOLOGY
represent oligodontia and exhibit numerous missing
teeth. Interestingly, the affected gene tends to correlate
to the pattern of missing teeth. It must be stressed that
these genes are involved in only a very small number
of affected patients with hypodontia, and the genetic
basis for the vast majority of hypodontia cases remains
elusive.
Less information is available on the genetics of
hyperdontia; however, like hypodontia, almost every
possible pattern of inheritance has been suggested. In
all likelihood, many cases are multifactorial and arise
from a combination of genetics and environmental
inﬂuences. In spite of this, studies on certain kindreds
have suggested an autosomal dominant pattern of
inheritance with incomplete penetrance, autosomal
recessive inheritance with lesser penetrance in females,
and X-linked inheritance.
Some investigators have implied that hypodontia is
a normal variant, suggesting that humans are in an
intermediate stage of dentitional evolution. A proposed
future dentition would contain one incisor, one canine,
one premolar, and two molars per quadrant. Con-
versely, others have suggested that hyperdontia repre-
sents atavism—the reappearance of an ancestral
condition. The latter hypothesis is difﬁcult to accept
because some patients have had as many as four pre-
molars in one quadrant, a situation that has never been
reported in other mammals. The most widely accepted
theory is that hyperdontia is the result of a localized
and independent hyperactivity of dental lamina.
In contrast, hypodontia correlates with the absence
of appropriate dental lamina. As discussed, the loss of
the developing tooth buds in most instances appears to
be genetically controlled. In spite of this, the environ-
ment most likely inﬂuences the ﬁnal result or, in some
cases, may be responsible completely for the lack of
tooth formation. The dental lamina is extremely sensi-
tive to external stimuli, and damage before tooth for-
mation can result in hypodontia. Trauma, infection,
radiation, chemotherapeutic medications, endocrine
disturbances, and severe intrauterine disturbances
have been associated with missing teeth.
Box 2-6
Syndromes Associated with Hypodontia
● Ankyloglossia superior
● Böök
● Cockayne
● Cofﬁn-Lowry
● Cranio-oculo-dental
● Crouzon
● Down
● Ectodermal dysplasia
●Ectodermal dysplasia, cleft lip, cleft palate
● Ehlers-Danlos
● Ellis-van Creveld
●Focal dermal hypoplasia
● Freire-Maia
● Frontometaphyseal dysplasia
● Goldenhar
● Gorlin
● Gorlin-Chaudhry-Moss
● Hallermann-Streiff
● Hanhart
● Hurler
● Hypoglossia-hypodactylia
● Incontinentia pigmenti
● Johanson-Blizzard
● Lipoid proteinosis
● Marshall-White
● Melanoleukoderma
● Monilethrix-anodontia
●Oral-facial-digital type I
● Otodental dysplasia
●Palmoplantar keratosis, hypotrichosis, cysts of eyelid
● Progeria
● Rieger
● Robinson
● Rothmund-Thomson
● Sturge-Weber
● Tooth-and-nail
● Turner
Box 2-7
Syndromes Associated with Hyperdontia
● Apert
● Angio-osteohypertrophy
● Cleidocranial dysplasia
● Craniometaphyseal dysplasia
● Crouzon
● Curtius
● Down
● Ehlers-Danlos
● Ellis-van Creveld
● Fabry-Anderson
● Fucosidosis
● Gardner
● Hallermann-Streiff
● Incontinentia pigmenti
● Klippel-Trénaunay-Weber
● Laband
● Leopard
● Nance-Horan
●Oral-facial-digital types I and III
● Sturge-Weber
● Tricho-rhino-phalangeal `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 79
CLINICAL FEATURES
HYPODONTIA
Failure of teeth to form is one of the most common
dental developmental abnormalities, with a reported
prevalence of 1.6% to 9.6% in permanent teeth when
absence of third molars is excluded. The prevalence
increases to 20% if third molars are considered.
A female predominance of approximately 1.5:1 is
reported. Anodontia is rare, and most cases occur in
the presence of hereditary hypohidrotic ectodermal
dysplasia (see page 741). Indeed, when the number
of missing teeth is high or involves the most stable
teeth (i.e., maxillary central incisors, ﬁrst molars), the
patient should be evaluated for ectodermal dysplasia.
Hypodontia is uncommon in the deciduous dentition,
with a prevalence that ranges from 0.5% to 0.9% and,
when present, most frequently involves the lateral inci-
sors. Absence of a deciduous tooth is associated strongly
with an increased prevalence of a missing successor.
Missing teeth in the permanent dentition are not rare,
with third molars being the most commonly affected.
After the molars, the second premolars and lateral inci-
sors are absent most frequently (Fig. 2-40). Hypodontia
is associated positively with microdontia (see page 83),
reduced alveolar development, increased freeway
space, and retained primary teeth (Fig. 2-41). In whites
with missing teeth, approximately 80% will demon-
strate loss of only one or two teeth.
Mutation of the PAX9 gene creates an autosomal
dominant pattern of oligodontia that can involve
various teeth but most commonly affects most of the
permanent molars. In severe cases, loss of the primary
molars, second premolars, and permanent mandibular
central incisors also may be seen. Mutation of the
MSX1 gene also is inherited as an autosomal dominant
trait. Those affected with this mutation tend to demon-
strate loss of the distal tooth of each type, with more
severely affected individuals also revealing anterior
progression of the agenesis. In these patients the most
commonly missing teeth are the second premolars and
third molars. In more severe cases, often the maxillary
ﬁrst premolars and maxillary lateral incisors also are
missing. With the MSX1 mutation, the degree of oligo-
dontia is severe, with an average of approximately 12
missing teeth per patient. The He-Zhao deﬁciency
arose in a large kindred from northwest China and
includes a highly variable pattern of missing teeth that
occurs only in the permanent dentition. The missing
teeth may affect the entire dentition, but the condition
most commonly involves the third molars, second pre-
molars, and maxillary lateral incisors.
For dentists and their patients, the most critical dis-
covery related to hypodontia revolves around the muta-
tion of the AXIN2 gene. This pattern of oligodontia is
inherited as an autosomal dominant disorder, with the
most commonly missing teeth being the permanent
Fig. 2-40 Hypodontia. Developmentally missing maxillary
lateral incisors. Radiographs revealed no underlying teeth,
and there was no history of trauma or extraction.
A
B
Fig. 2-41 Hypodontia. A, Multiple developmentally
missing permanent teeth and several retained deciduous
teeth in a female adult. B, The panoramic radiograph shows
no unerupted teeth in either jaw. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

80 ORAL AND MAXILLOFACIAL PATHOLOGY
second and third molars, second premolars, lower inci-
sors, and maxillary lateral incisors. The maxillary
central incisors always are present and usually accom-
panied by the canines, ﬁrst premolars, and ﬁrst molars.
However, the number and type of missing teeth are
highly variable, a typical ﬁnding of inheritable oligo-
dontia. Although the missing teeth can produce a sig-
niﬁcant oral problem, the presence of the AXIN2
mutation in these kindreds also has been associated
with development of adenomatous polyps of the colon
and colorectal carcinoma. This suggests that patients
with similar examples of oligodontia should be ques-
tioned closely for a family history of colon cancer, with
further medical evaluation recommended for those
possibly at risk.
Even in kindreds with an obviously inherited pattern
of hypodontia or oligodontia, it must be stressed that,
in the majority of the cases, the genes are yet to be dis-
covered. The most common form of inherited hypodon-
tia is an autosomal dominant pattern in which the
average number of missing teeth is slightly more than
two. Excluding the third molars, the most commonly
missing teeth in these cases are the lower second pre-
molars, upper second premolars, maxillary lateral inci-
sors, and lower central incisors.
HYPERDONTIA
The prevalence of supernumerary permanent teeth in
whites is between 0.1% and 3.8%, with a slightly higher
rate seen in Asian populations. The frequency in the
deciduous dentition is much lower and varies from
0.3% to 0.8%. Approximately 76% to 86% of cases rep-
resent single-tooth hyperdontia, with two supernu-
merary teeth noted in 12% to 23%, and three or more
extra teeth noted in less than 1% of cases. Single-tooth
hyperdontia occurs more frequently in the permanent
dentition, and approximately 95% present in the
maxilla, with a strong predilection for the anterior
region. The most common site is the maxillary incisor
region, followed by maxillary fourth molars and man-
dibular fourth molars, premolars, canines, and lateral
incisors (Fig. 2-42). Supernumerary mandibular inci-
sors are very rare. Although supernumerary teeth may
be bilateral, most occur unilaterally (Figs. 2-43 and
2-44). In contrast to single-tooth hyperdontia, non-
syndromic multiple supernumerary teeth occur most
frequently in the mandible. These multiple supernu-
merary teeth occur most often in the premolar region,
followed by the molar and anterior regions, respec-
tively (Fig. 2-45).
Although most supernumerary teeth occur in the
jaws, examples have been reported in the gingiva, max-
illary tuberosity, soft palate, maxillary sinus, spheno-
maxillary ﬁssure, nasal cavity, and between the orbit
and the brain. The eruption of accessory teeth is
Fig. 2-42 Hyperdontia (mesiodens). Erupted
supernumerary, rudimentary tooth of the anterior maxilla.
Fig. 2-43 Hyperdontia (mesiodens). Unilateral
supernumerary tooth of the anterior maxilla, which has
altered the eruption path of the maxillary right permanent
central incisor.
Fig. 2-44 Hyperdontia (mesiodens). Bilateral inverted
supernumerary teeth of the anterior maxilla. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 81
variable and dependent on the degree of space avail-
able; 75% of supernumerary teeth in the anterior
maxilla fail to erupt. Unlike hypodontia, hyperdontia
is positively correlated with macrodontia (see page 83)
and exhibits a 2:1 male predominance. Although
examples may be identiﬁed in older adults, most super-
numerary teeth develop during the ﬁrst two decades
of life.
Several terms have been used to describe supernu-
merary teeth, depending on their location. A supernu-
merary tooth in the maxillary anterior incisor region is
termed a mesiodens (see Fig. 2-42); an accessory
fourth molar is often called a distomolar or distodens.
A posterior supernumerary tooth situated lingually or
buccally to a molar tooth is termed a paramolar (Fig.
2-46).
Supernumerary teeth are divided into supplemen-
tal (normal size and shape) or rudimentary (abnormal
shape and smaller size) types. Rudimentary super-
numerary teeth are classiﬁed further into conical
(small, peg-shaped), tuberculate (barrel-shaped ante-
rior with more than one cusp), and molariform (small
premolar-like or molarlike). Although odontomas are
considered hamartomas and could be placed within
this classiﬁcation, these lesions traditionally are in-
cluded in the list of odontogenic neoplasms and are dis-
cussed in Chapter 15 (page 724). The conical mesiodens
represents one of the more common supernumerary
teeth and can erupt spontaneously, whereas tubercu-
late examples are less frequent and rarely erupt.
Occasionally, normal teeth may erupt into an inap-
propriate position (e.g., a canine present between
two premolars). This pattern of abnormal eruption is
called dental transposition. Such misplaced teeth
have been confused with supernumerary teeth; but in
reality, patients exhibiting dental transposition have
been reported to exhibit an increased prevalence of
hypodontia, not hyperdontia. The teeth involved most
frequently in transposition are the maxillary canines
and ﬁrst premolars. Crowding or malocclusion of these
normal teeth may dictate reshaping, orthodontics, or
extraction.
Accessory teeth may be present at or shortly after
birth. Historically, teeth present in newborns have
been called natal teeth; those arising within the ﬁrst
30 days of life are designated neonatal teeth. This is
an artiﬁcial distinction, and it appears appropriate to
call all of these teeth natal teeth (Fig. 2-47). Although
some authors have suggested that these teeth may rep-
resent predeciduous supernumerary teeth, most are
prematurely erupted deciduous teeth (not supernu-
merary teeth). Approximately 85% of natal teeth are
mandibular incisors, 11% are maxillary incisors, and
4% are posterior teeth.
Fig. 2-45 Hyperdontia. Right mandibular dentition
exhibiting four erupted bicuspids.
A B
Fig. 2-46 Paramolar. A, Rudimentary tooth situated palatal to a maxillary molar in a patient
who also exhibits hypodontia. B, Radiograph of the same patient showing a fully formed tooth
overlying the crown of the adjacent molar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

82 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
Sequelae associated with hypodontia include abnor-
mal spacing of teeth, delayed tooth formation, delayed
deciduous tooth exfoliation, late permanent tooth erup-
tion, and altered dimension of the associated gnathic
regions. The management of the patient with hypodon-
tia depends on the severity of the case. No treatment
may be required for a single missing tooth; prosthetic
replacement often is needed when multiple teeth are
absent. Therapeutic options include removable partial
dentures, traditional ﬁxed prosthodontics, resin-
bonded bridges, or osseointegrated implants with asso-
ciated prosthetic crowns. Use of ﬁxed prosthodontics
typically is not recommended for children because of
the risk of pulp exposure during abutment preparation
and because further growth can lead to infraocclusion
and ankylosis of teeth held together by the prosthesis.
Likewise, because implants act more like ankylosed
teeth than erupting teeth, their use is not recommended
before completion of skeletal growth except for patients
with anodontia. For these reasons, a removable appli-
ance or resin-bonded bridge often is appropriate in
children and young adults while waiting for full dental
and skeletal maturation.
In some cases of hypodontia, orthodontic therapy
may improve the restorative treatment or even negate
its need in selected patients. Patients with oligodontia
exhibit an increased prevalence of orthodontics-
associated external root resorption. This may be due to
the altered root anatomy or to the extensive tooth
movement that is required in some patients. Follow-up
radiographs are recommended after 6 to 9 months of
therapy to evaluate the root morphology for evidence
of excessive resorption.
The presence of supernumerary teeth should be sus-
pected if a signiﬁcant delay is observed in the eruption
of a localized portion of the dentition. Because of the
decreased clarity in the anterior portion of a panoramic
radiograph, this image should be combined with occlu-
sal and periapical radiographs to fully visualize the
area. Supernumerary teeth may develop long after
eruption of the permanent dentition. Several publica-
tions have documented supernumerary bicuspids
arising up to 11 years after completion of normal teeth
development. In patients previously diagnosed with
supernumerary teeth, or in those genetically predis-
posed, long-term monitoring for additional tooth devel-
opment is warranted.
Early diagnosis and treatment often are crucial in
minimizing the aesthetic and functional problems of
the adjacent teeth. Because only 7% to 20% of supernu-
merary teeth exist without clinical complications, the
standard of care is removal of the accessory tooth
during the time of the early mixed dentition. Complica-
tions created by anterior supernumerary teeth tend to
be more signiﬁcant than those associated with extra
teeth in the posterior regions. Reports have docu-
mented spontaneous eruption of the adjacent dentition
in 75% of the cases if the supernumerary tooth is
removed early. After removal of the supernumerary
tooth, full eruption typically occurs within 18 months
to 3 years. Impacted permanent teeth having closed
apices or those associated with a tuberculate mesiodens
may show a reduced tendency for spontaneous erup-
tion. Permanent teeth that fail to erupt are treated
best by surgical exposure with orthodontic eruption.
Removal of unerupted deciduous teeth is not recom-
mended, because most will erupt spontaneously.
A consequence of late therapy may include the
delayed eruption, resorption of the adjacent teeth, dis-
placement of the teeth with associated crowding, dilac-
eration, malocclusion, diastema formation, or eruption
into the nasal cavity. Supernumerary teeth also predis-
pose the area to subacute pericoronitis, gingivitis, peri-
odontitis, abscess formation, and the development of
any one of a large number of odontogenic cysts and
tumors. In selected cases, clinical judgment may not
dictate surgical removal, or patient resistance to therapy
may be present. In these instances, regular monitoring
is appropriate.
Natal teeth must be approached individually, with
sound clinical judgment guiding appropriate therapy.
As stated, the erupted teeth in most cases represent the
deciduous dentition, and removal should not be per-
formed hastily. If the teeth are mobile and at risk for
aspiration, then removal is indicated. If mobility is not
a problem and the teeth are stable, then they should
be retained. Traumatic ulcerations of the adjacent soft
tissue (Riga-Fede disease) (see page 287) may occur
during breast-feeding but often can be resolved with
appropriate measures.
Fig. 2-47 Natal teeth. Mandibular central incisors that
were erupted at birth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 83
DEVELOPMENTAL ALTERATIONS IN
THE SIZE OF TEETH
Tooth size is variable among different races and
between the sexes. The presence of unusually small
teeth is termed microdontia; the presence of teeth
larger than average is termed macrodontia. Although
heredity is the major factor, both genetic and environ-
mental inﬂuences affect the size of developing teeth.
The deciduous dentition appears to be affected more
by maternal intrauterine inﬂuences; the permanent
teeth seem to be more affected by environment.
CLINICAL FEATURES
Although the size of teeth is variable, the two sides of
the jaws are usually symmetrical. Despite this, when
signiﬁcant size variation is present, the entire dentition
rarely is affected. Typically, only a few teeth are altered
signiﬁcantly in size. Differences in tooth sizes cannot
be considered in isolation. Microdontia is associated
strongly with hypodontia (see page 79); macrodontia
often is seen in association with hyperdontia (see page
80). Females demonstrate a higher frequency of micro-
dontia and hypodontia; males have a greater preva-
lence of macrodontia and hyperdontia.
MICRODONTIA
The term microdontia should be applied only when
the teeth are physically smaller than usual. Normal-
sized teeth may appear small when widely spaced
within jaws that are larger than normal. This appear-
ance has been historically termed relative microdon-
tia, but it represents macrognathia (not microdontia).
Diffuse true microdontia is uncommon but may occur
as an isolated ﬁnding in Down syndrome, in pituitary
dwarﬁsm, and in association with a small number of
rare hereditary disorders that exhibit multiple abnor-
malities of the dentition (Fig. 2-48).
Isolated microdontia within an otherwise normal
dentition is not uncommon. The maxillary lateral
incisor is affected most frequently and typically appears
as a peg-shaped crown overlying a root that often is of
normal length (Fig. 2-49). The mesiodistal diameter is
reduced, and the proximal surfaces converge toward
the incisal edge. The reported prevalence varies from
0.8% to 8.4% of the population, and the alteration
appears to be autosomal dominant with incomplete
penetrance. In addition, isolated microdontia often
affects third molars. Interestingly, the maxillary lateral
incisors and the third molars are among the most
frequent teeth to be congenitally missing. When a
peg-shaped tooth is present, the remaining perma-
nent teeth often exhibit a slightly smaller mesiodistal
size.
MACRODONTIA
Analogous to microdontia, the term macrodontia
(megalodontia, megadontia) should be applied only
when teeth are physically larger than usual and should
not include normal-sized teeth crowded within a small
jaw (previously termed relative macrodontia). In
addition, the term macrodontia should not be used to
describe teeth that have been altered by fusion or gem-
ination. Diffuse involvement is rare, and typically only
a few teeth are abnormally large. Diffuse macrodontia
has been noted in association with pituitary gigantism
(see page 831), otodental syndrome, XYY males, and
pineal hyperplasia with hyperinsulinism. Macrodontia
with unilateral premature eruption is not rare in
hemifacial hyperplasia (see page 38). Authors have
postulated that the unilateral bone growth resulting
from this condition may also affect developing teeth on
the altered side. Isolated macrodontia is reported to
Fig. 2-48 Diffuse microdontia. Dentition in which the
teeth are smaller than normal and widely spaced within the
arch.
Fig. 2-49 Isolated microdontia (peg lateral). Small, cone-
shaped right maxillary lateral incisor. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

84 ORAL AND MAXILLOFACIAL PATHOLOGY
occur most frequently in incisors or canines but also
has been seen in second premolars and third molars.
In such situations, the alteration often occurs
bilaterally.
TREATMENT AND PROGNOSIS
Treatment of the dentition is not necessary unless
desired for aesthetic considerations. Maxillary peg
laterals often are restored to full size by porcelain
crowns.
DEVELOPMENTAL ALTERATIONS IN
THE SHAPE OF TEETH
GEMINATION, FUSION, AND
CONCRESCENCE
Double teeth (connated teeth, conjoined teeth) are two
separate teeth exhibiting union by dentin and (perhaps)
their pulps. The union may be the result of fusion of
two adjacent tooth buds or the partial splitting of one
into two. The development of isolated large or joined
(i.e., double) teeth is not rare, but the literature is con-
fusing when the appropriate terminology is presented.
Historically, gemination was deﬁned as an attempt of a
single tooth bud to divide, with the resultant formation
of a tooth with a biﬁd crown and, usually, a common
root and root canal. Conversely, fusion was considered
the union of two normally separated tooth buds with
the resultant formation of a joined tooth with conﬂu-
ence of dentin. Finally, concrescence was the union of
two teeth by cementum without conﬂuence of the
dentin.
Many investigators have found these deﬁnitions
confusing and open to debate. A double tooth found in
the place of a maxillary permanent central incisor is a
good example of the controversy. If the joined tooth is
counted as one and the tooth number is correct, then
the anomaly could result from the division of a single
tooth bud or the fusion of the permanent tooth bud
with the bud of an adjacent mesiodens. Some have
suggested that the terms gemination, fusion, and concres-
cence should be discontinued, and all of these anoma-
lies should be termed twinning. This also is confusing
because other investigators use twinning to refer to the
development of two separate teeth that arose from the
complete separation of one tooth bud (this also is
arguable).
Because of this confusion in terminology, the use of
the term twinning cannot be recommended. Extra teeth
are termed supernumerary, and another name is not
necessary. Even though the exact pathogenesis may be
questionable in some cases (whether caused by fusion
of adjacent buds or partial split of one bud), the terms
gemination, fusion, and concrescence serve a useful
purpose because they are the most descriptive of the
clinical presentation. Gemination is deﬁned as a single
enlarged tooth or joined (i.e., double) tooth in which
the tooth count is normal when the anomalous tooth is
counted as one. Fusion is deﬁned as a single enlarged
tooth or joined (i.e., double) tooth in which the tooth
count reveals a missing tooth when the anomalous
tooth is counted as one. Concrescence is union of two
adjacent teeth by cementum alone, without conﬂuence
of the underlying dentin. Unlike fusion and gemina-
tion, concrescence may be developmental or postin-
ﬂammatory. When two teeth develop in close proximity,
developmental union by cementum is possible. In
addition, areas of inﬂammatory damage to the roots of
teeth are repaired by cementum once the inciting
process resolves. Concrescence of adjacent teeth may
arise in initially separated teeth in which cementum
deposition extends between two closely approximated
roots in a previous area of damage.
CLINICAL FEATURES
GEMINATION AND FUSION
Double teeth (gemination and fusion) occur in both
the primary and the permanent dentitions, with a
higher frequency in the anterior and maxillary regions
(Figs. 2-50 to 2-54). In the permanent dentition, the
prevalence of double teeth in whites is approximately
0.3% to 0.5%, whereas the frequency in deciduous teeth
is greater, with a reported prevalence from 0.5% to
2.5%. Asian populations tend to demonstrate a higher
occurrence that exceeds 5% in some studies. In both
dentitions, incisors and canines are the most com-
monly affected teeth. Involvement of posterior primary
teeth, premolars, and permanent molars also can occur.
Fig. 2-50 Bilateral gemination. Two double teeth. The
tooth count was normal when each anomalous tooth was
counted as one. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 85
Gemination is more common in the maxilla, whereas
fusion tends to occur more frequently in the mandible.
Bilateral cases are uncommon (Fig. 2-55).
Gemination and fusion appear similar and may be
differentiated by assessing the number of teeth in the
dentition. Some authors have suggested that gemina-
tion demonstrates a single root canal. Separate canals
are present in fusion, but this does not hold true in all
cases (Fig. 2-56). A variety of appearances are noted
with both fusion and gemination. The processes may
result in an otherwise anatomically correct tooth that
is greatly enlarged. A biﬁd crown may be seen overly-
ing two completely separated roots, or the joined
crowns may blend into one enlarged root with a single
canal.
CONCRESCENCE
Concrescence is two fully formed teeth, joined along
the root surfaces by cementum. The process is noted
more frequently in the posterior and maxillary regions.
The developmental pattern often involves a second
molar tooth in which its roots closely approximate the
adjacent impacted third molar (Fig. 2-57). The postin-
ﬂammatory pattern frequently involves carious molars
Fig. 2-51 Gemination. Mandibular bicuspid exhibiting biﬁd
crown.
Fig. 2-52 Gemination. Same patient as depicted in Fig.
2-51. Note the biﬁd crown and shared root canal.
Fig. 2-53 Fusion. Double tooth in the place of the
mandibular right lateral incisor and cuspid.
Fig. 2-54 Fusion. Radiographic view of double tooth in the
place of the mandibular central and lateral incisors. Note
separate root canals. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

86 ORAL AND MAXILLOFACIAL PATHOLOGY
in which the apices overlie the roots of horizontally or
distally angulated third molars. This latter pattern most
frequently arises in a carious tooth that exhibits large
coronal tooth loss. The resultant large pulpal exposure
often permits pulpal drainage, leading to a resolution
of a portion of the intrabony pathosis. Cemental repair
then occurs (Figs. 2-58 and 2-59).
TREATMENT AND PROGNOSIS
The presence of double teeth (i.e., gemination or fusion)
in the deciduous dentition can result in crowding,
abnormal spacing, and delayed or ectopic eruption of
the underlying permanent teeth. When detected, the
progression of eruption of the permanent teeth should
be monitored closely by careful clinical and radio-
graphic observation. When appropriate, extraction
may be necessary to prevent an abnormality in erup-
tion. Occasionally, fusion in the primary dentition is
associated with absence of the underlying permanent
successor.
Several approaches are available for the treatment
of joined teeth in the permanent dentition, and the
treatment of choice is determined by the patient’s par-
ticular needs. Rare reports of successful surgical divi-
sion have been documented. In most cases of surgical
division, endodontic therapy was performed. Selected
shaping with or without placement of full crowns has
been used in many cases. Other patients exhibit pulpal
or coronal anatomic features that are resistant to
reshaping and require surgical removal with prosthetic
replacement. Double teeth often will demonstrate a
pronounced labial or lingual groove that may be prone
to develop caries. In such cases, placement of a ﬁssure
sealant or composite restoration is appropriate if the
tooth is to be retained.
Patients with concrescence often require no therapy
unless the union interferes with eruption; then surgical
removal may be warranted. Postinﬂammatory concres-
cence must be kept in mind whenever extraction is
planned for nonvital teeth with apices that overlie the
roots of an adjacent tooth. Signiﬁcant extraction difﬁ-
culties can be experienced on attempted removal of a
tooth that is unexpectedly joined to its neighbor. Surgi-
cal separation often is required to complete the pro-
cedure without loss of a signiﬁcant portion of the
surrounding bone.
Fig. 2-55 Fusion. Bilateral double teeth in the place of the
mandibular lateral incisors and cuspids.
Fig. 2-56 Fusion. Radiograph of the same patient depicted
in Fig. 2-55. Note the biﬁd crown overlying the single root
canal; the contralateral radiograph revealed a similar pattern.
Fig. 2-57 Concrescence. Union by cementum of adjacent
maxillary molars. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 87
ACCESSORY CUSPS
The cuspal morphology of teeth exhibits minor varia-
tions among different populations; of these, three
distinctive patterns deserve further discussion: (1)
cusp of Carabelli, (2) talon cusp, and (3) dens evagi-
natus. When an accessory cusp is present, the other
permanent teeth often exhibit a slightly increased
tooth size.
CLINICAL AND RADIOGRAPHIC
FEATURES
CUSP OF CARABELLI
The cusp of Carabelli is an accessory cusp located on
the palatal surface of the mesiolingual cusp of a maxil-
lary molar (Fig. 2-60). The cusp may be seen in the
permanent or deciduous dentitions and varies from a
deﬁnite cusp to a small indented pit or ﬁssure. When
present, the cusp is most pronounced on the ﬁrst molar
and is increasingly less obvious on the second and
third molars. When a cusp of Carabelli is present,
the remaining permanent teeth often are larger than
normal mesiodistally, but a similar association in
deciduous tooth size is typically not noted. A signiﬁcant
variation exists among different populations, with the
prevalence reported to be as high as 90% in whites and
rare in Asians. An analogous accessory cusp is seen
occasionally on the mesiobuccal cusp of a mandibular
permanent or deciduous molar and is termed a
protostylid.
TALON CUSP
A talon cusp is a well-delineated additional cusp that
is located on the surface of an anterior tooth and
extends at least half the distance from the cemento-
enamel junction to the incisal edge. A talon cusp is
thought to represent the end of a continuum that
extends from a normal cingulum, to an enlarged cin-
gulum, to a small accessory cusp, and, ﬁnally, to a full-
formed talon cusp. Investigators have muddied the
literature associated with this spectrum by categorizing
all enlarged cingula as talon cusps and developing a
classiﬁcation system for the degree of enlargement.
These classiﬁcation systems make prevalence data dif-
ﬁcult to evaluate and should be discouraged.
Three fourths of all reported talon cusps are located
in the permanent dentition. The cusps predominantly
Fig. 2-58 Concrescence. Union by cementum of maxillary
second and third molars. Note the large carious defect of the
second molar.
Fig. 2-59 Concrescence. Gross photograph of the same
teeth depicted in Fig. 2-58. Histopathologic examination
revealed that union occurred in the area of cemental repair
previously damaged by a periapical inﬂammatory lesion.
Fig. 2-60 Cusp of Carabelli. Accessory cusp on the
mesiolingual surface of the maxillary ﬁrst molar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

88 ORAL AND MAXILLOFACIAL PATHOLOGY
occur on permanent maxillary lateral (55%) or central
(33%) incisors but have been seen less frequently on
mandibular incisors (6%) and maxillary canines (4%)
(Fig. 2-61). Their occurrence in the deciduous denti-
tion is very rare, with the vast majority noted on maxil-
lary central incisors. In almost all cases the accessory
cusp projects from the lingual surface of the affected
tooth and forms a three-pronged pattern that resem-
bles an eagle’s talon. On rare occasions, the cusp may
project from the facial surface or from both surfaces of
a single tooth. A deep developmental groove may be
present where the cusp fuses with the underlying
surface of the affected tooth. Most, but not all, talon
cusps contain a pulpal extension. Radiographically, the
cusp is seen overlying the central portion of the crown
and includes enamel and dentin (Fig. 2-62). Only a few
cases demonstrate visible pulpal extensions on dental
radiographs.
Extensive prevalence studies have not been per-
formed, but estimates suggest the frequency of talon
cusp in the population ranges from less than 1% to 8%.
Variations among different population groups and
inconsistent deﬁnitions of a talon cusp make a deﬁni-
tive calculation difﬁcult. The process does appear to
occur more frequently in Asians, Native Americans,
the Inuit, and those of Arab descent. Both sexes may
be affected, and the occurrence may be unilateral or
bilateral. The accessory cusp has been seen in associa-
tion with other dental anomalies (e.g., supernumerary
teeth, odontomas, impacted teeth, peg-shaped lateral
incisors, dens invaginatus, posterior dens evaginatus).
In isolated cases, genetic inﬂuences appear to have
an effect, because identical talon cusps occasionally
have been documented in twins. Talon cusps also have
been seen in patients with Rubinstein-Taybi syndrome,
Mohr syndrome, Ellis-van Creveld syndrome, inconti-
nentia pigmenti achromians, and Sturge-Weber angio-
matosis. Although the strength of association between
the presence of talon cusps and these syndromes
generally is not clear, Rubinstein-Taybi syndrome is
strongly correlated as demonstrated by a study of 45
affected patients in which 92% demonstrated talon
cusps. Other characteristic features of this syndrome
include growth and mental retardation, broad thumbs
and great toes, and a number of other orodental fea-
tures (thin upper lip, retrognathia, micrognathia,
narrow high-arched palate, submucous cleft palate,
and cleft palate [rarely]).
DENS EVAGINATUS
Dens evaginatus (central tubercle, tuberculated cusp,
accessory tubercle, occlusal pearl, evaginated odon-
tome, Leong premolar, tuberculated premolar) is a
cusplike elevation of enamel located in the central
groove or lingual ridge of the buccal cusp of premolar
or molar teeth (Fig. 2-63). Although this pattern of
accessory cusps has been reported on molars, dens
evaginatus typically occurs on premolar teeth, is usually
bilateral, and demonstrates a marked mandibular pre-
dominance. Deciduous molars are affected infre-
quently. The accessory cusp normally consists of
enamel and dentin, with pulp present in about half of
the cases. Although the prevalence is variable, most
Fig. 2-61 Talon cusp. Accessory cusp present on the
lingual surface of a mandibular lateral incisor.
Fig. 2-62 Talon cusp. Radiograph of same patient shown
in Fig. 2-61. Note the enamel and dentin layers within the
accessory cusp. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 89
reviews suggest a frequency between 1% and 4%. The
anomaly is encountered most frequently in Asians,
the Inuit, and Native Americans but is rare in whites.
Researchers expect an increased prevalence of this
anomaly in the United States secondary to immigration
by Asians and by Hispanics of mestizo heritage (i.e.,
those of mixed European and Native American ances-
try). Radiographically, the occlusal surface exhibits a
tuberculated appearance, and often a pulpal extension
is seen in the cusp (Fig. 2-64). The accessory cusp fre-
quently creates occlusal interferences that are associ-
ated with signiﬁcant clinical problems. In one large
study, more than 80% of the tubercles were worn or
fractured, with pulpal pathosis noted in more than 25%
of patients. Pulpal necrosis is common and may occur
through a direct exposure or invasion of patent, imma-
ture dentinal tubules. In addition to abnormal wear
and pulpal pathosis, the accessory cusp also may result
in dilaceration, displacement, tilting, or rotation of the
tooth.
Frequently, dens evaginatus is seen in association
with another variation of coronal anatomy, shovel-
shaped incisors. This alteration also occurs predomi-
nantly in Asians, with a prevalence of approximately
15% in whites but close to 100% in Native Americans
and the Inuit. Affected incisors demonstrate promi-
nent lateral margins, creating a hollowed lingual
surface that resembles the scoop of a shovel (Fig. 2-65).
Typically, the thickened marginal ridges converge at
the cingulum; not uncommonly, a deep pit, ﬁssure, or
dens invaginatus is found at this junction. Maxillary
lateral and central incisors most frequently are affected,
with mandibular incisors and canines less commonly
reported.
TREATMENT AND PROGNOSIS
Patients with cusps of Carabelli require no therapy
unless a deep groove is present between the accessory
cusp and the surface of the mesiolingual cusp of the
Fig. 2-63 Dens evaginatus. Cusplike elevation located in
the central groove of mandibular ﬁrst bicuspid.
Fig. 2-64 Dens evaginatus. Radiograph of teeth depicted
in Fig. 2-63. Note the tuberculated occlusal anatomy.
Attrition on the accessory cusp led to pulpal necrosis and
periapical inﬂammatory disease.
Fig. 2-65 Shovel-shaped incisors. Chinese patient
exhibiting maxillary incisors with prominent lateral margins,
which create a hollowed lingual surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

90 ORAL AND MAXILLOFACIAL PATHOLOGY
molar. These deep grooves should be sealed to prevent
carious involvement.
Patients with talon cusps on mandibular teeth often
require no therapy; talon cusps on maxillary teeth
frequently interfere with occlusion and should be
removed. Other complications include compromised
aesthetics, displacement of teeth, caries, periodontal
problems, and irritation of the adjacent soft tissue (e.g.,
tongue or labial mucosa). Because many of these cusps
contain pulp, rapid removal often results in pulpal
exposure. Removal without the loss of vitality may be
accomplished through periodic grinding of the cusp,
with time allowed for tertiary dentin deposition and
pulpal recession. At the end of each grinding session,
the exposed dentin should be coated with a desensitiz-
ing agent such as ﬂuoride varnish, which also may
speed the rate of pulpal recession. Even with slow
reduction and no direct pulp exposure, loss of vitality
is possible when large numbers of immature dentin
tubules are exposed. After successful removal of the
cusp, the exposed dentin can be covered with calcium
hydroxide, the peripheral enamel etched, and a com-
posite resin placed.
On eruption, the affected tooth should be inspected
for the presence of a deep ﬁssure at the junction
between the talon cusp and the surface of the tooth. If
a ﬁssure is present, it should be restored to avoid early
carious extension into the nearby dental pulp. Reports
also have documented the continuation of this ﬁssure
down the surface of the root, with subsequent develop-
ment of lateral radicular inﬂammatory lesions second-
ary to the access provided to oral ﬂora by the deep
groove. In these latter cases, further surgery is required
to expose the groove for appropriate cleansing.
Dens evaginatus typically results in occlusal prob-
lems and often leads to pulpal death. In affected teeth,
removal of the cusp often is indicated, but attempts to
maintain vitality have met with only partial success.
Slow, periodic grinding of the cusp exposes immature
patent dentinal tubules and may lead to irreversible
pulpitis without direct exposure. To reduce the chance
of pulpal pathosis, elimination of opposing occlusal
interferences combined with removal of minimal
dentin and treatment of the area with stannous ﬂuo-
ride has been recommended. More rapid cuspal
removal with indirect or direct pulp capping also has
proven beneﬁcial in some patients. Other investigators
support removal of occlusal interferences, protection
of the cusp from fracture by the placement of sur-
rounding resin reinforcement, and delaying cuspal
removal until evidence of signiﬁcant dentinal matura-
tion, pulpal recession, and apical root closure are
present.
Shovel-shaped incisors should be inspected for
surface defects at the point where the marginal ridges
converge. Any deep ﬁssures or invaginations should be
restored shortly after eruption to prevent carious expo-
sure of the adjacent pulp.
DENS INVAGINATUS (DENS IN DENTE)
Dens invaginatus is a deep surface invagination of the
crown or root that is lined by enamel. Oehlers described
this condition thoroughly in three classic articles pub-
lished from 1957 to 1958. Two forms, coronal and
radicular, are recognized.
CLINICAL AND RADIOGRAPHIC
FEATURES
By a great margin, coronal dens invaginatus is seen
more frequently; the reported prevalence varies from
0.04% to 10% of all patients. In order of decreasing
frequency, the teeth affected most often include the
permanent lateral incisors, central incisors, premolars,
canines, and molars. Involvement of deciduous teeth
has been reported but is uncommon. A strong maxil-
lary predominance is seen.
The depth of the invagination varies from a slight
enlargement of the cingulum pit to a deep infolding
that extends to the apex. As would be expected, before
eruption the lumen of the invagination is ﬁlled with
soft tissue similar to the dental follicle (i.e., reduced
enamel epithelium with a ﬁbrous connective tissue
wall). On eruption, this soft tissue loses its vascular
supply and becomes necrotic.
Historically, coronal dens invaginatus has been clas-
siﬁed into three major types (Fig. 2-66). Type I exhibits
an invagination that is conﬁned to the crown. The
invagination in type II extends below the cemento-
Coronal dens invaginatus
Type I Type II Type III
Fig. 2-66 Dens invaginatus. Illustration depicting the
three types of coronal dens invaginatus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 91
enamel junction and ends in a blind sac that may or
may not communicate with the adjacent dental pulp
(Figs. 2-67 and 2-68). Large invaginations may become
dilated and contain dystrophic enamel in the base of
the dilatation (Fig. 2-69). Type III extends through the
root and perforates in the apical or lateral radicular
area without any immediate communication with the
pulp. In this latter type, the enamel that lines the invag-
ination is often replaced by cementum close to the
radicular perforation. This perforation provides direct
communication from the oral cavity to the intraosseous
periradicular tissues and often produces inﬂammatory
lesions in the presence of a vital pulp (Figs. 2-70 and
2-71).
Occasionally, the invagination may be rather large
and resemble a tooth within a tooth, hence the term
dens in dente. In other cases the invagination may be
dilated and disturb the formation of the tooth, resulting
in anomalous tooth development termed dilated
odontome. Involvement may be singular, multiple, or
bilateral.
Radicular dens invaginatus is rare and thought to
arise secondary to a proliferation of Hertwig’s root
sheath, with the formation of a strip of enamel that
extends along the surface of the root. This pattern of
Fig. 2-67 Coronal dens invaginatus type II. Maxillary
lateral incisor exhibiting invagination of the surface enamel
that extends below the cementoenamel junction.
Fig. 2-68 Coronal dens invaginatus type II. Bulbous
maxillary cuspid exhibiting a dilated invagination lined by
enamel.
A B
Fig. 2-69 Coronal dens invaginatus type II. Gross
photograph of a sectioned tooth. Note the dilated
invagination with apical accumulation of dystrophic enamel. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

92 ORAL AND MAXILLOFACIAL PATHOLOGY
enamel deposition is similar to that frequently seen in
association with radicular enamel pearls (see Ectopic
Enamel). Rather than protrude from the surface (as
seen in an enamel pearl), the altered enamel forms a
surface invagination into the dental papilla (Fig. 2-72).
Cementum-lined invaginations of the root have been
reported, but these represent a simple variation of root
morphology and should not be included under the
term radicular dens invaginatus.
Radiographically, the affected tooth demonstrates
an enlargement of the root. Close examination often
reveals a dilated invagination lined by enamel, with the
opening of the invagination situated along the lateral
aspect of the root.
TREATMENT AND PROGNOSIS
On eruption, the invagination of the affected tooth
communicates with the oral cavity, and the soft tissue
within the lumen undergoes necrosis (providing an
excellent environment for growth of bacteria). In small
type I invaginations, the opening of the invagination
should be restored after eruption in an attempt to
prevent carious involvement and subsequent pulpal
inﬂammation. If the invagination is not detected
quickly, then pulpal necrosis frequently results. With
larger invaginations the contents of the lumen and any
carious dentin must be removed; then a calcium
hydroxide base may be placed to help treat any possi-
ble microcommunications with the adjacent pulp. In
cases with obvious pulpal communication or signs of
pulpal pathosis, both the invagination and the adjacent
pulp canal require endodontic therapy. In teeth with
open apices, apexiﬁcation with calcium hydroxide or
mineral trioxide aggregate often is successful, followed
by ﬁnal obturation.
Type III invaginations associated with periradicular
inﬂammatory lesions require endodontic-like therapy
of the perforating invagination. Once again, before
ﬁnal obturation with gutta-percha, temporary place-
ment of calcium hydroxide helps to build dentinal
bridges and maintain vitality of the adjacent pulp. If
vitality is lost, endodontic therapy of the parallel root
canal also becomes necessary. Some cases do not
respond to conservative endodontic therapy and
require periapical surgery and retroﬁll. Large and
extremely dilated invaginations often have abnormal
crowns and need to be extracted.
If the invagination does not signiﬁcantly disrupt the
morphologic appearance of the tooth, then complica-
tions of radicular dens invaginatus are rare unless the
Fig. 2-70 Coronal dens invaginatus type III. Parulis
overlying vital maxillary cuspid and lateral incisor. The cuspid
contained a dens invaginatus that perforated the mesial
surface of its root.
Fig. 2-71 Coronal dens invaginatus type III. Maxillary
cuspid exhibiting an enamel invagination that parallels the
pulp canal and perforates the lateral root surface. (Courtesy of
Dr. Brian Blocher.)
Fig. 2-72 Radicular dens invaginatus. Illustration
depicting the radicular form of dens invaginatus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 93
radicular opening is exposed to the oral cavity. After
exposure occurs, carious involvement often leads to
pulpal necrosis. Openings close to the anatomic neck
of the tooth should be exposed and restored to mini-
mize damage to the tooth and surrounding structures.
ECTOPIC ENAMEL
Ectopic enamel refers to the presence of enamel in
unusual locations, mainly the tooth root. The most
widely known are enamel pearls. These are hemi-
spheric structures that may consist entirely of enamel
or contain underlying dentin and pulp tissue. Most
enamel pearls project from the surface of the root and
are thought to arise from a localized bulging of the
odontoblastic layer. This bulge may provide prolonged
contact between Hertwig’s root sheath and the devel-
oping dentin, triggering induction of enamel forma-
tion. Similar internal projections of enamel into the
underlying dentin rarely have been reported in the
crowns of teeth.
In addition to enamel pearls, cervical enamel
extensions also occur along the surface of dental roots.
These extensions represent a dipping of the enamel
from the cementoenamel junction toward the bifurca-
tion of molar teeth. This pattern of ectopic enamel
forms a triangular extension of the coronal enamel
that develops on the buccal surface of molar teeth
directly overlying the bifurcation. The base of the tri-
angle is continuous with the inferior portion of the
coronal enamel; the leading point of the triangle
extends directly toward the bifurcation of the tooth.
These areas of ectopic enamel have been called cervical
enamel projections, but this terminology is confusing
because no signiﬁcant exophytic projections are seen.
CLINICAL AND RADIOGRAPHIC
FEATURES
ENAMEL PEARLS
Enamel pearls are found most frequently on the roots
of maxillary molars (mandibular molars are the second
most frequent site). It is uncommon for maxillary pre-
molars and incisors to be affected. Involvement of
deciduous molars is not rare. The prevalence of enamel
pearls varies (1.1% to 9.7% of all patients) according to
the population studied and is highest in Asians. In most
cases, one pearl is found, but as many as four pearls
have been documented on a single tooth. The majority
occur on the roots at the furcation area or near the
cementoenamel junction (Fig. 2-73). Radiographically,
pearls appear as well-deﬁned, radiopaque nodules
along the root’s surface (Fig. 2-74). Mature internal
enamel pearls appear as well-deﬁned circular areas of
radiodensity extending from the dentinoenamel junc-
tion into the underlying coronal dentin.
The enamel surface of pearls precludes normal
periodontal attachment with connective tissue, and a
hemidesmosomal junction probably exists. This junc-
tion is less resistant to breakdown; once separation
occurs, rapid loss of attachment is likely. In addition,
the exophytic nature of the pearl is conducive to plaque
retention and inadequate cleansing.
Fig. 2-73 Enamel pearl. Mass of ectopic enamel located in
the furcation area of a molar tooth. (Courtesy of Dr. Joseph Beard.)
Fig. 2-74 Enamel pearl. Radiopaque nodule on the mesial
surface of the root of the maxillary third molar. Another less
distinct enamel pearl is present on the distal root of the
second molar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

94 ORAL AND MAXILLOFACIAL PATHOLOGY
CERVICAL ENAMEL EXTENSIONS
As mentioned previously, cervical enamel extensions
are located on the buccal surface of the root overlying
the bifurcation (Fig. 2-75). Mandibular molars are
affected slightly more frequently than maxillary molars.
In reviews of extracted teeth in the lower 48 United
States, the prevalence is surprisingly high, with approx-
imately 20% of molars being affected. Similar studies
demonstrate an even greater prevalence in other loca-
tions such as Japan, China, and Alaska, with cervical
enamel extensions discovered in 50% to 78% of
extracted molars. Cervical enamel extensions may
occur on any molar, but they are seen less frequently
on third molars. Because connective tissue cannot
attach to enamel, these extensions have been corre-
lated positively with localized loss of periodontal
attachment with furcation involvement. On review of
a large number of dentitions with periodontal furcation
involvement, a signiﬁcantly higher frequency of cervi-
cal enamel extensions was found compared with denti-
tions without furcation involvement. In addition, the
greater the degree of cervical extension, the higher the
frequency of furcation involvement.
In addition to periodontal furcation involvement,
cervical enamel extensions (in some cases) have been
associated with the development of inﬂammatory cysts
that are histopathologically identical to inﬂammatory
periapical cysts. The cysts develop along the buccal
surface over the bifurcation and most appropriately are
called buccal bifurcation cysts (see page 698). The
association between cervical enamel extensions and
this unique inﬂammatory cyst is controversial.
TREATMENT AND PROGNOSIS
When enamel pearls are detected radiographically,
the area should be viewed as a weak point of peri-
o dontal attachment. Meticulous oral hygiene should be
maintained in an effort to prevent localized loss of peri-
odontal support. If removal of the lesion is contem-
plated, then the clinician must remember that enamel
pearls occasionally contain vital pulp tissue.
For teeth with cervical enamel extensions and asso-
ciated periodontal furcation involvement, therapy is
directed at achieving a more durable attachment and
providing access to the area for appropriate cleaning.
Reports have suggested that ﬂattening or removing the
enamel in combination with an excisional new attach-
ment procedure and furcation plasty may accomplish
this.
TAURODONTISM
Taurodontism is an enlargement of the body and pulp
chamber of a multirooted tooth, with apical displace-
ment of the pulpal ﬂoor and bifurcation of the roots.
This pattern of molar formation has been found in
ancient Neanderthals, and the overall shape of the tau-
rodont resembles that of the molar teeth of cud-chewing
animals (tauro = bull; dont = tooth).
CLINICAL AND RADIOGRAPHIC
FEATURES
Affected teeth tend to be rectangular and exhibit pulp
chambers with a dramatically increased apicoocclusal
height and a bifurcation close to the apex (Fig. 2-76).
The diagnosis usually is made subjectively from the
radiographic appearance. The degree of taurodontism
Normal cervical enamel Cervical enamel extension
Fig. 2-75 Cervical enamel extension. Illustration of a
normal molar adjacent to a molar exhibiting V-shaped
elongation of enamel extending toward the bifurcation.
Fig. 2-76 Taurodontism. Mandibular molar teeth
exhibiting increased pulpal apicoocclusal height with apically
positioned pulpal ﬂoor and bifurcation. (Courtesy of Dr. Michael
Kahn.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 95
has been classiﬁed into mild (hypo taurodontism),
moderate (mesotaurodontism), and severe (hypertau-
rodontism), according to the degree of apical displace-
ment of the pulpal ﬂoor (Fig. 2-77). Witkop and
colleagues and Shifman and Chanannel presented
useful biometric criteria for the determination of tau-
rodontism. These reports contain information that is
useful in epidemiologic studies of the process.
Some investigators include examples of tau-
rodontism in premolar teeth; others argue that tau-
rodontism is not shown by premolars. This argument
is academic because the presence of taurodontism in
premolars cannot be documented in situ. Investiga-
tions of taurodontism in premolar teeth require the
examination of extracted teeth, because the necess-
ary radiographs depict the tooth in a mesiodistal
orientation.
Taurodontism may be unilateral or bilateral and
affects permanent teeth more frequently than decidu-
ous teeth. There is no sex predilection. The reported
prevalence is highly variable (0.5% to 46%) and most
likely is related to different diagnostic criteria and
racial variations. In the United States most reports indi-
cate a prevalence of 2.5% to 3.2% of the population.
Some investigators believe the alteration is more of a
variation of normal rather than a deﬁnitive pathologic
anomaly. The process often demonstrates a ﬁeld effect,
with the involvement of all molars. When this occurs,
the ﬁrst molar is usually affected least, with increasing
severity noted in the second and third molars,
respectively.
Taurodontism may occur as an isolated trait or
as a component of a speciﬁc syndrome (Box 2-8).
An increased frequency of taurodontism has been
reported in patients with hypodontia, cleft lip, and cleft
palate. Investigations have shown that taurodontism
may develop in the presence of any one of a large
number of different genetic alterations. These ﬁndings
suggest that chromosomal abnormalities may disrupt
the development of the tooth’s form and that tau-
rodontism is not the result of a speciﬁc genetic
abnormality.
TREATMENT AND PROGNOSIS
Patients with taurodontism require no speciﬁc therapy.
Coronal extension of the pulp is not seen; therefore, the
process does not interfere with routine restorative pro-
cedures. Some investigators have suggested the tau-
rodontic shape may exhibit decreased stability and
Normal
cynodont
Mild
hypotaurodont
Moderate
mesotaurodont
Severe
hypertaurodont
Fig. 2-77 Taurodontism. Illustration exhibiting the classiﬁcation of taurodontism according
to the degree of apical displacement of the pulpal ﬂoor.
Box 2-8
Syndromes Associated with Taurodontism
●Amelogenesis imperfecta, hypoplastic type IE
●Amelogenesis imperfecta-taurodontism type IV
● Cranioectodermal
● Ectodermal dysplasia
● Hyperphosphatasia-oligophrenia-taurodontism
● Hypophosphatasia
● Klinefelter
● Lowe
● Microdontia-taurodontia-dens invaginatus
● Microcephalic dwarﬁsm-taurodontism
● Oculo-dento-digital dysplasia
●Oral-facial-digital type II
● Rapp-Hodgkin
● Scanty hair-oligodontia-taurodontia
●Sex chromosomal aberrations (e.g., XXX, XYY)
● Down
●Tricho-dento-osseous types I, II, and III
● Tricho-onycho-dental
● Wolf-Hirschhorn `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

96 ORAL AND MAXILLOFACIAL PATHOLOGY
strength as an abutment tooth in prosthetic procedures,
but this hypothesis has not been veriﬁed. If endodontic
therapy is required, then the shape of the pulp chamber
frequently increases the difﬁculty of locating, instru-
menting, and obturating the pulp canals. One bit of
good news is that patients have to demonstrate
signiﬁcant periodontal destruction before bifurcation
involvement occurs.
HYPERCEMENTOSIS
Hypercementosis (cemental hyperplasia) is a non-
neoplastic deposition of excessive cementum that is
continuous with the normal radicular cementum.
CLINICAL AND RADIOGRAPHIC
FEATURES
Radiographically, affected teeth demonstrate a thick-
ening or blunting of the root, but the exact amount of
increased cementum often is difﬁcult to ascertain
because cementum and dentin demonstrate similar
radiodensities (Fig. 2-78). The enlarged root is sur-
rounded by the radiolucent PDL space and the adja-
cent intact lamina dura. On occasion, the enlargement
may be signiﬁcant enough to suggest the possibility of
a cementoblastoma (see page 655). However, the
cementoblastoma usually can be distinguished on the
basis of associated pain, cortical expansion, and contin-
ued enlargement.
Hypercementosis may be isolated, involve multiple
teeth, or appear as a generalized process. In a study of
more than 22,000 affected teeth, the mandibular
molars were affected most frequently, followed by the
mandibular and maxillary second premolars and man-
dibular ﬁrst premolars. In this study, a 2.5:1 mandibu-
lar predominance was noted.
Hypercementosis occurs predominantly in adult-
hood, and the frequency increases with age, most likely
secondary to cumulative exposure to causative inﬂu-
ences. Its occurrence has been reported in younger
patients, and many of these cases demonstrate a famil-
ial clustering, suggesting hereditary inﬂuence.
Box 2-9 lists several local and systemic factors that
have been associated with an increased frequency of
the cemental deposition. All of the listed systemic
factors exhibit a weak association with hypercemento-
sis except for Paget’s disease of bone (see page 623).
Numerous authors have reported signiﬁcant hyperce-
mentosis in patients with Paget’s disease, and this dis-
order should be considered whenever generalized
hypercementosis is discovered in a patient of the
appropriate age. In spite of the association with a
number of disorders, most localized cases of hyperce-
mentosis are not related to any systemic disturbance.
HISTOPATHOLOGIC FEATURES
The periphery of the root exhibits deposition of an
excessive amount of cementum over the original layer
of primary cementum. The excessive cementum may
be hypocellular or exhibit areas of cellular cementum
Fig. 2-78 Hypercementosis. Mandibular bicuspids
exhibiting thickening and blunting of the roots.
Box 2-9
Factors Associated with Hypercementosis
LOCAL FACTORS
●Abnormal occlusal trauma
● Adjacent inﬂammation (e.g., pulpal, periapical,
periodontal)
●Unopposed teeth (e.g., impacted, embedded, without
antagonist)
●Repair of vital root fracture
SYSTEMIC FACTORS
●Acromegaly and pituitary gigantism
● Arthritis
● Calcinosis
●Paget disease of bone
● Rheumatic fever
● Thyroid goiter
● Gardner syndrome
●Vitamin A deﬁciency (possibly) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 97
that resemble bone (osteocementum). Often the mate-
rial is arranged in concentric layers and may be applied
over the entire root or be limited to the apical portion.
On routine light microscopy, distinguishing between
dentin and cementum often is difﬁcult, but viewing the
section with polarized light helps to discriminate
between the two different layers (Fig. 2-79).
TREATMENT AND PROGNOSIS
Patients with hypercementosis require no treatment.
Because of a thickened root, occasional problems have
been reported during the extraction of an affected
tooth. Sectioning of the tooth may be necessary in
certain cases to aid in removal.
DILACERATION
Dilaceration is an abnormal angulation or bend in the
root or, less frequently, the crown of a tooth (Figs. 2-80
and 2-81). Although most examples are idiopathic, a
number of teeth with dilaceration appear to arise after
an injury that displaces the calciﬁed portion of the
tooth germ, and the remainder of the tooth is formed
at an abnormal angle. The damage frequently follows
avulsion or intrusion of the overlying primary prede-
cessor, an event that usually occurs before 4 years of
age. Injury-related dilaceration more frequently affects
the anterior dentition and often creates both a func-
tional and a cosmetic dental problem. Less frequently
the bend develops secondary to the presence of an
adjacent cyst, tumor, or odontogenic hamartoma (e.g.,
odontoma, supernumerary tooth) (Fig. 2-82).
CLINICAL AND RADIOGRAPHIC
FEATURES
In one review of 1166 randomly selected patients, 176
dilacerated teeth were identiﬁed. Of these teeth, the
most commonly affected were the mandibular third
molars, followed by the maxillary second premolars
and mandibular second molars. The maxillary and
mandibular incisors were the least frequently affected,
representing approximately 1% of the series. This con-
trasts with other authors who have reported a high
frequency of dilaceration involving anterior teeth. In
reality the molars most likely demonstrate the highest
A B
Fig. 2-79 Hypercementosis. A, Dental root exhibiting
excessive deposition of cellular and acellular cementum. The
dividing line between dentin and cementum is indistinct.
B, Polarized light demonstrating the sharp dividing line
between the tubular dentin and osteocementum.
Fig. 2-80 Dilaceration. Sharp curvature of the root of a
maxillary central incisor.
Fig. 2-81 Dilaceration. Maxillary second bicuspid
exhibiting mesial inclination of the root. The patient reported
no history of injury to this area. (Courtesy of Dr. Lawrence Bean.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

98 ORAL AND MAXILLOFACIAL PATHOLOGY
prevalence of dilaceration but are not highlighted
because of a lack of associated clinical problems in
most instances. Occasionally, involvement of the decid-
uous teeth is reported, and some have been associated
with prior trauma secondary to neonatal laryngoscopy
and endotracheal intubation. The age of the patient
and the direction and degree of force appear to deter-
mine the extent of the tooth’s malformation. The abnor-
mal angulation may be present anywhere along the
length of the tooth.
Altered maxillary anterior teeth frequently demon-
strate the bend in the crown or the coronal half of the
root; failure of eruption is often seen. Affected man-
dibular incisors also exhibit involvement of the crown
or the superﬁcial portion of the root, but more fre-
quently they erupt into full occlusion. Those that
achieve eruption often follow an altered path and
present in a labial or lingual position. Many of the
affected teeth, especially anterior mandibular teeth,
are nonvital and associated with periapical inﬂamma-
tory lesions. Typically, altered posterior teeth demon-
strate involvement of the apical half of the root and
frequently do not exhibit delayed eruption.
TREATMENT AND PROGNOSIS
The treatment and prognosis vary according to the
severity of the deformity. Altered deciduous teeth often
demonstrate inappropriate resorption and result in
delayed eruption of the permanent teeth. Extraction is
indicated when necessary for the normal eruption of
the succedaneous teeth. Patients with minor dilacera-
tion of permanent teeth frequently require no therapy.
Those teeth that exhibit delayed or abnormal eruption
may be exposed and orthodontically moved into posi-
tion. In some cases with extensive deformation of the
affected tooth, perforation of the buccal alveolar ridge
by the malpositioned root may occur on repositioning.
In such cases, amputation of the root apex with subse-
quent endodontic therapy may be necessary. Grossly
deformed teeth require surgical removal. The extrac-
tion of affected teeth may be difﬁcult and result in root
fracture on removal. When attempting to perform end-
odontic procedures, the clinician must use great care
to avoid root perforation of teeth with signiﬁcant
dilaceration.
Root dilaceration concentrates stress if the affected
tooth is used as an abutment for a dental prosthetic
appliance. This increased stress may affect the stability
and longevity of the abutment tooth. Splinting of the
dilacerated tooth to an adjacent tooth results in a mul-
tirooted abutment and overcomes the stress-related
problems.
SUPERNUMERARY ROOTS
The term supernumerary roots refers to the deve lop-
ment of an increased number of roots on a tooth
compared with that classically described in dental
anatomy.
CLINICAL AND RADIOGRAPHIC
FEATURES
Any tooth may develop accessory roots, and involve-
ment has been reported in both the deciduous and the
permanent dentitions. Data on the frequency of super-
numerary roots are sparse, but the prevalence appears
to vary signiﬁcantly among different races. The most
frequently affected teeth are the permanent molars
(especially third molars) from either arch and man-
dibular cuspids and premolars (Fig. 2-83). In some
instances the supernumerary root is divergent and
seen easily on radiographs; in other cases the addi-
tional root is small, superimposed over other roots, and
difﬁcult to ascertain.
TREATMENT AND PROGNOSIS
No treatment is required for supernumerary roots, but
the detection of the accessory root is of critical impor-
tance when endodontic therapy or exodontia is under-
taken. Extracted teeth always should be examined
closely to ensure that all roots have been removed suc-
cessfully, because accessory roots may not be obvious
on the presurgical radiographs. Just as important is the
Fig. 2-82 Dilaceration. Root angulation of a mandibular
cuspid. Development has been altered by the presence of an
adjacent compound odontoma. (Courtesy of Dr. Brent Bernard.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 99
search for accessory canals during endodontic access
procedures, because failure to discover these addi-
tional openings often results in a lack of resolution of
the associated inﬂammatory process.
DEVELOPMENTAL ALTERATIONS IN
THE STRUCTURE OF TEETH
AMELOGENESIS IMPERFECTA
Amelogenesis imperfecta encompasses a compli-
cated group of conditions that demonstrate develop-
mental alterations in the structure of the enamel in the
absence of a systemic disorder. Box 2-2 (see page 55)
lists several systemic diseases associated with enamel
disorders that are not considered isolated amelogene-
sis imperfecta.
At least 14 different hereditary subtypes of amelo-
genesis imperfecta exist, with numerous patterns of
inheritance and a wide variety of clinical manifesta-
tions. As proof of the complicated nature of the process,
several different classiﬁcation systems exist. The most
widely accepted is that developed by Witkop (Table
2-1), and this part of the text adheres to this classiﬁca-
tion. The dissertation by Witkop and Sauk (and Wit-
kop’s 1988 review) are works of art, and they should
be used if the clinician desires more information.
An ideal classiﬁcation system for amelogenesis
imperfecta has not been established yet. Witkop’s clas-
siﬁcation relies on the phenotype and pedigree (i.e.,
clinical appearance and apparent pattern of inheri-
tance). Classiﬁcation by clinical appearance is prob-
lematic, because different phenotypes have been noted
within a single affected family. In addition, similar phe-
notypes may be seen in individuals with very different
molecular patterns of disease. One example of the
potential confusion occurs in kindreds affected with
certain variants of autosomal dominant amelogenesis
imperfecta in which homozygotes exhibit generalized
thin hypoplasia, whereas heterozygotes exhibit local-
ized enamel pitting. Using the current nomenclature,
different individuals within this kindred would be
placed into multiple categories (e.g., types IB, ID, IF).
Although the molecular basis underlying the major-
ity of amelogenesis imperfecta remains poorly deﬁned,
the genetics associated with several variations of amelo-
A B
Fig. 2-83 Supernumerary root. A, Gross photograph
showing a mandibular molar with a supernumerary root.
B, Periapical radiograph of the extracted tooth.
Table 2-1 Classiﬁcation of Amelogenesis Imperfecta
Type Pattern Speciﬁc Features Inheritance
IA Hypoplastic Generalized pitted Autosomal dominant
IB Hypoplastic Localized pitted Autosomal dominant
IC Hypoplastic Localized pitted Autosomal recessive
ID Hypoplastic Diffuse smooth Autosomal dominant
IE Hypoplastic Diffuse smooth X-linked dominant
IF Hypoplastic Diffuse rough Autosomal dominant
IG Hypoplastic Enamel agenesis Autosomal recessive
IIA Hypomaturation Diffuse pigmented Autosomal recessive
IIB Hypomaturation Diffuse X-linked recessive
IIC Hypomaturation Snow-capped X-linked
IID Hypomaturation Snow-capped Autosomal dominant?
IIIA Hypocalciﬁed Diffuse Autosomal dominant
IIIB Hypocalciﬁed Diffuse Autosomal recessive
IVA Hypomaturation-hypoplastic Taurodontism present Autosomal dominant
IVB Hypoplastic-hypomaturation Taurodontism present Autosomal dominant
Modiﬁed from Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classiﬁcation, J Oral Pathol
17:547-553, 1988. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

100 ORAL AND MAXILLOFACIAL PATHOLOGY
genesis imperfecta has been clariﬁed. This has led inves-
tigators to suggest a future classiﬁcation system based
primarily on the mode of inheritance with secondary
discriminators that include the phenotype and molecu-
lar basis (site of chromosomal mutation, when known).
Although the push for a new classiﬁcation system is not
new, the progress in deﬁning the molecular genetics of
amelogenesis imperfecta has been slow and currently
prevents complete agreement on a transition to a genet-
ics-directed system of classiﬁcation. As the molecular
basis of the disease becomes better clariﬁed, the move
to a new pattern of classiﬁcation seems inevitable.
Investigations into the genetics are ongoing and pro-
ducing results that are not only interesting but also
directly applicable to patient care. To date, mutations
in ﬁve genes have been associated with amelogenesis
imperfecta. Each gene can be mutated in a variety of
ways, often creating diverse and distinct phenotypic
patterns.
The AMELX gene is associated with the enamel
protein amelogenin, which constitutes up to 90% of
enamel matrix. AMELX-associated variants of amelo-
genesis imperfecta are X-linked with 14 different
mutations currently known. Because of the effect of
lyonization, the male and female phenotypes are vari-
able but often associated with the genotype. The male
phenotypes include both the diffuse smooth hypoplas-
tic and the hypomaturation variants.
The ENAM gene is associated with another enamel
protein, enamelin, which represents approximately
1% to 5% of enamel matrix. Mutations of the ENAM
gene have been correlated with some autosomal domi-
nant and recessive patterns of hypoplastic amelogene-
sis imperfecta, ranging from minor pitting to diffuse
generalized thin enamel.
The MMP-20 gene codes for a proteinase named
enamelysin; mutation of this gene has been associated
with the autosomal recessive, pigmented hypomatura-
tion variant of amelogenesis imperfecta.
The protease, kallikrein-4, is associated with the
KLK4 gene, the mutation of which has been shown
to be involved with some forms of hypomaturation
amelogenesis imperfecta. Both enamelysin and
kallikrein-4 are thought necessary for the removal of
enamel matrix proteins during the maturation stage of
enamel development.
The DLX3 gene is in a group of genes that code
for a number of proteins that are critical for cranio-
facial, tooth, hair, brain, and neural development;
mutation of this gene has been associated with the
hypoplastic-hypomaturation variants of amelogenesis
imperfecta with taurodontism.
Another strong candidate is the AMBN gene that
codes for the protein ameloblastin, which constitutes
about 5% of enamel matrix. Although not proven to be
associated with amelogenesis imperfecta, this gene
locus is a strong candidate for some of the autosomal
dominant patterns.
Although no one has compiled a complete list of
amelogenesis imperfecta types using the proposed new
classiﬁcation, Table 2-2 provides a rough idea of how
this might be organized. Despite these exciting molecu-
lar genetic discoveries, it must be stressed how little is
known and how much remains to be investigated. When
studying large numbers of kindreds affected by amelo-
genesis imperfecta, only rare families will demonstrate
mutation of one of the currently known genes.
The formation of enamel is a multistep process, and
problems may arise in any one of the steps. In general,
the development of enamel can be divided into three
major stages:
1.Elaboration of the organic matrix
2.Mineralization of the matrix
3.Maturation of the enamel
Table 2-2 Modiﬁed Classiﬁcation of Amelogenesis Imperfecta
Inheritance Phenotype Related Genes
Autosomal dominant Generalized pitted
Autosomal dominant Localized hypoplastic ENAM
Autosomal dominant Generalized thin ENAM
Autosomal dominant Hypocalciﬁcation
Autosomal dominant With taurodontism DLX3
Autosomal recessive Localized hypoplastic
Autosomal recessive Generalized thin
Autosomal recessive Pigmented hypomaturation MMP20, KLK4
Autosomal recessive Hypocalciﬁcation
X-linked Generalized thin AMELX
X-linked Diffuse hypomaturation AMELX
X-linked Snow-capped hypomaturation `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 101
The hereditary defects of the formation of enamel
also are divided along these lines: hypoplastic, hypocal-
ciﬁed, and hypomaturation.
CLINICAL AND RADIOGRAPHIC
FEATURES
Amelogenesis imperfecta may be inherited as an auto-
somal dominant, autosomal recessive, or X-linked dis-
order, with an estimated frequency between 1:718 and
1:14,000 of the population. As in any hereditary condi-
tion, clustering of affected patients in certain geo-
graphic areas may occur (resulting in an increased
prevalence of the disorder in those areas). Additionally,
the stringency of the diagnostic criteria may inﬂuence
the reported prevalence in any given study. In general,
both the deciduous and the permanent dentitions are
diffusely involved.
HYPOPLASTIC AMELOGENESIS IMPERFECTA
In patients with hypoplastic amelogenesis imperfecta,
the basic alteration centers on inadequate deposition
of enamel matrix. Any matrix present is mineralized
appropriately and radiographically contrasts well with
the underlying dentin. In the generalized pattern,
pinpoint-to-pinhead–sized pits are scattered across the
surface of the teeth and do not correlate with a pattern
of environmental damage (Fig. 2-84). The buccal sur-
faces of the teeth are affected more severely, and the
pits may be arranged in rows or columns. Staining of
the pits may occur. Variable expressivity is seen within
groups of affected patients. The enamel between the
pits is of normal thickness, hardness, and coloration.
In the localized pattern, the affected teeth demon-
strate horizontal rows of pits, a linear depression, or
one large area of hypoplastic enamel surrounded by a
zone of hypocalciﬁcation. Typically, the altered area is
located in the middle third of the buccal surfaces of the
teeth. The incisal edge or occlusal surface usually is not
affected. Both dentitions (or only the primary teeth)
may be affected. All the teeth may be altered, or only
scattered teeth may be affected. When the involve-
ment is not diffuse, the pattern of affected teeth does
not correlate with a speciﬁc time in development. The
autosomal recessive type (type IC) is more severe and
typically demonstrates involvement of all teeth in both
dentitions.
In the autosomal dominant smooth pattern, the
enamel of all teeth exhibits a smooth surface and is
thin, hard, and glossy (Fig. 2-85). The absence of appro-
priate enamel thickness results in teeth that are shaped
like crown preparations and demonstrate open contact
points. The color of the teeth varies from opaque white
to translucent brown. Anterior open bite is not rare.
Radiographically, the teeth exhibit a thin peripheral
outline of radiopaque enamel. Often, unerupted teeth
exhibiting resorption are seen.
The X-linked smooth pattern has been stated to
arise from an X-linked dominant mutation and is a
lesson in the lyonization effect. On approximately the
sixteenth day of embryonic life in all individuals with
two X chromosomes, one member of the pair is inacti-
vated in each cell. As a result of this event, females are
mosaics, with a mixture of cells, some with active
maternal X chromosomes and others with active
paternal X chromosomes. Usually the mix is of
A B
Fig. 2-84 Hypoplastic amelogenesis imperfecta, generalized pitted pattern. A, Note the
numerous pinpoint pits scattered across the surface of the teeth. The enamel between the pits
is of normal thickness, hardness, and coloration. B, Occlusal view of same patient showing
diffuse involvement of all maxillary teeth, which would be inconsistent with environmental
damage. (A from Stewart RE, Prescott GH: Oral facial genetics, St Louis, 1976, Mosby; B courtesy of Dr. Joseph S.
Giansanti.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

102 ORAL AND MAXILLOFACIAL PATHOLOGY
approximately equal proportions. If one X were to
direct the formation of defective enamel and the other
X were to form normal enamel, then the teeth would
exhibit alternating zones of normal and abnormal
enamel. Aldred and Crawford have argued against
subdivision of X-linked amelogenesis imperfecta into
dominant and recessive variants, because both hetero-
zygous females and hemizygous males are affected
regardless of the mutation being dominant or reces-
sive. Although the intelligence of this suggestion is
less evident in an X-linked dominant pattern
of amelogenesis imperfecta, the argument is quite
convincing when associated with the X-linked “reces-
sive” hypomaturation pattern of amelogenesis imper-
fecta (see the discussion of the X-linked pattern of
hypomaturation amelogenesis imperfecta on page
103).
Males with the X-linked smooth pattern exhibit
diffuse thin, smooth, and shiny enamel in both denti-
tions. The teeth often have the shape of crown prepara-
tions, and the contact points are open. The color varies
from brown to yellow-brown. Radiographs demon-
strate a peripheral outline of radiopaque enamel.
Unerupted teeth may undergo resorption. On the other
hand, heterozygous females exhibit vertical furrows of
thin hypoplastic enamel, alternating between bands of
normal thickness. The banding often is detectable with
dental radiographs. An open bite is seen in almost all
males and in a minority of females.
In the rough pattern, the enamel is thin, hard, and
rough-surfaced. As in the smooth forms, the teeth taper
toward the incisal-occlusal surface and demonstrate
open contact points (Fig. 2-86). The color varies from
white to yellow-white. The enamel is denser than that
seen in the smooth patterns, and the teeth are less vul-
nerable to attrition. Radiographs exhibit a thin periph-
eral outline of radiodense enamel. Unerupted teeth,
often undergoing resorption, may be seen. An anterior
open bite is common.
As the name implies, enamel agenesis demon-
strates a total lack of enamel formation. The teeth are
the shape and color of the dentin, with a yellow-brown
hue, open contact points, and crowns that taper toward
the incisal-occlusal surface. The surface of the dentin
is rough, and an anterior open bite is seen frequently.
Radiographs demonstrate no peripheral enamel over-
lying the dentin. A lack of eruption of many teeth with
signiﬁcant resorption frequently occurs.
Many investigators have difﬁculty subdividing the
diffuse hypoplastic forms of amelogenesis imperfecta
into categories such as smooth, rough, and enamel
agenesis. In the autosomal recessive pattern of amelo-
genesis imperfecta previously termed enamel agenesis,
the presence of a thin band of enamel has been con-
ﬁrmed in many affected patients. In addition, the sepa-
ration between smooth and rough forms can be highly
subjective and problematic. Therefore, some investiga-
tors have suggested discontinuation of these subdivi-
sions and combining these phenotypic patterns into
one category termed generalized thin hypoplastic
amelogenesis imperfecta.
HYPOMATURATION
AMELOGENESIS IMPERFECTA
In a person with hypomaturation amelogenesis im-
perfecta, the enamel matrix is laid down appropriately
and begins to mineralize; however, there is a defect in
the maturation of the enamel’s crystal structure.
A B
Fig. 2-85 Hypoplastic amelogenesis imperfecta, autosomal dominant smooth pattern
(generalized thin pattern). A, Small, yellowish teeth exhibiting hard, glossy enamel with
numerous open contact points and anterior open bite. B, Radiograph of the same patient
demonstrating thin peripheral outline of radiopaque enamel. (B courtesy of Dr. John G. Stephenson.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 103
Affected teeth are normal in shape but exhibit
a mottled, opaque white-brown-yellow discoloration.
The enamel is softer than normal and tends to chip
from the underlying dentin. Radiographically, the
affected enamel exhibits a radiodensity that is similar
to dentin.
In the pigmented pattern the surface enamel is
mottled and agar-brown. The enamel often fractures
from the underlying dentin and is soft enough to be
punctured by a dental explorer. Anterior open bite and
unerupted teeth exhibiting resorption are uncommon.
Occasionally, the surface enamel may be affected
severely and be similar in softness to that of hypocalci-
ﬁed patterns. These cases often demonstrate extensive
calculus deposition.
The X-linked pattern is another lesson in lyoniza-
tion; however, the lyonization is not as obvious as that
seen in the X-linked hypoplastic pattern. Although the
mutation has been said to be recessive, hemizygous
males and heterozygous females will demonstrate clin-
ical changes. Affected males exhibit different patterns
in the deciduous and permanent dentitions. The decid-
uous teeth are opaque white with a translucent mot-
tling; the permanent teeth are opaque yellow-white
and may darken with age (Fig. 2-87, A). The enamel
tends to chip and often can be pierced with a dental
explorer point. The degree of enamel loss is more rapid
than that in normal teeth but does not approach that
seen in the hypocalciﬁed forms. Focal areas of brown
discoloration may develop within the white opaque
enamel. Radiographically, the contrast between enamel
and dentin is reduced.
Heterozygous females exhibit a similar pattern in
both dentitions. The teeth demonstrate vertical bands
of white opaque enamel and translucent enamel; the
bands are random and asymmetric (Fig. 2-87, B). The
banding can be seen under regular lighting but is more
obvious with transillumination. Radiographically, the
bands are not perceptible, and the contrast between
enamel and dentin is within normal limits. The obvious
clinical evidence of the mutation in heterozygous
females strongly argues for the pathosis to be desig-
nated as simply X-linked rather than X-linked
recessive.
The snow-capped patterns exhibit a zone of white
opaque enamel on the incisal or occlusal one quarter
to one third of the crown (Fig. 2-88). The altered areas
do not exhibit a distribution that would support an
environmental origin, and the surface lacks the irides-
cent sheen seen with mild ﬂuorosis. The affected teeth
often demonstrate an anterior-to-posterior distribution
and have been compared with a denture dipped in
white paint (only affected anteriors, the anteriors back
to the bicuspids, or the anteriors back to the molars).
Both the deciduous and the permanent dentitions are
affected. Most cases demonstrate an X-linked pattern
of inheritance, but an autosomal dominant form is
possible.
HYPOCALCIFIED AMELOGENESIS IMPERFECTA
In this type the enamel matrix is laid down appropri-
ately but no signiﬁcant mineralization occurs. In both
patterns of hypocalciﬁed amelogenesis imperfecta,
the teeth are appropriately shaped on eruption, but the
enamel is very soft and easily lost. On eruption the
enamel is yellow-brown or orange, but it often becomes
stained brown to black and exhibits rapid calculus
apposition (Fig. 2-89). With years of function much of
A B
Fig. 2-86 Hypoplastic amelogenesis imperfecta, rough pattern (generalized thin pattern).
A, Small, yellow teeth with rough enamel surface, open contact points, signiﬁcant attrition,
and anterior open bite. B, Radiograph of the same patient. Note the impacted tooth and the
thin peripheral outline of radiodense enamel. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

104 ORAL AND MAXILLOFACIAL PATHOLOGY
cases. Radiographically, the density of the enamel and
dentin are similar. Before eruption the teeth are normal
in shape; however, after a period of function much of
the cuspal enamel is lost, with the occlusal surface
becoming the most irregular.
AMELOGENESIS IMPERFECTA WITH
TAURODONTISM (HYPOMATURATION/
HYPOPLASTIC AMELOGENESIS IMPERFECTA)
This type of amelogenesis imperfecta exhibits enamel
hypoplasia in combination with hypomaturation. The
deciduous and the permanent dentitions are diffusely
involved. Historically, two patterns have been recog-
nized that are similar but differentiated by the thick-
ness of the enamel and the overall tooth size. When
studying a single kindred, phenotypic variation is seen
that would place members of the same family in both
A
B
Fig. 2-87 Hypomaturation amelogenesis imperfecta,
X-linked. A, Male patient exhibiting diffuse yellow-white
dentition. B, The patient’s mother exhibits vertical bands of
white, opaque enamel and translucent enamel. (Courtesy of Dr.
Carlos Salinas.)
Fig. 2-88 Hypomaturation amelogenesis imperfecta,
snow-capped pattern. Dentition exhibiting zone of white
opaque enamel in the incisal and occlusal one fourth of the
enamel surface. (Courtesy of Dr. Heddie O. Sedano.)
A B
Fig. 2-89 Hypocalciﬁed amelogenesis imperfecta. A, Dentition exhibiting diffuse yellow-
brown discoloration. Note numerous teeth with loss of coronal enamel except for the cervical
portion. B, Radiograph of the same patient. Note the extensive loss of coronal enamel and the
similar density of enamel and dentin.
the coronal enamel is removed, except for the cervical
portion that is occasionally calciﬁed better. Unerupted
teeth and anterior open bite are not rare. Both patterns
are similar, but the autosomal recessive examples are
generally more severe than the autosomal dominant `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 105
divisions; therefore, many believe these divisions
should be joined into one phenotype termed merely
amelogenesis imperfecta with taurodontism.
In the presentation known as the hypomaturation-
hypoplastic pattern, the predominant defect is one of
enamel hypomaturation in which the enamel appears
as mottled yellow-white to yellow-brown. Pits are seen
frequently on the buccal surfaces of the teeth. Radio-
graphically, the enamel appears similar to dentin in
density, and large pulp chambers may be seen in
single-rooted teeth in addition to varying degrees of
taurodontism.
In the hypoplastic-hypomaturation pattern, the
predominant defect is one of enamel hypoplasia in
which the enamel is thin but also hypomature. Except
for the decrease in the thickness of the enamel, this
pattern is radiographically similar to the hypomatura-
tion-hypoplastic variant.
A pattern of teeth alteration similar to amelogenesis
imperfecta with taurodontism is seen in the systemic
disorder, tricho-dento-osseous syndrome. This auto-
somal dominant disorder is mentioned here because
the diagnosis may not be readily apparent without a
high index of suspicion (Fig. 2-90). In addition to the
dental ﬁndings, the predominant systemic changes are
present variably and include kinky hair, osteosclerosis,
and brittle nails. The kinky hair is present at birth but
may straighten with age. The osteosclerosis primarily
affects the base of the skull and the mastoid process.
The mandible often exhibits a shortened ramus and an
obtuse angle.
Some authors have suggested that amelogenesis
imperfecta with taurodontism may represent partial
expression of the tricho-dento-osseous syndrome.
Recent studies have identiﬁed distinctly different gene
mutations that are responsible for tricho-dento-osseous
syndrome and amelogenesis imperfecta with tau-
rodontism. However, other investigators dispute this
fact, showing evidence that some examples of this
pattern of amelogenesis imperfecta appear allelic (dif-
ferent mutation on the same gene) to the syndrome. If
only dental changes are seen in the absence of hair or
bone changes, either in the individual or within the
family, then the diagnosis of amelogenesis imperfecta
appears appropriate.
HISTOPATHOLOGIC FEATURES
The histopathologic alterations present in amelogene-
sis imperfecta are not evident in routine preparations.
Because decalciﬁcation of the teeth is necessary before
processing to allow sectioning of parafﬁn-embedded
specimens, all the enamel is lost. To examine the
enamel structure of altered teeth, ground sections of
nondecalciﬁed specimens are prepared. The altera-
tions discovered are highly diverse and vary with each
clinical type of amelogenesis imperfecta. Detailed
descriptions of such alterations were provided by
Witkop and Sauk.
TREATMENT AND PROGNOSIS
The clinical implications of amelogenesis imperfecta
vary according to the subtype and its severity, but
the main problems are aesthetics, dental sensitivity,
and loss of vertical dimension. In addition, in some
types of amelogenesis imperfecta there is an increased
prevalence of caries, anterior open bite, delayed
eruption, tooth impaction, or associated gingival
inﬂammation.
A B
Fig. 2-90 Tricho-dento-osseous syndrome. A, Dentition exhibiting diffuse enamel
hypoplasia and hypomaturation. At birth, the patient exhibited a kinky “steel wool” texture to
her hair; with time, the hair straightened. A high index of suspicion was required to arrive at
the diagnosis. B, Radiograph of the same patient showing signiﬁcant taurodontism of the ﬁrst
molar and thin enamel, which is similar in density to the dentin. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

106 ORAL AND MAXILLOFACIAL PATHOLOGY
Patients with generalized thin enamel hypoplasia
demonstrate minimal normal enamel associated with
rapid attrition. These variants require full coverage as
soon as is practical; if the treatment is delayed, a loss
of usable crown length occurs. In those patients without
sufﬁcient crown lengths, full dentures (overdentures
in some cases) often become the only satisfactory
approach.
The other types of amelogenesis imperfecta demon-
strate less rapid tooth loss, and the aesthetic appear-
ance often is the prime consideration. Many less severe
cases can be improved by the placement of full crowns
or facial veneers on clinically objectionable teeth. In
some cases a lack of good enamel bonding of veneers
occurs and does not result in a durable restoration. The
use of glass ionomer cements with dentinal adhesives
often overcomes this weakness.
DENTINOGENESIS IMPERFECTA
(HEREDITARY OPALESCENT DENTIN;
CAPDEPONT’S TEETH)
Dentinogenesis imperfecta is a hereditary develop-
mental disturbance of the dentin in the absence of any
systemic disorder. Similar dental changes may be seen
in conjunction with the systemic hereditary disorder of
bone, osteogenesis imperfecta (see page 613). Dentin
defects associated with this bone disease are termed
osteogenesis imperfecta with opalescent teeth.
Extensive pedigrees of individuals with dentinogenesis
imperfecta have been studied, and none have exhib-
ited other changes suggestive of osteogenesis imper-
fecta. Genetic research has conﬁrmed that osteogenesis
imperfecta with opalescent teeth clearly is a separate
disease from dentinogenesis imperfecta.
The various types of osteogenesis imperfecta have
been associated with mutation of the COL1A1 or
COL1A2 gene that encodes production of type I
collagen; in contrast, dentinogenesis imperfecta is asso-
ciated with mutation of the DSPP (dentin sialophos-
phoprotein) gene. Currently, eight mutations of the
DSPP gene are known; seven are associated with den-
tinogenesis imperfecta, with the eighth known to create
dentin dysplasia type II.
Like amelogenesis imperfecta, the classiﬁcation of
the disorders of dentin is gradually evolving as the
result of these recent molecular genetic ﬁndings. Two
systems, one by Witkop and the other by Shields, his-
torically were well accepted but not totally satisfactory
(Table 2-3). Dentinogenesis imperfecta formerly was
divided into hereditary opalescent dentin (Shields type II)
and the Brandywine isolate (Shields type III).
The deﬁning phenotypic feature of the Brandywine
isolate was the presence of unusual pulpal enlarge-
ment known as shell teeth. Current evidence strongly
suggests that the Brandywine isolate represents nothing
more than variable expressivity of the gene for dentino-
genesis imperfecta. The original review of the isolate
revealed only 8% of the kindred with shell teeth. Inves-
tigators have documented enlarged pulps in affected
individuals whose parents and children have classic
dentinogenesis imperfecta. Finally, identical patterns
of expression have been seen in other large kindreds
with no connection to the Brandywine isolate. Subse-
quently, a single mutation of the DSPP gene has been
shown to cause both phenotypic patterns, strongly sup-
porting the assumption that the phenotypes previously
termed dentinogenesis imperfecta type II and dentinogene-
sis imperfecta type III represent a single disease with
variable expressions. A modiﬁed classiﬁcation of dentin
disorders therefore seems warranted (Table 2-4), and
continued use of the Shields or Witkop nomenclature
does not appear justiﬁed.
CLINICAL AND RADIOGRAPHIC
FEATURES
The prevalence of dentinogenesis imperfecta is not
randomly distributed throughout the United States and
Europe. Most cases can be traced to whites (people of
English or French ancestry) from communities close to
the English Channel. The disorder is autosomal domi-
nant and occurs in about 1:8000 whites in the United
States.
The dental alterations in dentinogenesis imperfecta
and osteogenesis imperfecta with opalescent teeth are
similar clinically, radiographically, and histopathologi-
cally. All teeth in both dentitions are affected. The
Table 2-3 Dentinogenesis Imperfecta
Shields Clinical Presentation Witkop
Dentinogenesis imperfecta I Osteogenesis imperfecta with opalescent teeth Dentinogenesis imperfecta
Dentinogenesis imperfecta II Isolated opalescent teeth Hereditary opalescent teeth
Dentinogenesis imperfecta III Isolated opalescent teeth Brandywine isolate
Data from Shields ED: A new classiﬁcation of heritable human enamel defects and a discussion of dentin defects. In Jorgenson RJ, Paul NW: Dentition:
genetic effects (birth defects original article series), vol 19, no. 1, pp 107-127, New York, 1983, Alan R Liss; Witkop CJ Jr: Amelogenesis imperfecta,
dentinogenesis imperfecta and dentin dysplasia revisited: problems in classiﬁcation, J Oral Pathol 17:547-553, 1988. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 107
severity of the dental alterations varies with the age
at which the tooth developed. Deciduous teeth are
affected most severely, followed by the permanent inci-
sors and ﬁrst molars, with the second and third molars
being least altered.
The dentitions have a blue-to-brown discoloration,
often with a distinctive translucence (Fig. 2-91). The
enamel frequently separates easily from the underly-
ing defective dentin. Once exposed, the dentin often
demonstrates signiﬁcantly accelerated attrition (Fig.
2-92). Radiographically, the teeth have bulbous crowns,
cervical constriction, thin roots, and early obliteration
of the root canals and pulp chambers (Fig. 2-93).
The trait exhibits close to 100% penetrance but vari-
able expressivity. Signiﬁcant, clinically obvious enamel
hypoplasia is noted in some patients (Fig. 2-94).
Researchers believe that the enamel abnormality is a
secondary defect and not a direct expression of the
dentinogenesis imperfecta gene. Although the pulps
are usually obliterated by excess dentin production,
some teeth may show normal-sized pulps or pulpal
enlargement (shell teeth).
Shell teeth demonstrate normal-thickness enamel
in association with extremely thin dentin and dramati-
cally enlarged pulps (Fig. 2-95). The thin dentin may
involve the entire tooth or be isolated to the root. This
rare abnormality has been seen most frequently in
deciduous teeth in the presence of dentinogenesis
imperfecta. The alteration may be unassociated with
dentinogenesis imperfecta as an isolated ﬁnding in
both dentitions and demonstrate normal tooth shape
and coloration, a negative family history, and diffuse
involvement. In the isolated variant, slow but progres-
sive root resorption occurs.
Table 2-4 Modiﬁed Classiﬁcation of Hereditary Disorders Affecting Dentin
Disorder Inheritance Involved Gene or Genes
Osteogenesis imperfecta with opalescent teethAutosomal dominant or recessive COL1A1, COL1A2
Dentinogenesis imperfecta Autosomal dominant DSPP
Dentin dysplasia type I Autosomal dominant
Dentin dysplasia type II Autosomal dominant DSPP
Fig. 2-91 Dentinogenesis imperfecta. Dentition exhibiting
diffuse brownish discoloration and slight translucence.
Fig. 2-92 Dentinogenesis imperfecta. Dentition exhibiting
grayish discoloration with signiﬁcant enamel loss and
attrition.
Fig. 2-93 Dentinogenesis imperfecta. Radiograph of
dentition exhibiting bulbous crowns, cervical constriction,
and obliterated pulp canals and chambers. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

108 ORAL AND MAXILLOFACIAL PATHOLOGY
Several kindreds affected with dentinogenesis
imperfecta also have been shown to demonstrate pro-
gressive, sensorineural, high-frequency hearing loss.
Jaw position has been shown to affect the anatomy of
the inner ear, and premature tooth loss has been asso-
ciated with hearing deﬁcits. At this time, it is unclear if
the hearing loss is correlated with the DSPP mutation
or an alteration secondary to the primary gnathic
changes. Investigators wonder if dental restoration
may prevent the hearing loss or if the DSPP gene may
directly affect bone formation and the structure of the
inner ear.
HISTOPATHOLOGIC FEATURES
As expected, affected teeth demonstrate altered dentin.
The dentin adjacent to the enamel junction appears
similar to normal dentin, but the remainder is distinctly
abnormal. Short misshapen tubules course through an
atypical granular dentin matrix, which often demon-
strates interglobular calciﬁcation (Fig. 2-96). Scanty
atypical odontoblasts line the pulp surface, and cells
can be seen entrapped within the defective dentin. In
ground sections the enamel is normal in most patients;
however, about one third of the patients have hypoplas-
tic or hypocalciﬁed defects.
TREATMENT AND PROGNOSIS
The entire dentition is at risk because of numerous
problems. The root canals become threadlike and may
develop microexposures, resulting in periapical inﬂam-
matory lesions. In spite of the risk of enamel loss and
signiﬁcant attrition, the teeth are not good candidates
for full crowns because of cervical fracture. The success
of full coverage is best in teeth with crowns and roots
that exhibit close to a normal shape and size. Overlay
dentures placed on teeth that are covered with ﬂuo-
ride-releasing glass ionomer cement have been used
with success in some cases.
Additional therapeutic approaches have been used,
but long-term follow-up is incomplete. In patients with
extensive attrition, the vertical dimension has been
rebuilt by placing nonprecious metal castings with
adhesive luting agents on teeth that have received no
preparation and are not subject to signiﬁcant occlusal
stress. The newer composites combined with a dentin-
bonding agent have been used in areas subject to occlu-
sal wear. When large kindreds have been followed
over a long term, most of those affected are candidates
for full dentures or implants by 30 years of age in spite
of the numerous interventions. Newer materials and
interventions may alter this outlook.
DENTIN DYSPLASIA
Dentin dysplasia was initially categorized in 1939. Two
major patterns exist: type I and type II. By deﬁnition,
dentin dysplasia should have no correlation with sys-
Fig. 2-94 Dentinogenesis imperfecta. Radiograph of
dentition exhibiting bulbous crowns, early obliteration of the
pulp, and enamel hypoplasia. (From Levin LS, Leaf SH, Jelmine RJ et
al: Dentinogenesis imperfecta in the Brandywine isolate (DI type III): clinical,
radiologic, and scanning electron microscopic studies of the dentition, Oral
Surg Oral Med Oral Pathol 56:267-274, 1983.)
Fig. 2-95 Shell teeth. Dentition exhibiting normal
thickness enamel, extremely thin dentin, and dramatically
enlarged pulps.
Fig. 2-96 Dentinogenesis imperfecta. Coronal dentin
exhibiting short misshapen tubules within atypical granular
dentin matrix. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 109
temic disease or dentinogenesis imperfecta. An unusual
combination of type I and type II dentin dysplasia has
been reported, but these cases represent variable
pulpal anatomy that has been documented well in
dentin dysplasia type I. Systemic diseases reported to
be associated with similar dentin changes are listed in
Box 2-10.
As evidenced by the clinical and radiographic
descriptions that follow, dentin dysplasia type II is
closely related to dentinogenesis imperfecta. In addi-
tion, genetic evaluation has shown that dentin dyspla-
sia type II arises from mutation of the DSPP gene (see
Dentinogenesis Imperfecta) and is allelic (different
mutation of the same gene) to dentinogenesis imper-
fecta. The phenotypic and genotypic ﬁndings are so
close that some might choose to classify dentin dyspla-
sia type II as a variation of dentinogenesis imperfecta
rather than grouping it with dentin dysplasia type I.
Indeed, before the current era of molecular genetics,
Witkop remarked on the close similarities of these
two diseases and mentioned the possibility of
reclassiﬁcation.
CLINICAL AND RADIOGRAPHIC
FEATURES
DENTIN DYSPLASIA TYPE I
Dentin dysplasia type I (radicular dentin dyspla-
sia), has been referred to as rootless teeth, because
the loss of organization of the root dentin often leads
to a shortened root length. The process exhibits an
autosomal dominant pattern of inheritance and an
approximate prevalence of 1:100,000. The enamel
and coronal dentin are normal clinically and well
formed (Fig. 2-97), but the radicular dentin loses all
organization and subsequently is shortened dramati-
cally (Fig. 2-98). Wide variation in root formation is
produced because dentinal disorganization may occur
during different stages of tooth development. If the
dentin organization is lost early in tooth development,
markedly deﬁcient roots are formed; later disorganiza-
tion results in minimal root malformation. The vari-
ability is most pronounced in permanent teeth and
may vary not only from patient to patient but also from
tooth to tooth in a single patient. Because of the short-
ened roots, the initial clinical signs are extreme tooth
mobility and premature exfoliation, spontaneously or
secondary to minor trauma. Less frequently, delayed
eruption is the presenting symptom. The strength of
the radicular dentin is reduced, with the teeth being
predisposed to fracture during extractions.
Radiographically, the deciduous teeth often are
affected severely, with little or no detectable pulp, and
roots that are markedly short or absent. The permanent
teeth vary according to the proportion of organized
versus disorganized dentin (Fig. 2-99). Several years
ago, a subclassiﬁcation of dentin dysplasia type I
was proposed and has become widely accepted
(Box 2-11).
Box 2-10
Systemic Diseases Correlated with Dentin
Dysplasia-like Alterations
● Calcinosis universalis
●Rheumatoid arthritis and vitaminosis D
●Sclerotic bone and skeletal anomalies
● Tumoral calcinosis
Fig. 2-97 Dentin dysplasia type I. Dentition exhibiting
attrition but otherwise normal coronal coloration and
morphology.
A B
Fig. 2-98 Dentin dysplasia type I. Posterior dentition
exhibiting dramatically shortened roots, absence of pulp
canals, and small, crescent-shaped pulp chambers. Note
radiolucency at apex of mandibular bicuspid. (Courtesy of Dr.
Michael Quinn.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

110 ORAL AND MAXILLOFACIAL PATHOLOGY
In general, the teeth without root canals are those
that frequently develop periapical radiolucencies
without obvious cause (see Fig. 2-98). The radiolucen-
cies represent periapical inﬂammatory disease and
appear secondary to caries or spontaneous coronal
exposure of microscopic threads of pulpal remnants
present within the defective dentin. The subclassiﬁca-
tion system has proven to be beneﬁcial, because it
assists in highlighting the mild DDId variant that often
is not quickly recognized as dentin dysplasia and can
be confused with dentin dysplasia type II. On occasion,
reports have demonstrated patients with classic DDId-
like involvement of the anteriors and bicuspids but
without affected molars.
A similar but unrelated disorder is ﬁbrous dyspla-
sia of dentin. This autosomal dominant disorder
exhibits teeth that are normal clinically. Radiographi-
cally the teeth are normal in shape but demonstrate a
radiodense product ﬁlling the pulp chambers and
canals. In contrast to dentinogenesis imperfecta, small
foci of radiolucency can be seen in the pulp. In contrast
to dentin dysplasia type I, no crescent pulp chambers
and no decrease in root length are seen. The radiodense
intrapulpal material consists of ﬁbrotic dentin.
DENTIN DYSPLASIA TYPE II
Dentin dysplasia type II (coronal dentin dysplasia)
is inherited as an autosomal dominant hereditary dis-
order that exhibits numerous features of dentinogene-
sis imperfecta. In contrast to dentin dysplasia type I, the
root length is normal in both dentitions. The deciduous
teeth closely resemble those of dentinogenesis imper-
fecta. Clinically, the teeth demonstrate a blue-to-amber-
to-brown translucence. Radiographically, the dental
changes include bulbous crowns, cervical constriction,
thin roots, and early obliteration of the pulp. The per-
manent teeth demonstrate normal clinical coloration;
however, radiographically, the pulp chambers exhibit
signiﬁcant enlargement and apical extension. This
altered pulpal anatomy has been described as thistle
tube–shaped or ﬂame-shaped (Figs. 2-100 and 2-101).
Pulp stones develop in the enlarged pulp chambers.
A similar but unrelated disorder is pulpal dyspla-
sia. This process develops in teeth that are normal
clinically. Radiographically, both dentitions exhibit
thistle tube–shaped pulp chambers and multiple pulp
stones.
HISTOPATHOLOGIC FEATURES
In patients with dentin dysplasia type I, the coronal
enamel and dentin are normal. Apical to the point of
disorganization, the central portion of the root forms
DDIdDDIcDDIbDDIa
Box 2-11
Subclassiﬁcation of Dentin Dysplasia
Type I
●DDIa: No pulp chambers, no root formation, and fre-
quent periapical radiolucencies
●DDIb: A single small horizontally oriented and cres-
cent-shaped pulp, roots only a few millimeters in
length, and frequent periapical radiolucencies
●DDIc: Two horizontally oriented and crescent-shaped
pulpal remnants surrounding a central island of
dentin, signiﬁcant but shortened root length, and
variable periapical radiolucencies
●DDId: Visible pulp chambers and canals, near normal
root length, enlarged pulp stones that are located in
the coronal portion of the canal and create a local-
ized bulging of the canal and root, constriction of the
pulp canal apical to the stone, and few periapical
radiolucencies
Fig. 2-99 Dentin dysplasia type I. Illustration demonstrating the variability of the
radiographic appearance according to the degree of dentin disorganization within the root. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 111
whorls of tubular dentin and atypical osteodentin.
These whorls exhibit a peripheral layer of normal
dentin, giving the root the appearance of a “stream
ﬂowing around boulders” (Fig. 2-102).
In patients with dentin dysplasia type II, the deci-
duous teeth demonstrate the pattern described in den-
tinogenesis imperfecta. The permanent teeth exhibit
normal enamel and coronal dentin. Adjacent to the
pulp, numerous areas of interglobular dentin are seen.
The radicular dentin is atubular, amorphous, and
hypertrophic. Pulp stones develop in any portion of
the chamber (Fig. 2-103).
TREATMENT AND PROGNOSIS
In patients with dentin dysplasia type I, preventive care
is of foremost importance. Perhaps as a result of short-
ened roots, early loss from periodontitis is frequent.
In addition, pulp vascular channels extend close to
the dentinoenamel junction; therefore, even shallow
occlusal restorations can result in pulpal necrosis.
Meticulous oral hygiene must be established and
maintained.
If periapical inﬂammatory lesions develop, the root
length guides the therapeutic choice. Conventional
endodontic therapy requires mechanical creation of
canal paths and has been successful in teeth without
extremely short roots. Teeth with short roots demon-
strate pulpal ramiﬁcations that eliminate conventional
Fig. 2-100 Dentin dysplasia type II. Permanent dentition
that does not exhibit translucence, as noted in the deciduous
teeth. The patient also exhibits mild ﬂuorosis of the enamel.
Fig. 2-101 Dentin dysplasia type II. Radiographic
appearance of the dentition depicted in Fig. 2-100. Note
thistle tube–shaped enlargements of the pulp chambers and
numerous pulp stones.
Fig. 2-102 Dentin dysplasia type I. Polarized light view of
affected tooth demonstrating a classic “stream ﬂowing
around boulders” appearance.
Fig. 2-103 Dentin dysplasia type II. Affected tooth
exhibiting large pulp stone within the pulp chamber. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

112 ORAL AND MAXILLOFACIAL PATHOLOGY
endodontic treatment as an appropriate therapeutic
option. Periapical curettage and retrograde amalgam
seals have demonstrated short-term success.
Dentin dysplasia type II demonstrates similar prob-
lems, and meticulous oral hygiene must be established.
The deciduous teeth can be approached in a manner
similar to that used for dentinogenesis imperfecta. In
the permanent teeth, an increased risk of periapical
inﬂammatory lesions is also seen. Because the pulp
canals are not usually obliterated completely, end-
odontic therapy is accomplished more readily.
REGIONAL ODONTODYSPLASIA
(GHOST TEETH)
Regional odontodysplasia is a localized, nonheredi-
tary developmental abnormality of teeth with extensive
adverse effects on the formation of enamel, dentin, and
pulp. Most cases are idiopathic, but a number have
been related to various syndromes, growth abnormali-
ties, neural disorders, and vascular malformations (Box
2-12). A number of causes have been proposed (Box
2-13), but the most popular theory revolves around an
alteration in the vascular supply. Several cases have
occurred in patients with vascular nevi of the head and
neck; in addition, similar changes have been induced
in animals by restricting the vascular ﬂow to an area of
the jaws.
CLINICAL AND RADIOGRAPHIC
FEATURES
Regional odontodysplasia is an uncommon ﬁnding that
occurs in both dentitions and exhibits no racial predi-
lection and a slight female predominance. A review of
the age at the time of diagnosis reveals a bimodal peak
that correlates with the normal time of eruption of the
deciduous (2 to 4 years) and permanent (7 to 11 years)
dentitions. Typically, the process affects a focal area of
the dentition, with involvement of several contiguous
teeth. A maxillary predominance exists with a predilec-
tion for the anterior teeth. Occasionally, an unaffected
tooth may be intermixed within a row of altered teeth.
Ipsilateral involvement of both arches and bilateral
changes in the same jaw have been reported. Although
rare generalized involvement has been documented,
the presence of regional odontodysplasia in more than
two quadrants is rare. Involvement of the deciduous
dentition is typically followed by similarly affected
permanent teeth. In the area of altered teeth, the
surrounding bone often exhibits a lower density; in
addition, hyperplasia of the soft tissue may be noted
overlying affected teeth that are impacted.
Many of the affected teeth fail to erupt. Erupted
teeth demonstrate small irregular crowns that are
yellow to brown, often with a very rough surface. Caries
and associated periapical inﬂammatory lesions are
fairly common. Because of dentinal clefts and very long
pulp horns, pulpal necrosis is common (often in the
absence of an obvious cause). Radiographically, the
altered teeth demonstrate extremely thin enamel and
dentin surrounding an enlarged radiolucent pulp,
resulting in a pale wispy image of a tooth; hence the
term ghost teeth (Fig. 2-104). A lack of contrast is seen
between the dentin and the enamel, with an indistinct
or “fuzzy” appearance of the coronal silhouette. Short
roots and open apices may be seen. The enlarged pulps
frequently demonstrate one or more prominent pulp
stones. The most common presenting signs and symp-
toms include delayed or failure of eruption, early exfo-
liation, abscess formation, malformed teeth, and
noninﬂammatory gingival enlargement.
HISTOPATHOLOGIC FEATURES
In ground sections the thickness of the enamel varies,
resulting in an irregular surface. The prism structure
of the enamel is irregular or lacking with a laminated
Box 2-12
Pathoses Noted in Association with
Regional Odontodysplasia
● Ectodermal dysplasia
● Epidermal nevi
● Hypophosphatasia
● Hydrocephalus
●Ipsilateral facial hypoplasia
● Neuroﬁbromatosis
● Orbital coloboma
●Rh factor incompatibility
● Vascular nevi
Box 2-13
Proposed Causations for Regional
Odontodysplasia
●Abnormal migration of neural crest cells
● Latent virus
●Local circulatory deﬁciency
●Local trauma or infection
● Hyperpyrexia
● Malnutrition
●Medication used during pregnancy
● Radiation therapy
● Somatic mutation `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 113
appearance. The dentin contains clefts scattered
through a mixture of interglobular dentin and amor-
phous material. Globular areas of poorly organized
tubular dentin and scattered cellular inclusions often
are seen. The pulp tissue contains free or attached
stones that may exhibit tubules or consist of laminated
calciﬁcation. The follicular tissue surrounding the
crown may be enlarged and typically exhibits focal col-
lections of basophilic enamel-like calciﬁcations called
enameloid conglomerates (Fig. 2-105). This pattern
of calciﬁcation is not speciﬁc for regional odontodys-
plasia and has been seen in other processes with
disturbed enamel formation, such as amelogenesis
imperfecta. Scattered islands of odontogenic epithe-
lium and other patterns of intramural calciﬁcation also
are seen.
TREATMENT AND PROGNOSIS
The basic approach to therapy of regional odontodys-
plasia is directed toward retention of the altered teeth,
whenever possible, to allow for appropriate develop-
ment and preservation of the surrounding alveolar
ridge. Endodontic therapy on nonvital teeth that have
sufﬁcient hard tissue to allow restoration has been per-
formed successfully. Unerupted teeth should remain
untouched, restoring function with a removable partial
prosthesis until the skeletal growth period has passed.
Erupted teeth can be covered with etched-retained res-
torations or stainless steel crowns until ﬁnal restora-
tions can be placed after the completion of growth.
Because of the fragile nature of the coronal hard tissue
and the ease of pulp exposure, tooth preparation is
contraindicated. Severely affected and infected teeth
often are not salvageable and need to be removed.
Although ankylosis has been seen with autotrans-
planted teeth, normal bicuspids have been autotrans-
planted into the extraction sites of the abnormal
dentition. This approach can successfully restore mas-
ticatory function, allowing appropriate facial develop-
ment, and preventing ridge atrophy and supereruption
of the opposing dentition. Osseointegrated implants
have been placed in growing children with hypodontia
and could be used in the setting of regional odontodys-
plasia. Because implants essentially become ankylosed,
they have the potential to become embedded upon
continued gnathic growth in a child. For this reason,
implants generally should be reserved for patients who
have completed pubertal growth.
Although vitality of the abnormal dentition often is
difﬁcult to maintain, such efforts may bring signiﬁcant
rewards. Several investigators have shown continued
dentinal development of teeth affected by regional
odontodysplasia. In cases monitored for many years,
the teeth lost their ghostly appearance and revealed a
resultant decrease in pulp size, a signiﬁcant increase in
dentin thickness, and ultimate relative normalization
of the radicular anatomy. In contrast, the enamel
remained hypoplastic. The surrounding bone became
well developed and lost its diminished density. Only a
few reports of this phenomenon exist, however, most
likely because the prior treatment of choice has been
extraction.
BIBLIOGRAPHY
General References
Gorlin RJ, Cohen MM, Hennekam RCM: Syndromes of the head
and neck, ed 4, New York, 2001, Oxford University Press.
Stewart RE, Prescott GH: Oral facial genetics, St Louis, 1976,
Mosby.
Fig. 2-104 Regional odontodysplasia (ghost teeth).
Posterior mandibular dentition exhibiting enlarged pulps and
extremely thin enamel and dentin. (Courtesy of Dr. John B. Perry.)
Fig. 2-105 Regional odontodysplasia. Follicular tissue
contains scattered collections of enameloid conglomerates
and islands of odontogenic epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

114 ORAL AND MAXILLOFACIAL PATHOLOGY
Witkop CJ: Clinical aspects of dental anomalies, Int Dent J
26:378-390, 1976.
Witkop CJ, Rao S: Inherited defects in tooth structure. In Bergsma
D: Birth defects. Original article series, vol 7, no 7, pp 153-184,
Baltimore, 1971, Williams & Wilkins.
Environmental Effects on Tooth Structure Development
Andreasen JO, Sundström B, Ravn JJ: The effect of traumatic
injuries to primary teeth on their permanent successors. 1. A
clinical and histologic study of 117 injured permanent teeth,
Scand J Dent Res 79:219-283, 1971.
Bentley EM, Ellwood RP, Davies RM: Fluoride ingestion
from toothpaste by young children, Br Dent J 186:460-462,
1999.
Broadbent JM, Thomson WM, Williams SM: Does caries in
primary teeth predict enamel defects in permanent teeth?
A longitudinal study, J Dent Res 84:260-264, 2005.
Brook AH, Smith JM: Environmental causes of enamel defects,
Ciba Found Symp 205:212-225, 1997.
Browne D, Whelton H, O’Mullane D: Fluoride metabolism and
ﬂuorosis, J Dent 33:177-186, 2005.
Centers for Disease Control and Prevention: Ten great public
health achievements—United States, 1990-1999, MMWR
Morb Mortal Wkly Rep 48:241-243, 1999.
Centers for Disease Control and Prevention: Recommenda-
tions for using ﬂuoride to prevent and control dental caries
in the United States, MMWR Recomm Rep 50(RR-14):1-42,
2001.
Churchill HV: Occurrence of ﬂuorides in some waters of the
United States, J Ind Eng Chem 23:996-998, 1931.
Croll TP: Esthetic correction for teeth with ﬂuorosis and ﬂuoro-
sis-like enamel dysmineralization, J Esthet Dent 10:21-29,
1998.
Dean HT: Endemic ﬂuorosis and its relation to dental caries,
Public Health Rep 53:1443-1452, 1938.
Fayle SA: Molar incisor hypomineralisation: restorative manage-
ment, Eur J Paediatr Dent 4:121-126, 2003.
Groeneveld A, Van Eck AAMJ, Backer Dirks O: Fluoride in caries
prevention: is the effect pre- or post-eruptive? J Dent Res
69(spec iss):751-755, 1990.
Holtta P, Alaluusua S, Saarinen-Pinkala UM et al: Long-term
adverse effects on dentition in children with poor-risk
and autologous stem cell transplantation with or without
total body irradiation, Bone Marrow Transplant 29:121-127,
2002.
Hong L, Levy SM, Warren JJ et al: Association of amoxicillin use
during early childhood with developmental tooth enamel
defects, Arch Pediatr Adolesc Med 159:943-948, 2005.
Kaste SC, Hopkins KP, Bowman LC: Dental abnormalities in
long-term survivors of head and neck rhabdomyosarcoma,
Med Pediatr Oncol 25:96-101, 1995.
Marec-Berard P, Azzi D, Chaux-Bodard AG et al: Long-term
effects of chemotherapy on dental status in children treated
for nephroblastoma, Pediatr Hematol Oncol 22:581-588,
2005.
Marshall TA, Levy SM, Warren JJ et al: Association between
intakes of ﬂuoride from beverages during infancy and
dental ﬂuorosis of primary teeth, J Am Col Nutr 23:108-116,
2004.
McKay FS, Black GV: An investigation of mottled teeth: an
endemic developmental imperfection of the enamel and
teeth, heretofore unknown in the literature of dentistry, Dent
Cosmos 58:477-484, 1916.
Montero MJ, Douglass JM, Mathieu GM: Prevalence of dental
caries and enamel defects in children in Connecticut Head
Start children, Pediatr Dent 25:235-239, 2003.
Pajari U, Lanning M: Developmental defects of teeth in survivors
of childhood ALL are related to the therapy and age at diag-
nosis, Med Pediatr Oncol 24:310-314, 1995.
Pendrys DG: Risk of enamel ﬂuorosis in nonﬂuoridated
and optimally ﬂuoridated populations: considerations for
the dental professional, J Am Dent Assoc 131:746-755,
2000.
Pendrys DG, Katz RV: Risk factors for enamel ﬂuorosis in opti-
mally ﬂuoridated children born after the US manufacturer’s
decision to reduce the ﬂuoride concentration of infant
formula, Am J Epidemiol 148:967-974, 1998.
Peterson J: Solving the mystery of the Colorado brown stain,
J Hist Dent 45:57-61, 1997.
Pourghadiri M, Longhurst P, Watson TF: A new technique for
the controlled removal of mottled enamel: measurement of
enamel loss, Br Dent J 184:239-241, 1998.
Price RBT, Loney RW, Doyle MG et al: An evaluation of a tech-
nique to remove stains from teeth using microabrasion, J Am
Dent Assoc 134:1066-1071, 2003.
Riordan PJ: The place of ﬂuoride supplements in caries preven-
tion today, Aust Dent J 41:335-342, 1996.
Riordan PJ: Fluoride supplements for young children; analysis of
the literature focusing on beneﬁts and risks, Community Dent
Oral Epidemiol 27:72-83, 1999.
Rodd HD, Davidson LE: The aesthetic management of severe
dental ﬂuorosis in the young patient, Dent Update 24:408-411
1997.
Seow WK: Clinical diagnosis of enamel defects: pitfalls and prac-
tical guidelines, Int Dent J 47:173-182, 1997.
Suckling GW: Developmental defects of enamel—historical and
present day perspective of their pathogenesis, Adv Dent Res
3:87-94, 1989.
Turner JG: Injury to the teeth of succession by abscess of the
temporary teeth, Brit Dent J 30:1233-1237, 1909.
von Arx T: Developmental disturbances of permanent teeth fol-
lowing trauma to the primary dentition, Aust Dent J 38:1-10,
1993.
Weerheijm KL: Molar incisor hypomineralisation (MIH), Eur J
Paediatr Dent 4:114-120, 2003.
Weerheijm KL: Molar incisor hypomineralisation (MIH): clinical
presentation, aetiology and management, Dent Update 31:9-
12, 2004.
Weerheijm KL, Groen HJ, Beentjes VEVM et al: Prevalence of
cheese molars in eleven-year-old Dutch children, J Dent Child
68:259-262, 2001.
Postdevelopmental Loss of Tooth Structure
Amaechi BT, Higham SM, Edgar WM: Inﬂuence of abrasion in
clinical manifestation of human dental erosion, J Oral Rehabil
30:407-413, 2003.
Bakland LK: Root resorption, Dent Clin North Am 36:491-507,
1992.
Beertsen W, Piscaer M, Van Winkelhoff AF et al: Generalized
cervical root resorption associated with periodontal disease,
J Clin Periodontol 28:1067-1073, 2001.
Caliskan MK, Türkün M: Prognosis of permanent teeth with
internal resorption: a clinical review, Endod Dent Traumatol
13:75-81, 1997.
Eccles JD: Tooth surface loss from abrasion, attrition and erosion,
Dent Update 7:373-381, 1982.
Fuss Z, Tsesis I, Lin S: Root resorption—diagnosis, classiﬁcation
and treatment choices based on stimulation factors, Dent
Traumatol 19:175-182, 2003.
Gartner AH, Mack T, Somerlott RG et al: Differential diagnosis
of internal and external resorption, J Endod 2:329-334,
1976. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 115
Goultschin J, Nitzan D, Azaz B: Root resorption. Review and
discussion, Oral Surg Oral Med Oral Pathol 54:586-590,
1982.
Grippo JO: Abfractions: a new classiﬁcation of hard tissue lesions
of teeth, J Esthet Dent 3:14-19, 1991.
Grippo JO, Simring M: Dental “erosions” revisited, J Am Dent
Assoc 126:619-630, 1995.
Grippo JO, Simring M, Schreiner S: Attrition, abrasion, corrosion
and abfraction revisited. A new perspective on tooth surface
lesions, J Am Dent Assoc 135:1109-1118, 2004.
Harris EF, Boggan BW, Wheeler DA: Apical root resorption in
patients treated with comprehensive orthodontics, J Tenn
Dent Assoc 81:30-33, 2001.
Heithersay GS: Clinical, radiologic, and histopathologic features
of invasive cervical resorption, Quintessence Int 30:27-37,
1999.
House RC, Grisius R, Bliziotes MM et al: Perimolysis: unveiling
the surreptitious vomiter, Oral Surg Oral Med Oral Pathol
51:152-155, 1981.
Kelleher M, Bishop K: The aetiology and clinical appearance
of tooth wear, Eur J Prosthodont Restor Dent 5:157-160,
1997.
Kelleher M, Bishop K: Tooth surface loss: an overview, Br Dent
J 186:61-66, 1999.
Khan F, Young WG, Daley TJ: Dental erosion and bruxism. A
tooth wear analysis from South East Queensland, Aust Dent
J 43:117-127, 1998.
Kofod T, Würtz V, Melsen B: Treatment of an anklosed central
incisor by single tooth dento-osseous osteotomy and a simple
distraction device, Am J Orthod Dentofacial Orthop 127:72-80,
2005.
Krasner P: Advances in the treatment of avulsed teeth, Dent
Today 22:84-87, 2003.
Lambrechts P, van Meerbeek B, Perdigão J et al: Restorative
therapy for erosive lesions, Eur J Oral Sci 104:229-240,
1996.
Lee WC, Eakle WS: Possible role of tensile stress in the etiology
of cervical erosive lesions of teeth, J Prosthet Dent 52:374-379,
1984.
Lee WC, Eakle WS: Stress-induced cervical lesions: review of
advances in the past 10 years, J Prosthet Dent 75:487-494,
1996.
Levitch LC, Bader JD, Shugars DA et al: Non-carious cervical
lesions, J Dent 22:195-207, 1994.
Litonjua LA, Andreana S, Bush PJ et al: Tooth wear: attrition,
erosion, and abrasion, Quintessence Int 34:435-446, 2003.
Litonjua LA, Andreana S, Patra AK et al: An assessment of stress
analyses in the theory of abfraction, Biomed Mater Eng 14:311-
321, 2004.
Litonjua LA, Bush PJ, Andreana S et al: Effects of occlusal load
in cervical lesions, J Oral Rehabil 31:225-232, 2004.
Massler M, Malone AJ: Root resorption in human permanent
teeth: a roentgenographic study, Am J Orthod 40:619-633,
1954.
Milosevic A: Toothwear: aetiology and presentation, Dent Update
25:6-11, 1998.
Milosevic A: Toothwear: management, Dent Update 25:50-55,
1998.
Moody GH, Muir KF: Multiple idiopathic root resorption. A case
report and discussion of pathogenesis, J Clin Periodontol
18:577-580, 1991.
Mummery JH: The pathology of “pink spots” on teeth, Br Dent J
41:301-311, 1920.
Ne RF, Witherspoon DE, Gutmann JL: Tooth resorption, Quintes-
sence Int 30:9-25, 1999.
Newman WG: Possible etiologic factors in external root resorp-
tion, Am J Orthod 67:522-539, 1975.
Rabinowitch BZ: Internal resorption, Oral Surg Oral Med Oral
Pathol 33:263-282, 1972.
Ram D, Cohenca N: Therapeutic protocols for avulsed perma-
nent teeth: review and clinical update, Pediatr Dent 26:251-
255, 2004.
Rees JS: The role of cuspal ﬂexure in the development of abfrac-
tion lesions: a ﬁnite element study, Eur J Oral Sci 106:1028-
1032, 1998.
Sameshima GT, Sinclair PM: Predicting and preventing root
resorption: I. Diagnostic factors, Am J Orthod Dentofacial
Orthop 119:505-510, 2001.
Schätzle M, Tanner SD, Bosshardt DD: Progressive, generalized,
apical idiopathic root resorption and hypercementosis, J Peri-
odontol 76:2002-2011, 2005.
Sivasithamparam K, Harbrow D, Vinczer E et al: Endodontic
sequelae of dental erosion, Aust Dent J 48:97-101, 2003.
Smith BGN, Bartlett DW, Robb ND: The prevalence, etiology
and management of tooth wear in the United Kingdom, J
Prosthet Dent 78:367-372, 1997.
Tronstad L: Root resorption-etiology, terminology and clinical
manifestations, Endod Dent Traumatol 4:241-252, 1988.
Yap AUJ, Neo JCL: Non-carious cervical tooth loss: part 1, Dent
Update 22:315-318, 1995.
Yap AUJ, Neo JCL: Non-carious cervical tooth loss: part 2, man-
agement, Dent Update 22:364-368, 1995.
Young WG: The oral medicine of tooth wear, Aust Dent J 46:236-
250, 2001.
Young WG: Tooth wear: diet analysis and advice, Int Dent J
55:68-72, 2005.
Young WG, Khan F: Sites of dental erosion are saliva-dependent,
J Oral Rehabil 29:35-43, 2002.
Discolorations of Teeth
Alto LAM, Pomarico L, Souza IPR et al: Green pigmentation of
deciduous teeth: report of two cases, J Dent Child 71:179-182,
2004.
Ayaslioglu E, Erkek E, Oba AA et al: Doxycycline-induced stain-
ing of permanent adult dentition, Aust Dent J 50:273-275,
2005.
Bowles WH: Protection against minocycline pigment formation
by ascorbic acid (vitamin C), J Esthet Dent 10:182-186, 1998.
Cabrerizo-Merino CC, Garcia-Ballesta C, Onate-Sanchez RE et
al: Stomatological manifestations of Günther’s disease, J Pedod
14:113-116, 1990.
Cheek CC, Heymann HO: Dental and oral discoloration associ-
ated with minocycline and other tetracycline analogs, J Esthet
Dent 11:43-48, 1999.
Dayan D, Heifferman A, Gorski M et al: Tooth discoloration—
extrinsic and intrinsic factors, Quintessence Int 14:195-199,
1983.
Eisenberg E, Bernick SM: Anomalies of the teeth with stains and
discolorations, J Prev Dent 2:7-20, 1975.
Friedman S: Internal bleaching: long-term outcomes and com-
plications, J Am Dent Assoc 128:51S-55S, 1997.
Giunta JL, Tsamtsouris A: Stains and discolorations of teeth:
review and case reports, J Pedod 2:175-182, 1978.
Holan G, Fuks AB: The diagnostic value of coronal dark-gray
discoloration in primary teeth following traumatic injuries,
Pediatr Dent 18:224-227, 1996.
Link J: Discoloration of the teeth in alkaptonuria (ochronosis)
and parkinsonism, Chronicle 36:130, 1973.
Morisaki I, Abe K, Tong LS et al: Dental ﬁndings of children with
biliary atresia: report of seven cases, J Dent Child 57:220-223,
1990. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

116 ORAL AND MAXILLOFACIAL PATHOLOGY
Nelson R, Parker SRS: Doxycycline-induced staining of adult
teeth: the ﬁrst reported case, Arch Dermatol 142:1081-1082,
2006.
Rendall JR, McDougall AC: Reddening of the upper central inci-
sors associated with periapical granuloma in lepromatous
leprosy, Br J Oral Surg 13:271-277, 1976.
Sainio P, Syrjanen S, Keijala JP et al: Postmortem pink teeth
phenomenon: an experimental study and a survey of the lit-
erature, Proc Finn Dent Soc 86:29-35, 1990.
Sánchez AR, Rogers RS III, Sheridan PJ: Tetracycline and other
tetracycline-derivative staining of the teeth and oral cavity,
Int J Dermatol 43:709-715, 2004.
Siekert RG, Gibilisco JA: Discoloration of the teeth in alkapton-
uria (ochronosis) and parkinsonism, Oral Surg Oral Med Oral
Pathol 29:197-199, 1970.
Tredwin CJ, Scully C, Bagan-Sebastian JV: Drug-induced disor-
ders of teeth, J Dent Res 84:596-602, 2005.
van der Bijl P, Pitigoi-Aron G: Tetracycline and calciﬁed tissues,
Ann Dent 54:69-72, 1995.
Watanabe K, Shibata T, Kurosawa T et al: Bilirubin pigmentation
of human teeth caused by hyperbilirubinemia, J Oral Pathol
Med 28:128-130, 1999.
Westbury LW, Najera A: Minocycline-induced intraoral phar-
macogenic pigmentation: case reports and review of the lit-
erature, J Periodontol 68:84-91, 1997.
Wray A, Welbury R: Treatment of intrinsic discoloration in per-
manent anterior teeth in children and adolescents, Int J Pae-
diatr Dent 11:309-315, 2001.
Localized Disturbances in Eruption
Alling CC III, Catone GA: Management of impacted teeth, J Oral
Maxillofac Surg 51(suppl 1):3-6, 1993.
Bianchi SD, Roccuzzo M: Primary impaction of primary teeth:
a review and report of three cases, J Clin Pediatr Dent 15:
165-168, 1991.
Chu FCS, Li TKL, Lui VKB et al: Prevalence of impacted teeth
and associated pathologies—a radiographic study of Hong
Kong Chinese population, Hong Kong Med J 9:158-163,
2003.
Curran AE, Damm DD, Drummond JF: Pathologically signiﬁ-
cant pericoronal lesions in adults: histopathologic evaluation,
J Oral Maxillofac Surg 60:613-617, 2002.
Dewhurst SN, Harris JC, Bedi R: Infraocclusion of primary
molars in monozygotic twins: report of two cases, Int J Paediatr
Dent 7:25-30, 1997.
Douglass J, Tinanoff N: The etiology, prevalence, and sequelae of
infraocclusion of primary molars, J Dent Child 58:481-483,
1991.
Ekim SL, Hatibovic-Kofman S: A treatment decision-making
model for infraoccluded primary molars, Int J Paediatr Dent
11:340-346, 2001.
Kim T-W, Årtun J, Behbehani F et al: Prevalence of third molar
impaction in orthodontic patients treated nonextraction and
with extraction of 4 premolars, Am J Orthod Dentofacial Orthop
123:138-145, 2003.
Frank CA: Treatment options for impacted teeth, J Am Dent Assoc
131:623-632, 2000.
Mercier P, Precious D: Risks and beneﬁts of removal of
impacted third molars, J Oral Maxillofac Surg 21:17-27,
1993.
Peterson LJ: Rationale for removing impacted teeth: when to
extract or not to extract, J Am Dent Assoc 123:198-204,
1992.
Qunitero E, Giunta ME, Cahuana A et al: Primary molars in
severe infraocclusion: a retrospective study, Eur J Paediatr
Dent 4:78-83, 2003.
Razdolsky Y, El-Biaky TH, Dessner S et al: Movement of anky-
losed permanent teeth with a distraction device, J Clin Orthod
38:612-620, 2004.
Developmental Alterations in Number of Teeth
Bodin I, Julin P, Thomsson M: Hyperdontia. I. Frequency and
distribution of supernumerary teeth among 21,609 patients,
Dentomaxillofac Radiol 7:15-17, 1978.
Carter NE, Gillgrass TJ, Hobson RS et al: The interdisciplinary
management of hypodontia: orthodontics, Br Dent J 194:361-
366, 2003.
Foley J: Surgical removal of supernumerary teeth and the fate of
incisor eruption, Eur J Paediatr Dent 5:35-40, 2004.
Frazier-Bowers SA, Guo DC, Cavender A et al: A novel mutation
in human PAX9 causes molar oligodontia, J Dent Res 81:129-
133, 2002.
Itro A, Difalco P, Urcicuolo V et al: The aesthetic and functional
restoration in the case of partial edentulism in young patients,
Minerva Stomatol 54:281-292, 2005.
Kates GA, Needleman HL, Holmes LB: Natal and neonatal teeth:
a clinical study, J Am Dent Assoc 109:441-443, 1984.
Kindelan JD, Rysiecki G, Childs WP: Hypodontia: genotype or
environment? A case report of monozygotic twins, Br J Orthod
25:175-178, 1998.
Kolens-Fus´e FJ: Tooth agenesis: in search of mutation behind
failed dental development, Med Oral Patol Oral Cir Bucal
9:385-395, 2004.
Lammi L, Arte S, Somer M et al: Mutations in AXIN2 cause
familial tooth agenesis and predispose to colorectal cancer,
Am J Hum Genet 74:1043-1050, 2004.
Lamour CJ, Mossey PA, Thind BS et al: Hypodontia—a retrospec-
tive review of prevalence and etiology. Part 1, Quintessence Int
36:263-270, 2005.
Lidral AC, Reising BC: The role of MSX1 in human tooth agene-
sis, J Dent Res 81:274-278, 2002.
Longtin R: Chew on this: mutation may be responsible for tooth
loss, colon cancer, J Natl Cancer Inst 96:987-989, 2004.
Peck S, Peck L: Classiﬁcation of maxillary tooth transposition,
Am J Orthod Dentofac Orthop 107:505-517, 1995.
Rajab LD, Hamdan MAM: Supernumerary teeth: review of
the literature and a survey of 152 cases, Int J Paediatr Dent
12:244-254, 2002.
Rao PP, Chidzonga MM: Supernumerary teeth: literature review,
Cent Afr J Med 47:22-26, 2001.
Russell KA, Flowarczna MA: Mesiodens—diagnosis and manage-
ment of a common supernumerary tooth, J Can Dent Assoc
69:362-366, 2003.
Salcido-Garc´ia JF, Ledesma-Montes C, Hernández-Flores F et al:
Frequency of supernumerary teeth in Mexican population,
Med Oral Pathol Oral Cir Bucal 9:403-409, 2004.
Shapira Y, Kuftinec MM: Tooth transposition—a review of the
literature and treatment considerations, Angle Orthod 59:271-
276, 1989.
Spouge JD, Feasby WH: Erupted teeth in the newborn, Oral Surg
Oral Med Oral Pathol 22:198-208, 1966.
Yusof WZ: Non-syndrome multiple supernumerary teeth: litera-
ture review, J Can Dent Assoc 56:147-149, 1990.
Developmental Alterations in Size of Teeth
Bailit HL: Dental variation among populations. An anthropologic
view, Dent Clin North Am 19:125-139, 1975.
Brook AH: A unifying aetiological explanation for anomalies of
human tooth number and size, Arch Oral Biol 29:373-378,
1984.
Dugmore CR: Bilateral macrodontia of mandibular second pre-
molars: a case report, Int J Paediatr Dent 11:69-73, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 117
Rootkin-Gray VFAI, Sheehy EC: Macrodontia of a mandibular
second premolar: a case report, J Dent Child 68:347-349,
2001.
Rushton MA: Partial gigantism of face and teeth, Br Dent J
62:572-578, 1937.
Townsend GC: Hereditability of deciduous tooth size in Austra-
lian aboriginals, Am J Phys Anthropol 53:297-300, 1980.
Townsend GC, Brown T: Hereditability of permanent tooth size,
Am J Phys Anthropol 49:497-504, 1978.
Gemination, Fusion, Concrescence
Alpöz AR, Munanogˇlu D, Oncag O: Mandibular bilateral fusion
in primary dentition: case report, J Dent Child 70:74-76,
2003.
Brook AH, Winter GB: Double teeth: a retrospective study of
“geminated” and “fused” teeth in children, Br Dent J 129:123-
130, 1970.
Duncan WK, Helpin ML: Bilateral fusion and gemination: a lit-
erature analysis and case report, Oral Surg Oral Med Oral
Pathol 64:82-87, 1987.
Hamasha AA, Al-Khateeb T: Prevalence of fused and geminated
teeth in Jordanian adults, Quintessence Int 35:556-559,
2004.
Levitas TC: Gemination, fusion, twinning and concrescence, J
Dent Child 32:93-100, 1965.
Romito LM: Concrescence: report of a rare case, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 97:325-327, 2004.
Ruprecht A, Batniji S, El-Neweihi E: Double teeth: the incidence
of gemination and fusion, J Pedod 9:332-337, 1985.
Tasa GL, Lukacs JR: The prevalence and expression of primary
double teeth in western India, J Dent Child 68:196-200,
2001.
Yuen SWH, Chan JCY, Wei SHY: Double primary teeth and
their relationship with the permanent successors: a radio-
graphic study of 376 cases, Pediatr Dent 9:42-48, 1987.
Accessory Cusps
Bailit HL: Dental variation among populations. An anthropologic
view, Dent Clin North Am 19:125-139, 1975.
Bloch-Zupan A, Stachtou J, Emmanouil D et al: Oro-dental fea-
tures as useful diagnostic tool in Rubinstein-Taybi syndrome,
Am J Med Genet A 143A:570-573, 2007.
Dankner E, Harari D, Rotstein I: Dens evaginatus of anterior
teeth. Literature review and radiographic survey of 15,000
teeth, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:472-
476, 1996.
Falomo OO: The cusp of Carabelli: frequency, distribution, size
and clinical signiﬁcance in Nigeria, West Afr J Med 21:322-
324, 2002.
Gaynor WN: Dens evaginatus—how does it present and how
should it be managed? N Z Dent J 98:104-107, 2002.
Geist JR: Dens evaginatus: case report and review of the litera-
ture, Oral Surg Oral Med Oral Pathol 67:628-631, 1989.
Glavina D, Škrinjaric´ T: Labial talon cusp on maxillary central
incisors: a rare development dental anomaly, Coll Antropol
29:227-231, 2005.
Hattab FN, Yassin OM, Al-Nimri KS: Talon cusp in permanent
dentition associated with other dental anomalies: review of
literature and reports of seven cases, J Dent Child 63:368-376,
1996.
Jeevarathan J, Deepti A, Muthu MS et al: Labial and lingual talon
cusps of a primary lateral incisor: a case report, Pediatr Dent
27:303-306, 2005.
Levitan ME, Himel VT: Dens evaginatus: literature review, patho-
physiology, and comprehensive treatment regimen, J Endod
32:1-9, 2006.
Liu JF, Chen LR: Talon cusp affecting the primary maxillary
central incisors in two sets of female twins: report of two
cases, Pediatr Dent 17:362-364, 1995.
McCulloch KJ, Mills CM, Greenfeld RS et al: Dens evaginatus:
review of the literature and report of several clinical cases,
J Can Dent Assoc 64:104-106, 110-113, 1998.
Mellor JK, Ripa LW: Talon cusp: a clinically signiﬁcant anomaly,
Oral Surg Oral Med Oral Pathol 29:225-228, 1970.
Ooshima T, Ishida R, Mishima K et al: The prevalence of devel-
opmental anomalies of teeth and their association with tooth
size in the primary and permanent dentitions of 1650 chil-
dren, Int J Paediat Dent 6:87-94, 1996.
Saini TS, Kharat DU, Mokeem S: Prevalence of shovel-shaped
incisors in Saudi Arabian dental patients, Oral Surg Oral Med
Oral Pathol 70:540-544, 1990.
Segura-Egea JJ, Jiménez-Rubio A, Ríos-Santos JV et al: Dens
evaginatus of anterior teeth (talon cusp): report of ﬁve cases,
Quintessence Int 34:272-277, 2003.
Dens Invaginatus
Hülsmann M: Dens invaginatus: aetiology, classiﬁcation, preva-
lence, diagnosis, and treatment considerations, Int Endod J
30:79-90, 1997.
Jaramillo A, Fernández R, Villa P: Endodontic treatment of dens
invaginatus: a 5-year follow-up, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 101:E15-E21, 2006.
Nallapati S: Clinical management of a maxillary lateral incisor
with vital pulp and type 3 dens invaginatus: a case report, J
Endod 30:726-731, 2004.
Oehlers FAC: Dens invaginatus (dilated composite odontome). I.
Variations of the invagination process and associated anterior
crown forms, Oral Surg Oral Med Oral Pathol 10:1204-1218,
1957.
Oehlers FAC: Dens invaginatus (dilated composite odontome).
II. Associated posterior crown forms and pathogenesis, Oral
Surg Oral Med Oral Pathol 10:1302-1316, 1957.
Oehlers FAC: The radicular variety of dens invaginatus, Oral Surg
Oral Med Oral Pathol 11:1251-1260, 1958.
Payne M, Craig GT: A radicular dens invaginatus, Br Dent J
169:94-95, 1990.
Ridell K, Mejàre I, Matsson L: Dens invaginatus: a retrospective
study of prophylactic invagination treatment, Int J Paediatr
Dent 11:92-97, 2001.
Ectopic Enamel
Cavanha AO: Enamel pearls, Oral Surg Oral Med Oral Pathol
19:373-382, 1965.
Craig GT: The paradental cyst, a speciﬁc inﬂammatory odonto-
genic cyst, Br Dent J 141:9-14, 1976.
Fowler CB, Brannon RB: The paradental cyst: a clinicopathologic
study of six new cases and review of the literature, J Oral
Maxillofac Surg 47:243-348, 1989.
Goldstein AR: Enamel pearls as a contributing factor in peri-
odontal breakdown, J Am Dent Assoc 99:210-211, 1979.
Hou G-L, Tsai C-C: Relationship between periodontal furcation
involvement and molar cervical enamel projections, J Peri-
odontol 58:715-721, 1987.
Kaugars GE: Internal enamel pearls: report of case, J Am Dent
Assoc 107:941-943, 1983.
Matthews DC, Tabesh M: Detection of localized tooth-related
factors that predispose to periodontal infections, Periodontol
2000 34:136-150, 2004.
Moskow BS, Canut PM: Studies on root enamel: (2) enamel
pearls—a review of their morphology, localization, nomencla-
ture, occurrence, classiﬁcation, histogenesis and incidence, J
Clin Periodontol 17:275-281, 1990. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

118 ORAL AND MAXILLOFACIAL PATHOLOGY
Pompura JR, Sándor GKB, Stoneman DW: The buccal bifurca-
tion cyst: a prospective study of treatment outcomes in 44
sites, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:215-
221, 1997.
Risnes S: The prevalence, location, and size of enamel pearls on
human molars, Scand J Dent Res 82:403-412, 1974.
Zee K-Y, Bratthall G: Prevalence of cervical enamel projection
and its correlation with furcation involvement in Eskimos’
dry skulls, Swed Dent J 27:43-48, 2003.
Taurodontism
Durr DP, Campos CA, Ayers CS: Clinical signiﬁcance of tau-
rodontism, J Am Dent Assoc 100:378-381, 1980.
Llamas R, Jimenez-Planas A: Taurodontism in premolars, Oral
Surg Oral Med Oral Pathol 75:501-505, 1993.
Ruprecht A, Batniji S, El-Neweihi E: The incidence of taur-
odontism in dental patients, Oral Surg Oral Med Oral Pathol
63:743-747, 1987.
Shaw JCM: Taurodont teeth in South African races, J Anat
62:476-498, 1928.
Shifman A, Chanannel I: Prevalence of taurodontism found
in radiographic dental examination of 1,200 young adult
Israeli patients, Community Dent Oral Epidemiol 6:200-203,
1978.
Tsesis I, Shifman A, Kaufman AY: Taurodontism: an endodontic
challenge. Report of a case, J Endod 29:353-355, 2003.
Witkop CJ, Keenan KM, Cervenka J et al: Taurodontism: an
anomaly of teeth reﬂecting disruptive developmental homeo-
stasis, Am J Med Genet 4(suppl):85-97, 1988.
Hypercementosis
Fox L: Paget’s disease (osteitis deformans) and its effect on maxil-
lary bones and teeth, J Am Dent Assoc 20:1823-1829, 1933.
Gardner BS, Goldstein H: The signiﬁcance of hypercementosis,
Dent Cosmos 73:1065-1069, 1931.
Leider AS, Garbarino VE: Generalized hypercementosis, Oral
Surg Oral Med Oral Pathol 63:375-380, 1987.
Napier-Souza L, Monteiro-Lima-Junio S, Garcia-Santos-Pimenta
FJ: Atypical hypercementosis versus cementoblastoma, Den-
tomaxillofac Radiol 33:267-270, 2004.
Rao VM, Karasick D: Hypercementosis—an important clue
to Paget disease of the maxilla, Skeletal Radiol 9:126-128,
1982.
See R, Nixon PP: Generalised hypercementosis: a case report,
Prim Dent Care 11:119-122, 2004.
Weinberger A: The clinical signiﬁcance of hypercementosis,
Oral Surg Oral Med Oral Pathol 7:79-87, 1954.
Dilaceration
Celik E, Aydinlik E: Effect of a dilacerated root in stress distribu-
tion to the tooth and supporting tissues, J Prosthet Dent 65:771-
777, 1991.
Chew MT, Ong M M-A: Orthodontic-surgical management of an
impacted dilacerated maxillary central incisor: a clinical case
report, Pediatr Dent 26:341-344, 2004.
Ligh RQ: Coronal dilaceration, Oral Surg Oral Med Oral Pathol
51:567, 1981.
Hamasha AA, Al-Khateeb T, Darwazeh A: Prevalence of dilac-
eration in Jordanian adults, Int Endod J 35:910-912, 2002.
Seow WK, Perham S, Young WG et al: Dilaceration of a primary
maxillary incisor associated with neonatal laryngoscopy,
Pediatr Dent 12:321-324, 1990.
Stewart DJ: Dilacerate unerupted maxillary central incisors, Br
Dent J 145:229-233, 1978.
van Gool AV: Injury to the permanent tooth germ after trauma
to the deciduous predecessor, Oral Surg Oral Med Oral Pathol
35:2-12, 1973.
Supernumerary Roots
Badger GR: Three-rooted mandibular ﬁrst primary molar, Oral
Surg Oral Med Oral Pathol 53:547, 1982.
Kannan SK, Suganya, Santharam H et al: Supernumerary roots,
Indian J Dent Res 13:116-119, 2002.
Krolls SO, Donahue AH: Double-rooted maxillary primary
canines, Oral Surg Oral Med Oral Pathol 49:379, 1980.
Younes SA, Al-Shammery AR, El-Angbawi MF: Three-rooted per-
manent mandibular ﬁrst molars of Asian and black groups in
the Middle East, Oral Surg Oral Med Oral Pathol 69:102-105,
1990.
Amelogenesis Imperfecta
Aldred MJ, Crawford PJM: Amelogenesis imperfecta—toward a
new classiﬁcation, Oral Dis 1:2-5, 1995.
Aldred MJ, Crawford PJM: Molecular biology of hereditary enamel
defects, Ciba Found Symp 205:200-209, 1997.
Aldred MJ, Crawford PJM, Savarirayan R et al: It’s only teeth—are
there limits to genetic testing? Clin Genet 63:333-339, 2003.
Aldred MJ, Savarirayan R, Crawford PJM: Amelogenesis imper-
fecta: a classiﬁcation and catalogue for the 21st century, Oral
Dis 9:19-23, 2003.
Aldred MJ, Savarirayan R, Lamande SR et al: Clinical and radio-
graphic features of a family with autosomal dominant amelo-
genesis imperfecta with taurodontism, Oral Dis 8:62-68,
2002.
Crawford PJM, Aldred MJ: Amelogenesis imperfecta with tau-
rodontism and the tricho-dento-osseous syndrome: separate
conditions or a spectrum of disease? Clin Genet 38:44-50,
1990.
Dong J, Amor D, Aldreds MJ et al: DLX3 mutation associated
with autosomal dominant amelogenesis imperfecta with tau-
rodontism, Am J Med Genet A 133A:138-141, 2005.
Kim J-W, Seymen F, Lin BP-J et al: ENAM mutations in autoso-
mal-dominant amelogenesis imperfecta, J Dent Res 84:278-
282, 2005.
Nusier M, Yassin O, Hart TC et al: Phenotypic diversity and revi-
sion of the nomenclature for autosomal recessive amelogen-
esis imperfecta, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 97:220-230, 2004.
Ozdemir D, Hart PS, Ryu OH et al: MMP20 active-site mutation
in hypomaturation amelogenesis imperfecta, J Dent Res
84:1031-1035, 2005.
Price JA, Wright JT, Walker SJ et al: Tricho-dento-osseous syn-
drome and amelogenesis imperfecta with taurodontism are
genetically distinct conditions, Clin Genet 56:35-40, 1999.
Seow WK: Clinical diagnosis and management strategies of
amelogenesis imperfecta variants, Pediatr Dent 15:384-393,
1993.
Seow WK: Taurodontism of the mandibular ﬁrst permanent
molar distinguishes between the tricho-dento-osseous (TDO)
syndrome and amelogenesis imperfecta, Clin Genet 43:240-
246, 1993.
Shields ED: A new classiﬁcation of heritable human enamel defects
and a discussion of dentin defects. In Jorgenson RJ, Paul NW:
Dentition: genetic effects, birth defects. Original article series, vol 19,
no 1, pp 107-127, New York, 1983, Alan R. Liss.
Stephanopoulos G, Garefalaki M-E: Genes and related proteins
involved in amelogenesis imperfecta, J Dent Res 84:1117-
1126, 2005.
Sundell S, Koch G: Hereditary amelogenesis imperfecta. I. Epi-
demiology and clinical classiﬁcation in a Swedish child popu-
lation, Swed Dent J 9:157-169, 1985.
Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis imper-
fecta and dentin dysplasia revisited: problems in classiﬁca-
tion, J Oral Pathol 17:547-553, 1988. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 2 ABNORMALITIES OF TEETH 119
Witkop CJ Jr, Sauk JJ Jr: Heritable defects of enamel. In Stewart
RE, Prescott GH: Oral facial genetics, pp 151-226, St Louis,
1976, Mosby.
Wright JT, Hart PS, Aldred MJ et al: Relationship of phenotype
and genotype in X-linked amelogenesis imperfecta, Connect
Tissue Res 44(suppl 1):72-78, 2003.
Dentinogenesis Imperfecta
Hursey RJ, Witkop CJ Jr, Miklashek D et al: Dentinogenesis
imperfecta in a racial isolate with multiple hereditary defects,
Oral Surg Oral Med Oral Pathol 9:641-658, 1956.
Joshi N, Parkash H: Oral rehabilitation in dentinogenesis imper-
fecta with overdentures: case report, J Clin Pediatr Dent 22:99-
102, 1998.
Kim J-W, Hu J C-C, Lee J-I et al: Mutational hot spot in the DSPP
gene causing dentinogenesis imperfecta type II, Hum Genet
116:186-191, 2005.
Kim J-W, Nam S-H, Jang K-T et al: A novel splice acceptor muta-
tion in the DSPP gene causing dentinogenesis imperfecta
type II, Hum Genet 115:248-254, 2004.
Levin LS: The dentition in the osteogenesis imperfecta syndrome,
Clin Orthop 159:64-74, 1981.
Levin LS, Leaf SH, Jelmini RJ et al: Dentinogenesis imperfecta in
the Brandywine isolate (DI type III): clinical, radiologic, and
scanning electron microscopic studies of the dentition, Oral
Surg Oral Med Oral Pathol 56:267-274, 1983.
Ranta H, Lukinmaa P-L, Waltimo J: Heritable dentin defects:
nosology, pathology, and treatment, Am J Med Genet 45:193-
200, 1993.
Rushton MA: A new form of dentinal dysplasia: shell teeth, Oral
Surg Oral Med Oral Pathol 7:543-549, 1954.
Shields ED, Bixler D, El-Kafrawy AM: A proposed classiﬁcation
for heritable human dentine defects with a description of a
new entity, Arch Oral Biol 18:543-553, 1973.
Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis imper-
fecta and dentin dysplasia revisited: problems in classiﬁca-
tion, J Oral Pathol 17:547-553, 1988.
Witkop CJ Jr: Hereditary defects of dentin, Dent Clin North Am
19:25-45, 1975.
Witkop CJ Jr, MacLean CJ, Schmidt PJ et al: Medical and dental
ﬁndings in the Brandywine isolate, Ala J Med Sci 3:382-403,
1966.
Dentin Dysplasia
Bixler D: Heritable disorders affecting dentin. In Stewart RE,
Prescott GH: Oral facial genetics, pp 227-262, St Louis, 1976.
Comer TL, Gound TG: Hereditary pattern for dentinal dysplasia
type Id: a case report, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 94:51-53, 2002.
Duncan WK, Perkins TM, O’Carroll MK: Type I dentin dysplasia:
report of two cases, Ann Dent 50:18-21, 1991.
O’Carroll MK, Duncan WK, Perkins TM: Dentin dysplasia:
review of the literature and a proposed subclassiﬁcation
based on radiographic ﬁndings, Oral Surg Oral Med Oral Pathol
72:119-125, 1991.
Parekh S, Kyriazidou A, Bloch-Zupan A et al: Multiple pulp
stones and shortened roots of unknown etiology, Oral Surg
Oral Med Oral Pathol, Oral Radiol Endod 101:e139-142,
2006.
Rajpar MH, Koch MJ, Davies RM et al: Mutation of the signal
peptide region of the bicistronic gene DSPP affects transloca-
tion to the endoplasmic reticulum and results in defective
dentine biomineralization, Hum Mol Genet 11:2559-2565,
2002.
Ranta H, Lukinmaa P-L, Waltimo J: Heritable dentin defects:
nosology, pathology, and treatment, Am J Med Genet 45:193-
200, 1993.
Rao SR, Witkop CJ Jr, Yamane GM: Pulpal dysplasia, Oral Surg
Oral Med Oral Pathol 30:682-689, 1970.
Rosenberg LR, Phelan JA: Dentin dysplasia type II: review of the
literature and report of a family, J Dent Child 50:372-375,
1983.
Rushton MA: A case of dentinal dysplasia, Guys Hosp Rep 89:369-
373, 1939.
Scola SM, Watts PG: Dentinal dysplasia type I. A subclassiﬁca-
tion, Br J Orthod 14:175-179, 1987.
Shields ED, Bixler D, El-Kafrawy AM: A proposed classiﬁcation
for heritable human dentine defects with a description of a
new entity, Arch Oral Biol 18:543-553, 1973.
Steidler NE, Radden BG, Reade PC: Dentinal dysplasia: a clini-
copathologic study of eight cases and review of the literature,
Br J Oral Maxillofac Surg 22:274-286, 1984.
Tidwell E, Cunningham CJ: Dentinal dysplasia: endodontic treat-
ment, with case report, J Endod 5:372-376, 1979.
Van Dis ML, Allen CM: Dentinal dysplasia type I: a report of four
cases, Dentomaxillofac Radiol 18:128-131, 1989.
Wesley RK, Wysocki GP, Mintz SM et al: Dentin dysplasia type
I. Clinical, morphologic, and genetic studies of a case, Oral
Surg Oral Med Oral Pathol 41:516-524, 1976.
Witkop CJ Jr: Manifestations of genetic diseases in the human
pulp, Oral Surg Oral Med Oral Pathol 32:278-316, 1971.
Witkop CJ Jr: Hereditary defects of dentin, Dent Clin North Am
19:25-45, 1975.
Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis imper-
fecta and dentin dysplasia revisited: problems in classiﬁca-
tion, J Oral Pathol 17:547-553, 1988.
Regional Odontodysplasia
Cahuana A, González Y, Palma C: Clinical management of
regional odontodysplasia, Pediatr Dent 27:34-39, 2005.
Crawford PJM, Aldred MJ: Regional odontodysplasia: a bibliog-
raphy, J Oral Pathol Med 18:251-263, 1989.
Gardner DG: The dentinal changes in regional odontodysplasia,
Oral Surg Oral Med Oral Pathol 38:887-897, 1974.
Hamdan MA, Sawair FA, Rajab LD et al: Regional odontodyspla-
sia: a review of the literature and report of a case, Int J Paediatr
Dent 14:363-370, 2004.
Kahn MA, Hinson RL: Regional odontodysplasia. Case report
with etiologic and treatment considerations, Oral Surg Oral
Med Oral Pathol 72:462-467, 1991.
Kerebel L-M, Kerebel B: Soft-tissue calciﬁcations of the dental
follicle in regional odontodysplasia: a structural and ultra-
structural study, Oral Surg Oral Med Oral Pathol 56:396-404,
1983.
Lowe O, Duperon DF: Generalized odontodysplasia, J Pedod
9:232-243, 1985.
Sadeghi EM, Ashraﬁ MH: Regional odontodysplasia: clinical,
pathologic and therapeutic considerations, J Am Dent Assoc
102:336-339, 1981.
Tervonon SA, Stratmann U, Mokrys K et al: Regional odontodys-
plasia: a review of the literature and report of four cases, Clin
Oral Invest 8:45-51, 2004.
von Arx T: Autotransplantation for treatment of regional odonto-
dysplasia. Case report with 6-year follow-up, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 85:304-307, 1998.
Walton JL, Witkop CJ Jr, Walker PO: Odontodysplasia. Report
of three cases with vascular nevi overlying the adjacent skin
of the face, Oral Surg Oral Med Oral Pathol 46:676-684,
1978.
Zegarelli EV, Kutscher AH, Applebaum E et al: Odontodysplasia,
Oral Surg Oral Med Oral Pathol 16:187-193, 1963. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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120
3
Pulpal and Periapical Disease
CHAPTER OUTLINE
Pulpitis
Secondary and Tertiary Dentin
Pulpal Calciﬁcations
Periapical Granuloma
Periapical Cyst
Periapical Abscess
Cellulitis
Osteomyelitis
Diffuse Sclerosing Osteomyelitis
Condensing Osteitis
Osteomyelitis with Proliferative Periostitis
Alveolar Osteitis
ﬂamed tissue and increased drainage. In this manner,
the increased ﬂuid pressure from inﬂammation is
counteracted and typically does not lead to a general-
ized increase in pulpal ﬂuid pressure, effectively pre-
venting “self-strangulation.” Although many consider
the dental pulp very fragile, the defense mechanisms
work well the vast majority of time and rarely result in
widespread necrosis. Localized pulpal abscesses often
are able to heal after formation of reparative dentin
and cessation of the noxious stimulus. In spite of numer-
ous defense mechanisms, severe localized pulpal
damage can overwhelm the system and spread pro-
gressively to the apical portion of the pulp, potentially
producing widespread pulpal necrosis. In caries, when-
ever bacteria reach the tertiary dentin, the defense bar-
riers have been breached, the degree of pulpitis will
be severe, and the chance for pulpal recovery is
minimal.
Four main types of noxious stimuli are common
causes of pulpal inﬂammation:
1. Mechanical damage. Mechanical sources of injury
include traumatic accidents, iatrogenic damage
from dental procedures, attrition, abrasion, and
barometric changes.
2.Thermal injury. Severe thermal stimuli can be trans-
mitted through large uninsulated metallic restora-
tions or may occur from such dental procedures as
cavity preparation, polishing, and exothermic chem-
ical reactions of dental materials.
PULPITIS
The initial response of the dental pulp to injury is not
signiﬁcantly different from that seen in other tissues.
However, the ﬁnal result can be different because of
the rigid dentinal walls of the pulp chamber. When
external stimuli reach a noxious level, degranulation
of mast cells, decreased nutrient ﬂow, and cellular
damage occur. Numerous inﬂammatory mediators
(e.g., histamine, bradykinin, neurokinins, neuropep-
tides, prostaglandins) are released. These mediators
cause vasodilation, increased blood inﬂow, and vascu-
lar leakage with edema. In normal tissue, increased
blood ﬂow promotes healing through removal of
inﬂammatory mediators, and swelling of the injured
tissue usually occurs. However, the dental pulp exists
in a very conﬁned area.
Pulpal response to noxious stimuli is meant to elimi-
nate any invading organisms, remove cellular debris,
and limit tissue damage. Paradoxically, the inﬂamma-
tory reaction can lead to increased pulpal injury or
even death of the pulp. Previous theories have sug-
gested that the associated increased vascular pulpal
pressures could compress venous return and lead to
“self-strangulation” and pulpal necrosis. Today research-
ers recognize that the increased ﬂuid pressure usually
is localized to the area of inﬂamed pulp immediately
adjacent to the affected dentin. Increased interstitial
pressure in areas of inﬂammation leads to increased
ﬂow of ﬂuid back into capillaries of adjacent unin- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 3 PULPAL AND PERIAPICAL DISEASE 121
pressure that can keep patients awake at night. At
this point, heat increases the pain; however, cold may
produce relief. The tooth responds to electric pulp
testing at higher levels of current or demonstrates no
response. Mobility and sensitivity to percussion are
usually absent because signiﬁcant inﬂammation has
not spread yet to the apical area. If pulpal drainage
occurs (e.g., crown fracture, ﬁstula formation), then the
symptoms may resolve—only to return if the drainage
ceases.
The dramatic and painful cases of acute pulpitis are
the ones that are recalled most easily by both patients
and clinicians. In spite of this, the process may take
years, the pattern of symptomatology is highly variable,
and often the patient may have no symptoms. A number
of large retrospective studies of patients presenting for
endodontic therapy of teeth with radiographic evi-
dence of periapical inﬂammatory disease have shown
that in approximately half of these cases the associated
pulpitis and necrosis were asymptomatic. Severe
pulpitis with abscess formation and necrosis may be
asymptomatic, whereas mild pulpitis may cause excru-
ciating pain.
CHRONIC HYPERPLASTIC PULPITIS
One unique pattern of pulpal inﬂammation is chronic
hyperplastic pulpitis (pulp polyp). This condition
occurs in children and young adults who have large
exposures of the pulp in which the entire dentinal roof
often is missing. The most frequently involved teeth are
the deciduous or succedaneous molars, which have
large pulp chambers in these age groups. Mechanical
irritation and bacterial invasion result in a level of
chronic inﬂammation that produces hyperplastic gran-
ulation tissue that extrudes from the chamber and
often ﬁlls the associated dentinal defect (Figs. 3-1 to
3-3). The apex may be open and reduces the chance of
pulpal necrosis secondary to venous compression. The
tooth is asymptomatic except for a possible feeling of
pressure when it is placed into masticatory function.
Typically, the diagnosis of pulpitis is straightforward
and easily correlated with a diseased tooth that can be
stimulated to produce the associated symptoms. If such
a correlation is not obvious, then it should raise suspi-
cion that the symptoms may not be pulpally related.
The tooth that is the source of pulpal pain may be dif-
ﬁcult to identify in some instances. Although pulpal
pain never crosses the midline, it can be referred from
arch to arch, making pulp testing of both arches a
necessity in difﬁcult cases. Numerous disorders such
as myofascial pain, trigeminal neuralgia, atypical facial
neuralgia, migraine headaches, cluster headaches,
nasal or sinus pathoses, and angina pectoris have been
reported to mimic pulpalgia in some patients. If these
conditions are not recognized as causing pain, then
3.Chemical irritation. Chemical-related damage can
arise from erosion or from the inappropriate use of
acidic dental materials.
4.Bacterial effects. Bacteria can damage the pulp
through toxins or directly after extension from caries
or transportation via the vasculature.
Pulpitis can be classiﬁed as the following:
●Acute or chronic
●Subtotal or generalized
●Infected or sterile
The best classiﬁcation system is one that guides the
appropriate treatment. Reversible pulpitis denotes a level
of pulpal inﬂammation in which the tissue is capable
of returning to a normal state of health if the noxious
stimuli are removed. Irreversible pulpitis implies that a
higher level of inﬂammation has developed in which
the dental pulp has been damaged beyond the point of
recovery. Often, frank invasion by bacteria is the cross-
over point from reversible to irreversible pulpitis.
CLINICAL FEATURES
REVERSIBLE PULPITIS
When exposed to temperature extremes, teeth with
reversible pulpitis exhibit a sudden mild-to-moderate
pain (pulpalgia) of short duration. Although heat may
initiate pain, the affected tooth responds most to cold
stimuli (e.g., ice, beverages, cold air). Contact with
sweet or sour foods and beverages also may cause pain.
The pain does not occur without stimulation and sub-
sides within seconds after the stimulus is removed.
Typically, the tooth responds to electric pulp testing at
lower levels of current than an appropriate control
tooth. Mobility and sensitivity to percussion are absent.
If the pulpitis is allowed to progress, then the duration
of the pain on stimulation can become longer and the
pulp may become affected irreversibly.
IRREVERSIBLE PULPITIS
Patients with early irreversible pulpitis generally
have sharp, severe pain on thermal stimulation, and the
pain continues after the stimulus is removed. Cold is
especially uncomfortable, although heat or sweet and
acidic foods also can elicit pain. In addition, the pain
may be spontaneous or continuous and may be exacer-
bated when the patient lies down. The tooth responds
to electric pulp testing at lower levels of current.
In the early stages of irreversible pulpitis, the pain
often can be localized easily to the individual offend-
ing tooth; with increasing discomfort, however, the
patient is unable to identify the offending tooth within
a quadrant.
In the later stages of irreversible pulpitis, the pain
increases in intensity and is experienced as a throbbing `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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122 ORAL AND MAXILLOFACIAL PATHOLOGY
sequential extractions or endodontic procedures may
be performed inappropriately.
The diagnosis of pulpalgia is made from a combina-
tion of the clinical presentation and the response of the
teeth to percussion, thermal stimuli, and electric pulp
testing. The predictive value of these tests is sometimes
less than optimal. When the procedures demonstrate
that the pulp is disease free, results are highly reliable.
However, when a pulp appears to test positively for
irreversible pulpitis, histopathologic examination may
demonstrate no obvious evidence of pulpal disease.
The practitioner should use all available tests, clinical
information, and personal judgment in an attempt to
arrive at an appropriate diagnosis. Future improve-
ments in diagnostic methods, such as laser Doppler
ﬂowmetry and pulse oximetry devices, may help to
increase accuracy.
HISTOPATHOLOGIC FEATURES
Basically, the histopathology is primarily of academic
interest and does not usually affect treatment signiﬁ-
cantly. Numerous investigations have shown a surpris-
ing lack of correlation between histopathologic ﬁndings
and the clinical symptoms in the majority of pulps
examined.
In patients with reversible pulpitis, the pulp usually
shows hyperemia, edema, and a few inﬂammatory
cells underlying the area of affected dentinal tubules
(Fig. 3-4). Tertiary dentin may be noted in the adjacent
Fig. 3-1 Chronic hyperplastic pulpitis. Erythematous
granulation tissue extruding from the pulp chamber of the
mandibular ﬁrst molar.
Fig. 3-2 Chronic hyperplastic pulpitis. Gross photograph
demonstrating hyperplastic pulp tissue ﬁlling a large coronal
carious defect. Arrows delineate the previous roof of the pulp
chamber.
Fig. 3-3 Chronic hyperplastic pulpitis. Same tooth as
depicted in Fig. 3-2. Chronically inﬂamed granulation tissue
ﬁlls the coronal defect. Note surface stratiﬁed squamous
epithelium.
Fig. 3-4 Reversible pulpitis. Dental pulp exhibiting
hyperemia and edema. The adjacent dentin was cut recently
during placement of a dental restoration. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 3 PULPAL AND PERIAPICAL DISEASE 123
dentinal wall, and scattered acute inﬂammatory cells
are found occasionally.
Irreversible pulpitis often demonstrates congestion
of the venules that results in focal necrosis. This necrotic
zone contains polymorphonuclear leukocytes and his-
tiocytes (Fig. 3-5). The surrounding pulp tissue usually
exhibits ﬁbrosis and a mixture of plasma cells, lympho-
cytes, and histiocytes (Fig. 3-6).
Chronic hyperplastic pulpitis demonstrates a cap of
subacutely inﬂamed granulation tissue that ﬁlls the
entire space of the original pulp chamber and histo-
pathologically resembles a pyogenic granuloma (see
page 518). The surface of the polyp may or may not be
covered with stratiﬁed squamous epithelium, which
migrates from the adjacent gingiva or arises from
sloughed epithelium within the oral ﬂuids (see Fig.
3-3). The deeper pulp tissue within the canals typically
demonstrates ﬁbrosis and a chronic inﬂammatory inﬁl-
trate. Pulpal calciﬁcations are common in both the
radicular and coronal portions. Often the apical portion
of the pulp tissue is normal, with minimal inﬂamma-
tion or ﬁbrosis.
TREATMENT AND PROGNOSIS
Reversible pulpitis is treated by removal of the local
irritant. On occasion, analgesic medications sometimes
are desirable. The prognosis of reversible pulpitis is
good if action is taken early enough. The tooth should
be tested for vitality after the symptoms have subsided
to ensure that irreversible damage has not occurred.
Irreversible and chronic hyperplastic pulpitis are
treated by extraction of the tooth or by root canal
therapy.
SECONDARY AND TERTIARY DENTIN
Formation of dentin proceeds throughout life. The
dentin formed before completion of the crown is called
primary dentin. This process is followed by the forma-
tion of secondary dentin. The same odontoblasts that
formed the primary dentin remain functional and
produce secondary dentin. With advancing age, depo-
sition of secondary dentin leads to smaller pulp cham-
bers and canal systems. The deposition of dentin is
slow and gradual but does increase after the age of 35
to 40 years. Forensic scientists have shown that the
formation of secondary dentin occurs so consistently
that the width ratio of the dentin taken at three differ-
ent root levels correlates very closely with age. Early
widespread formation of secondary dentin has been
seen in association with progeria, a condition associ-
ated with accelerated aging. On occasion, signiﬁcant
traumatic injury can lead to early obliteration of the
pulp chamber and canal (calciﬁc metamorphosis) in
the affected tooth.
In functioning teeth, deposition begins in the coronal
portions of the tooth and proceeds to the apical areas.
Many investigators believe that this type of dentin,
termed physiologic secondary dentin, occurs as a
result of aging. A signiﬁcantly decreased amount of
secondary dentin has been described in impacted
teeth, suggesting that functional forces of occlusion
promote the deposition. Interestingly, the deposition in
impacted teeth appears to begin in the apical areas and
spreads coronally.
Although production of physiologic secondary
dentin and a resultant decrease in pulpal size are
related most strongly to aging, the process is more
advanced in males and has been associated positively
with calciﬁcation-related diseases (e.g., arthritis, gout,
kidney stones, gall stones, atherosclerosis, hyperten-
Fig. 3-5 Irreversible pulpitis. Dental pulp exhibiting acute
inﬂammatory inﬁltrate consisting predominantly of
polymorphonuclear leukocytes.
Fig. 3-6 Irreversible pulpitis. Same tooth as depicted in
Fig. 3-5. The dental pulp exhibits an area of ﬁbrosis and
chronic inﬂammation peripheral to the zone of abscess
formation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

124 ORAL AND MAXILLOFACIAL PATHOLOGY
sion). Deposition within the pulp chamber often is not
totally uniform. In posterior teeth, the greatest deposi-
tion is seen on the pulpal ﬂoor, to a lesser extent on the
roof, and least on the sidewalls. Therefore, with age,
pulp chambers decrease signiﬁcantly in height but not
extensively in width.
Localized new dentin also is laid down in areas of
focal injury. This dentin is more haphazardly organized
and is termed tertiary (reactionary, reparative,
irregular, or irritation) dentin. This localized dentin
formation may occur in response to the following:
● Attrition
● Fracture
● Erosion
● Abrasion
● Caries
● Periodontal disease
●Mechanical injury from dental procedures
●Irritation from dental materials
Injury of the peripheral odontoblastic processes is
all that is required to initiate tertiary dentin formation.
If the stimulus is mild to moderate, then the tertiary
dentin typically is produced by surviving odontoblasts
and is termed reactionary dentin. This type of tertiary
dentin is more regular in appearance and continuous
with the tubules of the primary and secondary dentin.
If the stimulus is more severe and leads to the death of
the primary odontoblasts, then a new generation of
odontoblasts may arise from undifferentiated cells
within the pulp and continue to form tertiary dentin
that is termed reparative dentin. Researchers believe
that these new odontoblasts arise from subodontoblas-
tic cells or pericytes. During primary dentin formation,
the odontoblasts incorporate a number of growth
factors, such as transforming growth factor-β (TGF-β),
into the intertubular matrix. Investigators have sug-
gested that these growth factors may be released sec-
ondary to dentinal injury or cavity restoration and may
be involved in the signaling for differentiation of the
secondary generation of odontoblasts. Demineraliza-
tion of dentin during caries also releases signiﬁcant
amounts of calcium and phosphates. These minerals
often diffuse toward the pulp and assist in sclerosis of
the tubules as calcium phosphate. In many ways, dentin
not only acts as the backbone of the tooth but also as a
storehouse of bioactive materials awaiting release
during critical times of injury.
The initial layer of reparative dentin is atubular and
known as interface dentin (ﬁbrodentin). This thin band
may be acellular or exhibit scattered nuclear inclu-
sions. After deposition of the interface dentin, the
remainder of the reparative dentin is tubular but not
continuous with the primary, secondary, or reactionary
dentin. This lack of communication further assists in
protecting the pulp from the external stimulus. When
the primary odontoblasts die, their dentinal tubules are
ﬁlled with degenerated odontoblastic processes and
are termed dead tracts. These tubules usually are sealed
off from the pulp by the reparative dentin.
CLINICAL AND RADIOGRAPHIC
FEATURES
As noted on periapical radiographs, the deposition of
secondary dentin results in diminishing size of pulp
chambers and canals. In addition to being used as an
estimate of age, secondary dentin appears to reduce
sensitivity of the affected teeth, susceptibility to den-
tinal caries, and the trauma of dental procedures.
Although production of secondary dentin makes pulp
exposure during operative procedures less likely, it also
increases the difﬁculty of locating the pulp chamber
and canals during endodontic therapy. On occasion,
large inﬂammatory lesions may involve more than one
apex; the size of the canals can be used to help deter-
mine the original focus of infection because the canal
may be larger in the tooth that became nonvital earlier
(Fig. 3-7). Teeth affected by calciﬁc metamorphosis
often are discovered clinically by a yellow discoloration
of the crown; radiographically, the affected teeth
exhibit an accelerated closure of the pulp chamber and
Fig. 3-7 Physiologic secondary dentin. Periapical abscess
with all four teeth nonresponsive to electric pulp testing.
Decreased deposition of physiologic secondary dentin on the
right central incisor (arrow) delineated the origin of the
infection; endodontic treatment of this tooth resolved the
lesion. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 125
canal when compared with adjacent or contralateral
teeth (Fig. 3-8). In such cases the pulpal space may
appear to be obliterated completely or reduced dra-
matically. This alteration usually follows trauma to the
tooth and may be seen as early as 3 months after the
traumatic episode; however, usually the condition is
not detected for about 1 year.
HISTOPATHOLOGIC FEATURES
Physiologic secondary dentin consists of regular tubular
dentin that is applied onto the primary dentin. These
two layers of dentin can be separated by a line of
demarcation, often indicated by a bending of the
tubules (Fig. 3-9). With advancing age, as the odonto-
blasts undergo degenerative changes, the physiologic
secondary dentin becomes more irregular with fewer
tubules.
The quality and appearance of tertiary dentin
depend on the severity of the noxious stimulus that
promoted its formation. Tertiary dentin is localized to
the pulpal end of the odontoblastic processes that were
affected (Fig. 3-10). With a mild stimulus, such as abra-
sion or attrition, reactionary dentin exhibits slow depo-
sition characterized by tubules that are continuous
with the secondary dentin and only slightly irregular.
With more severe damage (e.g., a rapidly progressing
carious lesion), reparative dentin is formed, a process
that occurs more rapidly and consists of a thin layer of
interface dentin on which is deposited irregular dentin
with widely scattered, disorganized tubules.
TREATMENT AND PROGNOSIS
In studies of teeth exhibiting calciﬁc metamorphosis,
the vast majority of affected teeth never develop clini-
cal or radiographic features suggestive of periapical
inﬂammatory disease; therefore, endodontic therapy
A
B
Fig. 3-8 Calciﬁc metamorphosis. A, Left deciduous
maxillary central incisor exhibiting yellow discoloration.
B, Radiograph of the same patient showing total calciﬁcation
of the pulp chambers and canals of the deciduous maxillary
incisors. (Courtesy of Dr. Jackie L. Banahan.)
Fig. 3-9 Physiologic secondary dentin. A distinct line of
demarcation (arrow) separates the primary dentin and
physiologic secondary dentin.
Fig. 3-10 Reparative secondary dentin. Localized
deposition of secondary dentin (bottom) at the pulpal end of
the dentinal tubules affected by the carious process. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

126 ORAL AND MAXILLOFACIAL PATHOLOGY
should be performed only if periapical pathosis or
negative vitality testing is present. Even if a canal space
cannot be identiﬁed radiographically, conventional
root canal therapy usually can locate and negotiate the
pulp canal. Because of the dramatically reduced canal
space, location of the pulp canal can be difﬁcult, and
care must be exercised during access preparation to
prevent perforation. If endodontic therapy is unsuc-
cessful, then periapical surgery can be performed in
those cases with evidence of periapical inﬂammatory
disease. If vitality testing is positive, then periodic
reevaluation appears prudent. To improve dental aes-
thetics, full coverage is recommended for discolored
anterior teeth with large restorations. Otherwise,
bleaching often effectively resolves the discoloration.
PULPAL CALCIFICATIONS
Calciﬁcations within the dental pulp are not rare, but
the frequency is difﬁcult to determine. Reported rates
vary from 8% to 90%, but several investigators have
documented a prevalence of approximately 20% in
individual teeth reviewed radiographically. Because
radiographically detectable pulp stones typically
exceed 200 μm in diameter, the prevalence in a histo-
pathologic review would be expected to be much
higher. There appears to be a strong association
between long-standing chronic pulpitis and the pres-
ence of pulpal calciﬁcation; in addition, the prevalence
of pulpal calciﬁcations increases with age. However,
some examples appear to be developmental with a
familial tendency.
The three types of pulpal calciﬁcations are:
1. Denticles
2. Pulp stones
3. Diffuse linear calciﬁcations
All pulpal calciﬁcations start out as free bodies within
the pulp tissue, but many may become attached or
embedded in the dentinal walls of the pulp.
Denticles are believed to form as a result of an
epitheliomesenchymal interaction within the develop-
ing pulp. Epithelial strands originating from the root
sheath, or cervical extensions into the pulp chamber
adjacent to furcations, induce odontoblastic differenti-
ation of the surrounding mesenchyme of the dental
papilla, forming the core of the denticle. Odontoblasts
deposit tubular dentin as they move away from the
central epithelium and produce thimble-shaped struc-
tures surrounding the epithelium. Denticles form
during the period of root development and occur in the
root canal and the pulp chamber adjacent to the furca-
tion areas of multirooted teeth. Because denticle devel-
opment typically precedes completion of the primary
dentin, most denticles become attached to or embed-
ded in the dentin.
Pulp stones are believed to develop around a
central nidus of pulp tissue (e.g., collagen ﬁbril, ground
substance, necrotic cell remnants). Initial calciﬁcation
begins around the central nidus and extends outward
in a concentric or radial pattern of regular calciﬁed
material. Pulp stones are formed within the coronal
portions of the pulp and may arise as a part of age-
related or local pathologic changes. Most pulp stones
develop after tooth formation is completed and are
usually free or attached. In rare instances, stones may
become embedded.
Diffuse linear calciﬁcations do not demonstrate
the lamellar organization of pulp stones; they exhibit
areas of ﬁne, ﬁbrillar, irregular calciﬁcation that often
parallel the vasculature. These calciﬁcations may be
present in the pulp chamber or canals, and the fre-
quency increases with age.
CLINICAL AND RADIOGRAPHIC
FEATURES
Denticles and pulp stones can reach sufﬁcient size
to be detected on intraoral radiographs as radiopaque
enlargements within the pulp chamber or canal
(Fig. 3-11). Diffuse calciﬁcations are not detectable
radiographically.
Other than rare difﬁculties during endodontic pro-
cedures, pulpal calciﬁcations are typically of little
clinical signiﬁcance. Some investigators associate the
calciﬁcations with dental neuralgias, but the high fre-
quency of these lesions in the absence of clinical symp-
toms argues against this relationship. On occasion, the
pulpal calciﬁcations may become very large and may
interfere with root formation, possibly leading to early
periodontal destruction and tooth loss. Prominent
pulpal calciﬁcations have been noted in association
with certain disease processes, such as the following:
Fig. 3-11 Pulp stones. Multiple teeth demonstrating
radiographically obvious calciﬁcations within the pulp
chambers. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 127
●Dentin dysplasia type Id (see page 108)
●Dentin dysplasia type II (see page 108)
●Pulpal dysplasia (see page 110)
● Tumoral calcinosis
● Calcinosis universalis
●Ehlers-Danlos syndrome (see page 755)
If all of the patient’s teeth have enlarged pulp cham-
bers containing calciﬁcations, the possibility of dentin
dysplasia type II should be investigated. If the stones
are located in the coronal portion of root canals that
exhibit enlargement and bulging, then dentin dysplasia
type 1d should be considered. Both of these rare con-
ditions are associated with abnormally shaped pulp
chambers or canals; therefore, such a diagnosis should
not be considered when pulp stones are noted in the
absence of pulpal changes.
HISTOPATHOLOGIC FEATURES
Denticles consist of tubular dentin surrounding a
central nest of epithelium. With time, the central epi-
thelium degenerates and the tubules undergo sclerosis,
making their detection difﬁcult. Most denticles are
attached or embedded. Those that remain free in the
pulp occasionally develop outer layers of irregular
ﬁbrillar calciﬁcation or lamellated layers of calciﬁca-
tion similar to those seen in pulp stones.
Pulp stones demonstrate a central amorphous mass
of irregular calciﬁcation surrounded by concentric
lamellar rings of regular calciﬁed material (Fig. 3-12).
Occasionally, a peripheral layer of tubular dentin may
be applied by odontoblasts, which arise from the sur-
rounding pulp tissue in response to the presence of the
pulp stone. In addition, ﬁbrillar irregular calciﬁed
material also may be evident on the periphery of pulp
stones.
Diffuse linear calciﬁcations consist entirely of ﬁne,
ﬁbrillar, and irregular calciﬁcations that develop in the
pulp chambers and canals (Fig. 3-13). This material
often is deposited in a linear fashion along the course
of a blood vessel or nerve.
TREATMENT AND PROGNOSIS
No treatment is required. Most pulpal calciﬁcations are
not associated with any signiﬁcant clinical alterations.
PERIAPICAL GRANULOMA (CHRONIC
APICAL PERIODONTITIS)
The term periapical granuloma refers to a mass of
chronically or subacutely inﬂamed granulation tissue
at the apex of a nonvital tooth. This commonly used
name is not totally accurate because the lesion does not
show true granulomatous inﬂammation microscopi-
cally. Although the term apical periodontitis may be
more appropriate, it may prove confusing to the clini-
cian. Formation of apical inﬂammatory lesions repre-
sents a defensive reaction secondary to the presence of
microbial infection in the root canal with spread of
related toxic products into the apical zone. Initially, the
defense reaction eliminates noxious substances that
exit the canals. With time, however, the host reaction
becomes less effective with microbial invasion or
spread of toxins into the apical area. Although the
infection typically is bacterial in origin, the presence of
yeasts occasionally is demonstrated. Although contro-
versial, an increased prevalence of human cytomega-
lovirus and, to a lesser extent, Epstein-Barr virus has
been documented in symptomatic periapical inﬂam-
matory disease; some clinicians believe this to be more
than a secondary infestation.
Fig. 3-12 Pulp stones. Multiple stones within the pulp
chamber.
Fig. 3-13 Diffuse linear pulpal calciﬁcations. Fine, ﬁbrillar
calciﬁcations parallel the course of the neurovascular
channels within the pulp canal. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

128 ORAL AND MAXILLOFACIAL PATHOLOGY
In the early stages of infection, neutrophils predomi-
nate and radiographic alterations are not present; this
phase of periapical inﬂammatory disease is termed
acute apical periodontitis. The involved inﬂammatory
cells are primarily neutrophils and release prostaglan-
dins, which activate osteoclasts to resorb the sur-
rounding bone, leading to a detectable periapical
radiolucency. Researchers believe that this bone
destruction is an attempt to prevent the spread of the
infection and provide space for the arrival of defense
cells specialized against the infectious process. With
time, chronic inﬂammatory cells begin to dominate the
host response. Mediators released by lymphocytes
reduce further osteoclastic activity while also stimulating
ﬁbroblasts and the microvasculature. Because of these
actions, chronic lesions often are asymptomatic and
demonstrate little additional change radiographically.
Periapical granulomas may arise after quiescence of
a periapical abscess or may develop as the initial peri-
apical pathosis. These lesions are not necessarily static.
In addition to possible periapical cyst formation, a
worsening of the pulpal infection can lead to a reap-
pearance of inﬂammation, redevelopment of symp-
toms, and possible enlargement of the associated
radiolucency. Secondary acute inﬂammatory changes
within a periapical granuloma have been termed a
phoenix abscess, after the mythical bird that would die,
only to arise again from its own ashes. In progressive
periapical granulomas, the enlargement often is not
continuous but occurs in spurts associated with peri-
odic acute exacerbations.
CLINICAL AND RADIOGRAPHIC
FEATURES
The initial phase of periapical inﬂammatory disease—
acute periapical periodontitis—creates a constant dull,
throbbing pain. The associated tooth responds nega-
tively to vitality testing or reveals a delayed positive
result. Typically, pain on biting or percussion is present,
and no obvious radiographic alterations are noted. If
the acute inﬂammatory process evolves into a chronic
pattern, then the associated symptoms diminish. In
many instances, chronic periapical inﬂammatory
disease is detected without any previous recollection of
a prior acute phase.
Most periapical granulomas are asymptomatic, but
pain and sensitivity can develop if acute exacerbation
occurs. Typically, the involved tooth does not demon-
strate mobility or signiﬁcant sensitivity to percussion.
The soft tissue overlying the apex may or may not be
tender. The tooth does not respond to thermal or elec-
tric pulp tests unless the pulpal necrosis is limited to a
single canal in a multirooted tooth. Periapical granulo-
mas represent approximately 75% of apical inﬂamma-
tory lesions and 50% of those that have failed to respond
to conservative endodontic measures.
Most lesions are discovered on routine radiographic
examination. The associated radiolucencies are vari-
able, ranging from small, barely perceptible lesions to
lucencies exceeding 2 cm in diameter (Figs. 3-14 to
3-16). Affected teeth typically reveal loss of the apical
lamina dura. The lesion may be circumscribed or ill-
deﬁned and may or may not demonstrate a surround-
ing radiopaque rim. Root resorption is not uncommon
(Fig. 3-17). Although lesions greater than 200 mm
2
often represent periapical cysts, numerous investiga-
tors have been unable to distinguish periapical granu-
lomas from periapical cysts simply on the basis of size
and radiographic appearance. Because periapical
inﬂammatory disease is not static and granulomas can
transform into cysts or abscesses (and vice versa)
without signiﬁcant radiographic change, it is not
Fig. 3-14 Periapical granulomas. Discrete periapical
radiolucencies associated with the apices of the mandibular
ﬁrst molar. (Courtesy of Dr. Garth Bobrowski.)
Fig. 3-15 Periapical granuloma. Well-deﬁned radiolucency
associated with the apex of the maxillary ﬁrst bicuspid.
(Courtesy of Dr. Frank Beylotte.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 129
surprising that the radiographic features are not
diagnostic.
HISTOPATHOLOGIC FEATURES
Periapical granulomas consist of inﬂamed granulation
tissue surrounded by a ﬁbrous connective tissue wall.
The granulation tissue demonstrates a variably dense
lymphocytic inﬁltrate that is intermixed frequently
with neutrophils, plasma cells, histiocytes, and, less fre-
quently, mast cells and eosinophils (Fig. 3-18). When
numerous plasma cells are present, scattered eosino-
philic globules of gamma globulin (Russell bodies)
may be seen. In addition, clusters of lightly basophilic
particles (pyronine bodies) also may be present in
association with the plasmacytic inﬁltrate. Both of
these plasma cell products are not speciﬁc for the peri-
apical granuloma and may be found within any accu-
mulation of plasma cells. Epithelial rests of Malassez
may be identiﬁed within the granulation tissue. Collec-
tions of cholesterol clefts, with associated multinucle-
ated giant cells and areas of red blood cell extravasation
with hemosiderin pigmentation, may be present.
Although the source of the cholesterol is unclear, this
material often is noted in areas of long-term inﬂamma-
tion and may accumulate from dying inﬂammatory
cells, disintegrating red blood cells, or degenerating
cystic epithelium. The cholesterol attracts macro-
phages and foreign body giant cells, which are unable
to degrade the material but release inﬂammatory
and bone resorptive mediators. Signiﬁcant cholesterol
accumulation can continue the inﬂammatory process
in the absence of active microbial infection. Small foci
of acute inﬂammation with focal abscess formation
may be seen but do not warrant the diagnosis of peri-
apical abscess.
TREATMENT AND PROGNOSIS
Apical inﬂammatory lesions result from the presence
of microorganisms or their toxic products in the root
canal, the apical tissues, or both. Successful treatment
depends on the reduction and control of the offending
organisms. Because of the anatomic complexity of the
root canal systems, some investigators believe absolute
eradication of all microorganisms is unlikely; the goal
of endodontics is to reduce the microbial load to a level
that is insufﬁcient to maintain periapical inﬂammation.
If the tooth can be maintained, then root canal therapy
can be performed. Nonrestorable teeth must be ex-
tracted, followed by curettage of all apical soft tissue.
In symptomatic cases, nonsteroidal antiinﬂammatory
Fig. 3-16 Periapical granuloma. Large, well-deﬁned
radiolucency associated with the apices of the mandibular
ﬁrst molar. (Courtesy of Dr. Robert E. Loy.)
Fig. 3-17 Periapical granuloma. Ill-deﬁned radiolucency
associated with the mandibular ﬁrst molar, which exhibits
signiﬁcant root resorption.
Fig. 3-18 Periapical granuloma. Granulation tissue
exhibits mixed inﬂammatory inﬁltrate consisting of
lymphocytes, plasma cells, and histiocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

130 ORAL AND MAXILLOFACIAL PATHOLOGY
drugs (NSAIDs) are beneﬁcial; use of systemic antibi-
otic medications is not recommended unless associ-
ated swelling or systemic changes are present.
Teeth treated endodontically should be evaluated at
1- and 2-year intervals (at a minimum) to rule out pos-
sible lesional enlargement and to ensure appropriate
healing. In addition, many clinicians believe that evalu-
ations at 1, 3, and 6 months are appropriate. Strong
emphasis should be placed on the importance of the
recall appointments.
Lesions may fail to heal for several reasons:
● Cyst formation
●Persistent pulpal infection (e.g., poor access
design, missed canals, perforated canals, vertical
root fractures, inadequate aseptic technique or
instrumentation, leaking ﬁllings)
● Extraradicular infection (usually localized peri-
apical actinomycotic colonization)
●Accumulation of endogenous debris (e.g., choles-
terol crystals)
●Periapical foreign material
●Associated periodontal disease
●Penetration of the adjacent maxillary sinus
●Fibrous scar formation (see following)
If initial conventional therapy is unsuccessful, end-
odontic retreatment represents the best approach for
minimizing the bacterial contamination and should
be considered before periapical surgery. Periapical
surgery remains an important tool for resolution of
periapical inﬂammatory disease, but often it is reserved
for lesions larger than 2 cm or those associated with
teeth that are not appropriate for conventional end-
odontic therapy. Periapical surgery should include
thorough curettage of all periradicular soft tissue,
amputation of the apical portion of the root, and sealing
the foramen of the canal.
All soft tissue removed during periapical surgical
procedures should be submitted for histopathologic
examination. These surgical sites represent areas that
have failed to respond to appropriate therapy; as such,
histopathologic examination and diagnostic conﬁrma-
tion are mandatory. The primary motivation for this
examination is not to discover whether the lesion rep-
resents a periapical granuloma or cyst; the examination
is conducted to eliminate the possibility of a more
serious process unrelated to periapical inﬂammatory
disease. In an active oral and maxillofacial pathology
service, discovery of unexpected neoplasms within
specimens removed during periapical surgery is not
rare.
On occasion, the defect created by periapical inﬂam-
matory lesions may ﬁll with dense collagenous tissue
rather than normal bone (Fig. 3-19). These ﬁbrous
(periapical) scars occur most frequently when both
the facial and lingual cortical plates have been lost (Fig.
3-20); however, they occasionally arise in areas with
intact cortical plates. If during surgery both plates are
discovered to be missing, then the patient should be
informed of the possibility of scar formation. The devel-
opment of a periapical scar is not an indication for
future surgery.
PERIAPICAL CYST (RADICULAR CYST;
APICAL PERIODONTAL CYST)
Epithelium at the apex of a nonvital tooth presumably
can be stimulated by inﬂammation to form a true epi-
thelium-lined cyst, or periapical cyst. The inﬂamma-
tory response appears to increase the production of
keratinocyte growth factor by periodontal stroma cells,
leading to increased proliferation of normally quies-
cent epithelium in the area. The source of the epithe-
lium is usually a rest of Malassez but also may be traced
to crevicular epithelium, sinus lining, or epithelial
lining of ﬁstulous tracts. Cyst development is common;
the reported frequency varies from 7% to 54% of peri-
apical radiolucencies.
The wide disparity of prevalence most likely is
related to the stringency of the diagnostic criteria used
in a particular study. Several investigators believe the
diagnosis of a periapical cyst can be made only after a
lesion has been examined entirely with serial or step
sectioning of the specimen. Review of random sections
of a fragmented and epithelialized periapical granu-
loma could appear to be an epithelium-lined cavity that
did not exist in reality. When strict criteria are used,
the prevalence of periapical cysts appears to be approx-
imately 15%. When the cyst and root are removed
totally, two variations of periapical cyst have been
described. Periapical pocket cysts are characterized
by an incomplete epithelial lining because of extension
Fig. 3-19 Periapical ﬁbrous scar. Dense, ﬁbrous
connective tissue with vital bone and no signiﬁcant
inﬂammatory inﬁltrate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 131
of the apical portion of the tooth into the cyst lumen.
Periapical true cysts form a complete epithelium-
lined baglike structure that is adjacent to, but separated
from, the tooth apex. Because distinguishing between
an epithelialized periapical granuloma, a “pocket” cyst,
or a “true” cyst has little postsurgical implications, labo-
rious histopathologic examination and subclassiﬁca-
tion are impractical.
Periapical cysts represent a ﬁbrous connective tissue
wall lined by epithelium with a lumen containing ﬂuid
and cellular debris. Theoretically, as the epithelium
desquamates into the lumen, the protein content is
increased. Fluid enters the lumen in an attempt to
equalize the osmotic pressure, and slow enlargement
occurs. Most periapical cysts grow slowly and do not
attain a large size.
On occasion, a similar cyst, best termed a lateral
radicular cyst, may appear along the lateral aspect of
the root. Like the periapical cyst, this lesion also usually
arises from rests of Malassez, and the source of inﬂam-
mation may be periodontal disease or pulpal necrosis
with spread through a lateral foramen. Radiographi-
cally, these cysts mimic developmental lateral peri-
odontal cysts (see page 692). Histopathologically,
however, they are consistent with cysts of inﬂamma-
tory origin.
Periapical inﬂammatory tissue that is not curetted
at the time of tooth removal may give rise to an inﬂam-
matory cyst called a residual periapical cyst. With
time, many of these cysts exhibit an overall reduction
in size, and spontaneous resolution can occur from a
lack of continued inﬂammatory stimulus.
CLINICAL AND RADIOGRAPHIC
FEATURES
PERIAPICAL CYST
Typically, patients with periapical cysts have no symp-
toms unless there is an acute inﬂammatory exacerba-
tion. In addition, if the cyst reaches a large size, then
swelling and mild sensitivity may be noted. Movement
and mobility of adjacent teeth are possible as the cyst
enlarges. The tooth from which the cyst originated does
not respond to thermal and electric pulp testing.
The radiographic pattern is identical to that of a
periapical granuloma. Cysts may develop even in small
periapical radiolucencies, and the radiographic size
cannot be used for the deﬁnitive diagnosis. A loss of the
lamina dura is seen along the adjacent root, and a
rounded radiolucency encircles the affected tooth apex
(Fig. 3-21). Root resorption is common (Fig. 3-22).
With enlargement, the radiolucency often ﬂattens out
as it approaches adjacent teeth. Signiﬁcant growth is
possible, and lesions occupying an entire quadrant
have been noted (Fig. 3-23). Although periapical cysts
more frequently achieve greater size than periapical
Fig. 3-20 Periapical ﬁbrous scar. Periapical radiolucency
of maxilla at the previous site of extraction in which both
cortical plates were lost. The site was ﬁlled with dense
collagenous tissue. (Courtesy of Dr. James Tankersley.)
Fig. 3-21 Periapical cyst. Well-circumscribed radiolucency
intimately associated with the apex of the mandibular central
incisor. Note the loss of lamina dura in the area of the lesion. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

132 ORAL AND MAXILLOFACIAL PATHOLOGY
granulomas, neither the size nor the shape of the lesion
can be considered a deﬁnitive diagnostic criterion.
Periapical cysts also are known to involve deciduous
teeth. These are most frequently associated with molar
teeth and appear as a radiolucent zone that surrounds
the roots and ﬁlls the interradicular space at the bifur-
cation (Fig. 3-24).
LATERAL RADICULAR CYST
Lateral radicular cysts appear as discrete radiolucen-
cies along the lateral aspect of the root (Fig. 3-25).
Loss of lamina dura and an obvious source of inﬂam-
mation may not be detected without a high index of
suspicion. Before surgical exploration of laterally posi-
tioned radiolucencies, a thorough evaluation of the
periodontal status and vitality of adjacent teeth should
be performed. Many examples of the so-called globu-
lomaxillary cyst (see page 28) prove to be of inﬂam-
matory origin and represent lateral radicular cysts
(Fig. 3-26).
RESIDUAL PERIAPICAL CYST
The residual periapical cyst appears as a round-to-oval
radiolucency of variable size within the alveolar ridge
at the site of a previous tooth extraction (Figs. 3-27 and
3-28). As the cyst ages, degeneration of the cellular
contents within the lumen occasionally leads to dystro-
phic calciﬁcation and central luminal radiopacity
(Fig. 3-29).
HISTOPATHOLOGIC FEATURES
The histopathologic features of all three types of inﬂam-
matory cysts are similar. The cyst is lined by stratiﬁed
squamous epithelium, which may demonstrate exocy-
tosis, spongiosis, or hyperplasia (Fig. 3-30). As seen in
dentigerous cysts, scattered mucous cells or areas of
ciliated pseudostratiﬁed columnar epithelium may
be noted in periapical cysts (Fig. 3-31). Although some
maxillary periapical cysts lined by pseudostratiﬁed
columnar epithelium may have originated from the
adjacent sinus lining, the presence of mucous cells or
respiratory-like epithelium also can be observed in
mandibular cysts. The ability of odontogenic epithe-
lium to demonstrate such specialized differentiation
represents an example of prosoplasia (forward metapla-
sia) and highlights the diverse potential of odontogenic
epithelium. The cyst lumen may be ﬁlled with ﬂuid and
Fig. 3-22 Periapical cyst. Radiolucency associated with the
maxillary central incisor, which exhibits signiﬁcant root
resorption.
Fig. 3-23 Periapical cyst. Large unilocular radiolucency
extending from the mandibular ﬁrst molar to the
contralateral ﬁrst molar. (Courtesy of Dr. John R. Cramer.)
Fig. 3-24 Periapical cyst. Radiolucency involving the
bifurcation and apices of the deciduous right mandibular
second molar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 133
cellular debris. On occasion, the lining epithelium
may demonstrate linear or arch-shaped calciﬁcations
known as Rushton bodies (Fig. 3-32). Dystrophic calciﬁ-
cation, cholesterol clefts with multinucleated giant
cells, red blood cells, and areas of hemosiderin pig-
mentation may be present in the lumen, wall, or both.
The wall of the cyst consists of dense ﬁbrous connective
tissue, often with an inﬂammatory inﬁltrate containing
lymphocytes variably intermixed with neutrophils,
plasma cells, histiocytes, and (rarely) mast cells and
eosinophils.
Occasionally, the walls of inﬂammatory cysts will
contain scattered hyaline bodies (pulse granuloma,
giant-cell hyaline angiopathy). These bodies appear
as small circumscribed pools of eosinophilic material
that exhibits a corrugated periphery of condensed col-
lagen often surrounded by lymphocytes and multinu-
cleated giant cells (Fig. 3-33). The eosinophilic material
may be uniform or contain a variable mixture of lym-
phocytes, plasma cells, multinucleated giant cells, neu-
trophils, necrotic debris, and dystrophic calciﬁcation.
Initially, these foci were thought to be a vascular degen-
erative process or a foreign body reaction to machinery
oil or vegetable matter. Subsequently, these bodies
A B
Fig. 3-25 Lateral radicular cyst. A, Periapical radiograph of the left side of the posterior
mandible taken at time of completion of endodontic therapy of the bicuspid and molars.
B, Subsequent radiograph taken 27 months later. Note radiolucency between bicuspid and
ﬁrst molar extending laterally from the mesial root of the ﬁrst molar. (Courtesy of Dr. Carroll
Gallagher.)
Fig. 3-26 Lateral radicular cyst. Inverted pear-shaped
radiolucency between the maxillary lateral incisor and cuspid
(arrow). The lateral incisor ultimately proved to be nonvital.
Fig. 3-27 Residual periapical cyst. Persistent radiolucency
of the mandibular body at the site of previous tooth
extraction. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

134 ORAL AND MAXILLOFACIAL PATHOLOGY
Fig. 3-28 Residual periapical cyst. Well-circumscribed
radiolucency in the extraction site of the left mandibular ﬁrst
molar.
Fig. 3-29 Residual periapical cyst. Radiolucency with
central radiopacity of the right mandibular body.
Fig. 3-30 Periapical cyst. Cyst lined by stratiﬁed squamous
epithelium. Note connective tissue wall, which contains a
chronic inﬂammatory inﬁltrate and numerous cholesterol
clefts.
Fig. 3-31 Periapical cyst. Stratiﬁed squamous epithelial
lining containing numerous mucous cells.
Fig. 3-32 Periapical cyst. Squamous epithelial cyst lining
exhibiting numerous irregular and curvilinear Rushton bodies.
A B
Fig. 3-33 Hyaline bodies. A, Multiple hyaline bodies
appearing as corrugated collagenous rings surrounding
lymphocytes and plasma cells; note early hyaline body ﬁlled
with serum. B, Multiple hyaline bodies with numerous
multinucleated giant cells within and around the corrugated
collagenous rings. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 135
have been shown to represent pools of inﬂammatory
exudate (i.e., extravasated serum) that ultimately under-
goes ﬁbrosis and occasionally dystrophic calciﬁcation.
The multinucleated giant cells are drawn to the site for
removal of insoluble hemosiderin granules. Hyaline
bodies may be found in any area of chronic intraosse-
ous inﬂammation, especially periapical inﬂammatory
disease.
TREATMENT AND PROGNOSIS
A periapical cyst is treated in the same manner as a
periapical granuloma. When clinical and radiographic
features indicate a periapical inﬂammatory lesion,
extraction or conservative nonsurgical endodontic
therapy is performed. Although some authors believe
that large cystic lesions cannot be resolved with con-
ventional endodontics, experienced clinicians have
successfully used nonsurgical root canal therapy for
large areas of periapical inﬂammatory disease that
approach 2 cm in diameter. Larger lesions associated
with restorable teeth have been treated successfully
with conservative endodontic therapy when combined
with biopsy and marsupialization, decompression, or
fenestration. As with any periapical inﬂam matory
lesion, minimal follow-up at 1 and 2 years is advised
strongly.
If the radiolucency fails to resolve, then the lesion
often can be managed successfully by nonsurgical end-
odontic retreatment. As previously mentioned, periapi-
cal surgery typically is performed for lesions exceeding
2 cm and those associated with teeth that are not suit-
able for conventional endodontics. Biopsy is indicated
to rule out other possible pathologic processes.
Because any number of odontogenic and nonodon-
togenic cysts and tumors can mimic the appearance of
a residual periapical cyst, all of these cysts should be
excised surgically. All inﬂammatory foci in the area of
a lateral radicular cyst should be eliminated and the
patient observed in a manner similar to that described
for the periapical cyst. In some instances, lateral radic-
ular cysts are removed before tooth vitality testing or
periodontal evaluation for an adjacent focus of infec-
tion. If this diagnosis is made, then a thorough evalua-
tion for an inﬂammatory source is mandatory.
Cysts of inﬂammatory origin do not recur after
appropriate management. Fibrous scars are possible,
especially when both cortical plates have been lost;
once diagnosed, no further therapy for ﬁbrous scars is
indicated. In rare instances, development of squamous
cell carcinoma has been reported within periapical
cysts; therefore, even in the absence of symptoms,
treatment is required for all persistent intrabony
pathoses that have not been diagnosed deﬁnitively by
histopathologic examination.
PERIAPICAL ABSCESS
The accumulation of acute inﬂammatory cells at the
apex of a nonvital tooth is termed a periapical abscess.
Acute inﬂammatory lesions with abscess formation
may arise as the initial periapical pathosis or from an
acute exacerbation of a chronic periapical inﬂamma-
tory lesion (see discussion of phoenix abscess, page
128). Frequently, the source of the infection is obvious.
On occasion, however, pulpal death may be trauma
related, and the tooth may contain neither a cavity nor
a restoration.
In the earliest stage of all forms of periapical inﬂam-
matory disease, the periapical periodontal ligament
(PDL) ﬁbers may exhibit acute inﬂammation but no
frank abscess formation. This localized alteration, best
termed acute apical periodontitis, may or may not
proceed to abscess formation. Although this process
often occurs in association with a nonvital tooth, acute
apical periodontitis may be found in vital teeth second-
ary to trauma, high occlusal contacts, or wedging by a
foreign object. The clinical presentation often closely
resembles that of a periapical abscess and must be
considered in the differential diagnosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
Many investigators subdivide periapical abscesses into
acute and chronic types. However, these are misno-
mers because both types represent acute inﬂammatory
reactions. Periapical abscesses should be designated as
symptomatic or asymptomatic on the basis of their
clinical presentations.
Periapical abscesses become symptomatic as the
purulent material accumulates within the alveolus.
The initial stages produce tenderness of the affected
tooth that often is relieved by direct application of pres-
sure. With progression, the pain becomes more intense,
often with extreme sensitivity to percussion, extrusion
of the tooth, and swelling of the tissues. The offending
tooth does not respond to cold or electric pulp testing.
Headache, malaise, fever, and chills may be present.
Radiographically, abscesses may demonstrate a
thickening of the apical periodontal ligament, an ill-
deﬁned radiolucency, or both; however, often no
appreciable alterations can be detected because insuf-
ﬁcient time has occurred for signiﬁcant bone destruc-
tion. Phoenix abscesses demonstrate the outline of the
original chronic lesion, with or without an associated
ill-deﬁned bone loss.
With progression, the abscess spreads along the
path of least resistance. The purulence may extend
through the medullary spaces away from the apical
area, resulting in osteomyelitis, or it may perforate the `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

136 ORAL AND MAXILLOFACIAL PATHOLOGY
cortex and spread diffusely through the overlying
soft tissue (as cellulitis). Each of these occurrences is
described later in the chapter.
Once an abscess is in soft tissue, it can cause cellu-
litis or may channelize through the overlying soft tissue.
The cortical plate may be perforated in a location that
permits entrance into the oral cavity. The purulent
material can accumulate in the connective tissue over-
lying the bone and can create a sessile swelling or per-
forate through the surface epithelium and drain
through an intraoral sinus (Figs. 3-34 and 3-35). At the
intraoral opening of a sinus tract, a mass of subacutely
inﬂamed granulation tissue often is found, known as a
parulis (gum boil) (Figs. 3-36 and 3-37). Occasionally,
the nonvital tooth associated with the parulis may be
difﬁcult to determine, and insertion of a gutta-percha
point into the tract can aid in detection of the offending
tooth during radiographic examination (Fig. 3-38).
Dental abscesses also may channelize through the
overlying skin and drain via a cutaneous sinus (Fig.
3-39).
Most dental-related abscesses perforate buccally
because the bone is thinner on the buccal surface.
However, infections associated with maxillary lateral
incisors, the palatal roots of maxillary molars, and man-
dibular second and third molars typically drain through
the lingual cortical plate.
If a chronic path of drainage is achieved, a periapi-
cal abscess typically becomes asymptomatic because of
Fig. 3-34 Periapical abscess. Bilateral soft tissue swelling
of the anterior palate.
Fig. 3-35 Periapical abscess. Same patient as depicted in
Fig. 3-34. Multiple, overlapping radiolucencies of the anterior
maxilla are present. All four maxillary incisors exhibit pulpal
necrosis.
Fig. 3-36 Parulis. Erythematous mass of granulation tissue
overlying the left maxillary central incisor. Note discoloration
of the maxillary right central incisor.
Fig. 3-37 Parulis. Normal connective tissue has been
replaced by acutely inﬂamed granulation tissue, which
exhibits focal areas of neutrophilic abscess formation. Note
the central sinus tract, which courses from the base of the
specimen toward the surface epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 137
a lack of accumulation of purulent material within the
alveolus. Occasionally, such infections are discovered
during a routine oral examination after detection of a
parulis or drainage through a large carious defect (Figs.
3-40 and 3-41). If the drainage site becomes blocked,
then signs and symptoms of the abscess frequently
become evident in a short time. On occasion, periapi-
cal infections can spread through the bloodstream and
result in systemic symptoms such as fever, lymphade-
nopathy, and malaise. The risk of dissemination appears
to be less for periapical abscesses that drain freely.
HISTOPATHOLOGIC FEATURES
Biopsy specimens from pure abscesses are uncommon
because the material is in liquid form. Abscesses consist
of a sea of polymorphonuclear leukocytes often inter-
mixed with inﬂammatory exudate, cellular debris,
A B
Fig. 3-38 Periapical abscess. A, Same patient as depicted in Fig. 3-36. None of the incisors
demonstrates an obvious periapical radiolucency. (The large radiolucency at the top is the
anterior portion of the maxillary sinus.) B, Gutta-percha point revealed that the right maxillary
incisor was the source of the infection.
Fig. 3-39 Cutaneous sinus. Erythematous, ﬁrm, and
sensitive enlargement of the skin inferior to the right body of
the mandible.
Fig. 3-40 Parulis. Asymptomatic yellow-red nodule of the
anterior mandibular alveolar mucosa. The adjacent teeth
were asymptomatic and appeared clinically normal. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

138 ORAL AND MAXILLOFACIAL PATHOLOGY
necrotic material, bacterial colonies, or histiocytes (Fig.
3-42). Phoenix abscesses can maintain a soft tissue
component; they present as subacutely inﬂamed peri-
apical granulomas or cysts intermixed with areas of
signiﬁcant abscess formation. In these cases the pathol-
ogist typically diagnoses the primary lesion but com-
ments about the abscess formation.
TREATMENT AND PROGNOSIS
Treatment of the patient with a periapical abscess con-
sists of drainage and elimination of the focus of infec-
tion. Those abscesses associated with a patent ﬁstulous
tract may be asymptomatic but, nevertheless, should be
treated. With localized periapical abscesses, the signs
and symptoms typically diminish signiﬁcantly within
48 hours of initiation of appropriate drainage. When
the abscess causes clinical expansion of the bone or soft
tissue adjacent to the apex of the affected tooth, inci-
sional drainage of the swelling should be considered
because this technique appears to be associated with
more rapid resolution of the inﬂammatory process
when compared with drainage through the root canal.
If the affected tooth is extruded, then reduction of the
occlusion is recommended because chronic occlusal
trauma has been shown to delay resolution of the
inﬂammatory process. Unless contraindicated, treat-
ment with NSAIDs usually is appropriate preopera-
tively, immediately postoperatively, and for subsequent
pain control. Typically, use of antibiotic medications
for a well-localized and easily drained periapical
abscess in a healthy patient is unnecessary. Antibiotic
coverage should be reserved for the medically compro-
mised and patients with signiﬁcant cellulitis or clinical
evidence of dissemination (i.e., fever, lymphadenopa-
thy, malaise). Medical conditions that favor more wide-
spread infection include diabetes mellitus, neutropenia,
malignancy, immunosuppression, or use of therapeutic
corticosteroid medications or cytotoxic drugs. Patients
with signiﬁcant cellulitis must be treated aggressively
and monitored closely. Complications, such as cavern-
ous sinus thrombosis, mediastinitis, cervical necrotiz-
ing fasciitis, and cerebral abscess, can be life threatening.
Once the infection has been resolved by extraction or
appropriate endodontic therapy, the affected bone
typically heals.
Usually, a sinus tract resolves spontaneously after
the offending tooth is extracted or endodontically
treated. Sinus tracts that persist are thought to contain
sufﬁcient infectious material along the ﬁstulous tract
to maintain the surface granulation tissue, and surgical
removal with curettage of the tract is required for
resolution.
CELLULITIS
If an abscess is not able to establish drainage through
the surface of the skin or into the oral cavity, it may
spread diffusely through fascial planes of the soft tissue.
This acute and edematous spread of an acute inﬂam-
matory process is termed cellulitis. Although numer-
ous patterns of cellulitis can be seen from the spread
of dental infections, two especially dangerous forms
warrant further discussion: (1) Ludwig’s angina and
(2) cavernous sinus thrombosis.
Ludwig’s angina, named after the German physician
who described the seriousness of the disorder in 1836,
Fig. 3-41 Periapical abscess. Same patient as depicted in
Fig. 3-40. Periapical radiolucency associated with the
nonvital mandibular lateral incisor.
Fig. 3-42 Periapical abscess. Sheet of polymorphonuclear
leukocytes intermixed with scattered histiocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 139
refers to cellulitis of the submandibular region. Angina
comes from the Latin word angere, which means to
strangle (an apt term, considering the clinical features
described in the following section). In approximately
70% of cases, Ludwig’s angina develops from spread of
an acute infection from the lower molar teeth. Other
situations associated with this clinical presentation are
peritonsillar or parapharyngeal abscesses, oral lacera-
tions, fractures of the mandible, or submandibular sial-
adenitis. Although the process may occur in otherwise
healthy individuals, there is an increased prevalence in
patients who are immunocompromised secondary to
disorders such as diabetes mellitus, organ transplanta-
tion, acquired immunodeﬁciency syndrome (AIDS),
and aplastic anemia.
The cavernous sinus is a major dural sinus that is
encased between the meningeal and periosteal layers
of the dura. The meningeal layer contains the trochlear
and oculomotor nerves and the maxillary and ophthal-
mic branches of the trigeminal nerve. In addition, the
internal carotid artery and abducens nerve travel
within the sinus. The sinus receives venous drainage
from the orbit via the superior and inferior ophthalmic
veins. Infection of the sinus can produce a variety of
clinical symptoms related to the numerous anatomic
structures that course through this site.
Cavernous sinus thrombosis can occur via an ante-
rior or posterior pathway. Infection from the maxillary
anterior teeth can perforate the facial maxillary bone
and spread to the canine space. A septic thrombus
develops in the valveless facial veins coursing through
this space, propagating in a retrograde fashion from the
angular vein to the inferior ophthalmic vein through
the inferior orbital ﬁssure into the cavernous sinus. The
posterior pathway is followed by infections originating
from maxillary premolar or molar teeth, which dem-
onstrate buccal or infratemporal space involvement
that may spread via the emissary veins from the ptery-
goid venous plexus to the inferior petrosal sinus and
into the cavernous sinus. Overall, cavernous sinus
thrombosis is relatively uncommon, and orodental
infections are responsible in approximately 10% of
the cases.
CLINICAL FEATURES
LUDWIG’S ANGINA
Ludwig’s angina is an aggressive and rapidly spreading
cellulitis that involves the sublingual, submandibular,
and submental spaces. Once the infection enters the
submandibular space, it may extend to the lateral pha-
ryngeal space and then to the retropharyngeal space.
This extension may result in spread to the mediasti-
num, with several serious consequences.
Ludwig’s angina creates massive swelling of the
neck that often extends close to the clavicles (Fig.
3-43). Involvement of the sublingual space results in
elevation, posterior enlargement, and protrusion of the
tongue (woody tongue), which can compromise the
airway. Submandibular space spread causes enlarge-
ment and tenderness of the neck above the level of the
hyoid bone (bull neck). Although initially unilateral,
spread to the contralateral neck typically occurs. Pain
in the neck and ﬂoor of mouth may be seen in addition
to restricted neck movement, dysphagia, dysphonia,
dysarthria, drooling, and sore throat. Involvement of
the lateral pharyngeal space can cause respiratory
obstruction secondary to laryngeal edema. Tachypnea,
dyspnea, tachycardia, stridor, restlessness, and the
patient’s need to maintain an erect position suggest
airway obstruction. Fever, chills, leukocytosis, and an
elevated sedimentation rate may be seen. Classically,
obvious collections of pus are not present.
CAVERNOUS SINUS THROMBOSIS
Cavernous sinus thrombosis appears as an edematous
periorbital enlargement with involvement of the eyelids
and conjunctiva. In cases involving the canine space,
swelling is also typically present along the lateral border
Fig. 3-43 Ludwig’s angina. Soft tissue swelling of the right
submandibular region. (Courtesy of Dr. Brian Blocher.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

140 ORAL AND MAXILLOFACIAL PATHOLOGY
of the nose and may extend up to the medial aspect of
the eye and periorbital area (Fig. 3-44). Protrusion and
ﬁxation of the eyeball often are evident, in addition to
induration and swelling of the adjacent forehead and
nose. Pupil dilation, lacrimation, photophobia, and loss
of vision may occur. Pain over the eye and along the
distribution of the ophthalmic and maxillary branches
of the trigeminal nerve often are present. Proptosis,
chemosis, and ptosis are noted in greater than 90% of
affected patients. The cavernous sinuses freely com-
municate via the intercavernous sinus. Although many
cases are initially unilateral, without appropriate
therapy, the infection may spread to the contralateral
side.
Fever, chills, headache, sweating, tachycardia,
nausea, and vomiting can occur. With progression,
signs of central nervous system (CNS) involvement
develop. Meningitis, tachycardia, tachypnea, irregular
breathing, stiffening of the neck, and deepening stupor
with or without delirium indicate advanced toxemia
and meningeal involvement. Occasionally, brain abs-
cesses may result.
TREATMENT AND PROGNOSIS
LUDWIG’S ANGINA
Treatment of Ludwig’s angina centers around four
activities:
1. Maintenance of the airway
2. Incision and drainage
3. Antibiotic therapy
4. Elimination of original focus of infection
Of primary importance is management of an intact
airway. On initial observation, many clinicians admin-
ister systemic corticosteroid medications, such as intra-
venous (IV) dexamethasone, in an attempt to reduce
the cellulitis. This procedure often protects the airway
and allows more rapid penetration of antibiotic medi-
cations in the infected fascial spaces. Such therapy sig-
niﬁcantly reduces the need for an artiﬁcial airway; in
the majority of the cases, tracheotomy or intubation is
not required.
If signs or symptoms of impending airway obstruc-
tion develop, ﬁber-optic nasotracheal intubation or
tracheostomy should be performed. Orotracheal intu-
bation often is very difﬁcult because of the presence of
trismus and swollen soft tissues. Because intubation is
difﬁcult in patients with such massive neck enlarge-
ment and may cause laryngospasm or discharge of pus
into the bronchial tree, tracheostomy is preferred if
there is any chance of signiﬁcant intubation complica-
tions. On occasion, cricothyroidotomy is performed
instead of a tracheostomy because of a perceived lower
risk of spreading the infection to the mediastinum.
High-dose penicillin is the antibiotic of choice.
Aminoglycoside therapy is given for resistant organ-
isms, and clindamycin or chloramphenicol is used
in penicillin-sensitive patients. The antibiotic medica-
tion is adjusted according to the patient’s response
and culture results from aspirates of ﬂuid from the
enlargements.
Although large accumulations of purulent material
are rare, decompression of the sublingual, submental,
and submandibular spaces should be performed when
ﬂuctuance is present. If the infection remains diffuse,
indurated, and brawny, then surgical intervention is at
the discretion of the clinician and often is governed by
the patient’s response to noninvasive therapy. Com-
puted tomography (CT) of the neck and chest is recom-
mended for patients with extensive cervical infection
to rule out spread into the mediastinum.
Before the use of modern antibiotic medications,
the mortality from Ludwig’s angina often exceeded
50%. Although this rate has been reduced to less than
10%, deaths still occur as the result of complications
Fig. 3-44 Cellulitis involving canine space. Erythematous
and edematous enlargement of the left side of the face with
involvement of the eyelids and conjunctiva. Patients with
odontogenic infections involving the canine space are at risk
for cavernous sinus thrombosis. (Courtesy of Dr. Richard Ziegler.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 141
such as pericarditis, pneumonia, mediastinitis, sepsis,
empyema, and respiratory obstruction.
CAVERNOUS SINUS THROMBOSIS
The therapeutic cornerstones for cavernous sinus
thrombosis secondary to dental infections are surgical
drainage combined with high-dose antibiotic medica-
tions similar to those administered for patients with
Ludwig’s angina. The offending tooth should be
extracted, and drainage is required if ﬂuctuance is
present. Administration of systemic corticosteroid
drugs is indicated only in patients who have developed
pituitary insufﬁciency in advanced cases of cavernous
sinus thrombosis. Some investigators also prescribe
anticoagulant medications to prevent thrombosis and
septic emboli; conversely, others believe that thrombo-
sis limits the infection and that the use of anticoagulant
drugs may promote hemorrhagic lesions in the orbit
and brain.
In older series the mortality rate approached 75%.
Even with current medical advances and modern anti-
biotic medications, the mortality rate remains at
approximately 30%, with fewer than 40% of patients
achieving full recovery.
OSTEOMYELITIS
Osteomyelitis is an acute or chronic inﬂammatory
process in the medullary spaces or cortical surfaces of
bone that extends away from the initial site of involve-
ment. The term osteomyelitis has been used to encom-
pass a wide variety of pathoses. This section describes
the classic pattern of osteomyelitis. The vast majority of
osteomyelitis cases are caused by bacterial infections
and result in an expanding lytic destruction of the
involved bone, with suppuration and sequestra forma-
tion. Many believe that this condition is more appro-
priately termed suppurative osteomyelitis, bacterial
osteomyelitis, or secondary osteomyelitis. This pattern of
osseous pathosis is in contrast to an ill-deﬁned group
of idiopathic inﬂammatory disorders of bone that do
not respond consistently to antibacterial medications
and typically demonstrate ultimate sclerosis of bone
without suppuration or sequestra formation. This
second pattern of inﬂammatory bone disease is most
appropriately termed primary chronic osteomyelitis but
often is included under the term diffuse sclerosing osteo-
myelitis. This disorder and several other patterns of
inﬂammatory bone disease (e.g., focal sclerosing osteo-
myelitis, proliferative periostitis, alveolar osteitis) are
unique and are covered separately later in the chapter.
Osteoradionecrosis is excluded from this discussion
because this is primarily a problem of hypoxia, hypo-
cellularity, and hypovascularity in which the presence
of bacteria represents a secondary colonization of non-
healing bone rather than a primary bacterial infection
(see page 296). In addition, bisphosphonate-associated
osteonecrosis represents another unique pattern that is
discussed in a later chapter and appears more strongly
related to altered bone metabolism (see page 299).
Suppurative osteomyelitis of the jaws is uncommon
in developed countries, but it continues to be a source
of signiﬁcant difﬁculty in developing nations. In Europe
and North America, most cases arise after odontogenic
infections or traumatic fracture of the jaws. In addition,
many cases reported in Africa occur in the presence
of acute necrotizing ulcerative gingivitis (ANUG) or
noma.
Chronic systemic diseases, immunocompromised
status, and disorders associated with decreased vascu-
larity of bone appear to predispose people to osteomy-
elitis. Tobacco use, alcohol abuse, IV drug abuse,
diabetes mellitus, exanthematous fevers, malaria, sickle
cell anemia, malnutrition, malignancy, collagen vascu-
lar diseases, and AIDS have been associated with an
increased frequency of osteomyelitis. In addition to
radiation, several diseases (e.g., osteopetrosis, dysosteo-
sclerosis, late Paget’s disease, end-stage cemento-
osseous dysplasia) may result in hypovascularized bone
that is predisposed to necrosis and inﬂammation.
Acute suppurative osteomyelitis exists when an
acute inﬂammatory process spreads through the med-
ullary spaces of the bone and insufﬁcient time has
passed for the body to react to the presence of the
inﬂammatory inﬁltrate. Chronic suppurative osteo-
myelitis exists when the defensive response leads to
the production of granulation tissue, which subse-
quently forms dense scar tissue in an attempt to wall
off the infected area. The encircled dead space acts as
a reservoir for bacteria, and antibiotic medications
have great difﬁculty reaching the site. This pattern
begins to evolve about 1 month after the spread of the
initial acute infection and results in a smoldering
process that is difﬁcult to manage unless the problem
is approached aggressively.
CLINICAL AND RADIOGRAPHIC
FEATURES
Patients of all ages can be affected by osteomyelitis.
There is a strong male predominance, approaching
75% in some reviews. Most cases involve the mandible.
Maxillary disease becomes important primarily in
pediatric patients and in cases that arise from ANUG
or noma (in African populations).
ACUTE SUPPURATIVE OSTEOMYELITIS
Patients with acute osteomyelitis have signs and
symptoms of an acute inﬂammatory process that has
typically been less than 1 month in duration. Fever, `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

142 ORAL AND MAXILLOFACIAL PATHOLOGY
leukocytosis, lymphadenopathy, signiﬁcant sensitivity,
and soft tissue swelling of the affected area may be
present. The radiographs may be unremarkable or may
demonstrate an ill-deﬁned radiolucency (Fig. 3-45).
Periosteal new bone formation also may be seen in
response to subperiosteal spread of the infection. This
proliferation is more common in young patients and
presents as a single-layered linear radiopaque line
separated from the normal cortex by an intervening
radiolucent band. On occasion, paresthesia of the lower
lip, drainage, or exfoliation of fragments of necrotic
bone may be discovered. A fragment of necrotic bone
that has separated from the adjacent vital bone is
termed a sequestrum. Sequestra often exhibit sponta-
neous exfoliation (Fig. 3-46). On occasion, fragments of
necrotic bone may become surrounded by new vital
bone, known as an involucrum.
CHRONIC SUPPURATIVE OSTEOMYELITIS
If acute osteomyelitis is not resolved expeditiously, the
entrenchment of chronic osteomyelitis occurs, or the
process may arise primarily without a previous acute
episode. Swelling, pain, sinus formation, purulent dis-
charge, sequestrum formation, tooth loss, or pathologic
fracture may occur. Patients may experience acute
exacerbations or periods of decreased pain associated
with chronic smoldering progression (Fig. 3-47).
Radiographs reveal a patchy, ragged, and ill-deﬁned
radiolucency that often contains central radiopaque
sequestra. On CT scan, the osteolytic change is contin-
Fig. 3-45 Acute osteomyelitis. Ill-deﬁned area of
radiolucency of the right body of the mandible.
Fig. 3-46 Acute osteomyelitis with sequestrum.
Radiolucency of the right body of the mandible with central
radiopaque mass of necrotic bone. (Courtesy of Dr. Michael
Meyrowitz.)
A B
Fig. 3-47 Chronic osteomyelitis. A, Ill-deﬁned area of radiolucency of the right body of the
mandible adjacent to a recent extraction site. B, After the initial intervention, the patient
failed to return for follow-up because of lack of signiﬁcant pain. An enlarged, ill-deﬁned
radiolucency of the right body of the mandible was discovered 2 years after the initial surgery.
(Courtesy of Dr. Charles Waldron.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 143
uous and may exhibit spread to the periosteum by
direct extension. This is in contrast to primary chronic
osteomyelitis, in which multifocal and separate areas
of osteolysis are present within zones of sclerosis. Occa-
sionally, the surrounding bone may exhibit an increased
radiodensity, and the cortical surface can demonstrate
signiﬁcant osteogenic periosteal hyperplasia. In spite of
the potential for peripheral sclerosis, the main radio-
graphic feature of suppurative osteomyelitis is one of
an expanding radiolucent osteolytic change.
Because of an anatomic peculiarity, large portions
of each jawbone receive their blood supply through
multiple arterial loops originating from a single vessel.
Involvement of this single feeder vessel can lead to
necrosis of a large portion of the affected bone. Seques-
tration that has involved an entire quadrant of the jaw
has been reported in long-standing cases of chronic
osteomyelitis.
HISTOPATHOLOGIC FEATURES
ACUTE SUPPURATIVE OSTEOMYELITIS
Generation of biopsy material from patients with acute
osteomyelitis is not common because of the predomi-
nantly liquid content and lack of a soft tissue compo-
nent. When submitted, the material consists
predominantly of necrotic bone. The bone shows a
loss of the osteocytes from their lacunae, peripheral
resorption, and bacterial colonization (Fig. 3-48). The
periphery of the bone and the haversian canals contain
necrotic debris and an acute inﬂammatory inﬁltrate
consisting of polymorphonuclear leukocytes. The sub-
mitted material will be diagnosed as a sequestrum
unless a good clinicopathologic correlation points to
the appropriate diagnosis of acute osteomyelitis.
CHRONIC SUPPURATIVE OSTEOMYELITIS
Biopsy material from patients with chronic osteomyeli-
tis demonstrates a signiﬁcant soft tissue component
that consists of chronically or subacutely inﬂamed
ﬁbrous connective tissue ﬁlling the intertrabecular
areas of the bone (Fig. 3-49). Scattered sequestra and
pockets of abscess formation are common.
TREATMENT AND PROGNOSIS
ACUTE SUPPURATIVE OSTEOMYELITIS
If obvious abscess formation is noted, the treatment of
acute osteomyelitis consists of antibiotic medications
and drainage. Microbiologic study of the infectious
material typically reveals a polymicrobial infection of
organisms normally present in the oral cavity. The anti-
biotic medications most frequently selected include
penicillin, clindamycin, cephalexin, cefotaxime, tobra-
mycin, and gentamicin.
In most patients a sufﬁcient and appropriate antibi-
otic regimen aborts the infection and averts the need
for surgical intervention. In patients receiving appro-
priate antibiotic medications, investigators have sug-
gested that nonvital bone fragments could be allowed
to remain in place as scaffolding for the future develop-
ment of new bone.
CHRONIC SUPPURATIVE OSTEOMYELITIS
Chronic osteomyelitis is difﬁcult to manage medically,
presumably because pockets of dead bone and organ-
isms are protected from antibiotic drugs by the sur-
rounding wall of ﬁbrous connective tissue. Surgical
intervention is mandatory. The antibiotic medications
are similar to those used in the acute form but must be
given intravenously in high doses.
Fig. 3-48 Acute osteomyelitis. Nonvital bone exhibits loss
of the osteocytes from the lacunae. Peripheral resorption,
bacterial colonization, and surrounding inﬂammatory
response also can be seen.
Fig. 3-49 Chronic osteomyelitis. Chronically inﬂamed and
reactive ﬁbrous connective tissue ﬁlling the intertrabecular
spaces. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

144 ORAL AND MAXILLOFACIAL PATHOLOGY
The extent of the surgical intervention depends on
the spread of the process; removal of all infected mate-
rial down to good bleeding bone is mandatory in all
cases. For small lesions, curettage, removal of necrotic
bone, and saucerization are sufﬁcient. In patients with
more extensive osteomyelitis, decortication or saucer-
ization often is combined with transplantation of can-
cellous bone chips. In cases of persisting osteomyelitis,
resection of the diseased bone followed by immediate
reconstruction with an autologous graft is required.
Weakened jawbones must be immobilized.
The goal of surgery is removal of all infected tissue.
Persistence of chronic osteomyelitis is typically the
result of incomplete removal of diseased tissue. On suc-
cessful elimination of all infected material, resolution
is expected. Adjunctive procedures (e.g., hyperbaric
oxygen) are rarely necessary if thorough surgical curet-
tage and sequestrectomy have been accomplished. In
an attempt to remove all areas of necrotic bone thor-
oughly, tetracycline has been administered 48 hours in
advance of surgery and used as a ﬂuorescent marker of
vital bone. At the time of surgery, necrotic bone will not
ﬂuoresce under the ultraviolet (UV) light of a Wood’s
lamp, indicating that it should be removed.
Management of persistent cases of chronic osteomy-
elitis often requires use of more sophisticated tech-
niques. Scintigraphic techniques with technetium
99m (
99m
Tc-labeled phosphorus compounds) can be
used to evaluate the therapeutic response and progress
of treatment. Hyperbaric oxygen is recommended pri-
marily for the rare patient who does not respond to
standard therapy or for disease arising in hypovascu-
larized bone (e.g., osteoradionecrosis, osteopetrosis,
Paget’s disease, cemento-osseous dysplasia).
DIFFUSE SCLEROSING OSTEOMYELITIS
Diffuse sclerosing osteomyelitis is an ill-deﬁned,
highly controversial, evolving area of dental medicine.
This diagnosis encompasses a group of presentations
that are characterized by pain, inﬂammation, and
varying degrees of gnathic periosteal hyperplasia, scle-
rosis, and lucency. On occasion, diffuse sclerosing
osteomyelitis can be confused with secondarily
inﬂamed intraosseous pathoses (ﬂorid cemento-osseous
dysplasia) (see page 641) or Paget’s disease of bone (see
page 623). In spite of the clinical and radiographic
similarities, these processes can be separated from
diffuse sclerosing osteomyelitis because of various clin-
ical, radiographic, and histopathologic differences.
The remaining pathoses can be grouped under three
categories:
1.Diffuse sclerosing osteomyelitis
2.Primary chronic osteomyelitis
3.Chronic tendoperiostitis
Although the concepts regarding the nature of these
conditions continue to be clariﬁed, many believe
chronic tendoperiostitis may represent a subset of
primary chronic osteomyelitis, whereas two other dis-
orders, synovitis-acne-pustulosis hyperostosis-
osteomyelitis (SAPHO) syndrome and chronic
recurrent multifocal osteomyelitis (CRMO), consti-
tute primary chronic osteomyelitis with additional
extragnathic manifestations. Whether these represent
variations of a single disorder or different pathologic
processes is highly debated with no clear answer at this
time. It appears prudent for clinicians to consider all
possibilities in an effort to ensure the most appropriate
care for patients affected by these conditions.
In the purist’s view, diffuse sclerosing osteomyeli-
tis is different from primary chronic osteomyelitis and
all its variants. This term should be used only when an
obvious infectious process directly is responsible for
sclerosis of bone. In these cases, chronic intraosseous
bacterial infection creates a smoldering mass of chroni-
cally inﬂamed granulation tissue that incites sclerosis
of the surrounding bone.
Primary chronic osteomyelitis often is confused
with, but must be distinguished from, chronic suppura-
tive osteomyelitis (secondary chronic osteomyelitis). In
contrast to suppurative osteomyelitis, an association
with a bacterial infection is not obvious, and suppura-
tion and sequestration characteristically are absent. A
number of causes have been proposed, such as an altered
immune response to an organism of low virulence, but
no single theory has received widespread acceptance. In
contrast to suppurative osteomyelitis, a primary infec-
tious cause cannot be proven, because many studies
have been unable to culture organisms and the condi-
tion does not respond to long-term antibiotic therapy.
Although initially thought to be an obscure infec-
tious process, the clinical presentation of chronic ten-
doperiostitis is similar to that of primary chronic
osteomyelitis; today many clinicians believe it repre-
sents a reactive alteration of bone that is initiated and
exacerbated by chronic overuse of the masticatory
muscles, predominantly the masseter and digastric. In
a large series of patients, parafunctional muscle habits
(e.g., bruxism, clenching, nail biting, co-contraction,
inability to relax jaw musculature) were known or
became evident during follow-up. In neurophysiologic
studies, masseter inhibitory reﬂexes were abnormal in
the vast majority of patients studied. The cause of
chronic tendoperiostitis is controversial, and some
investigators believe this disorder may represent a
variation of primary chronic osteomyelitis, in which
parafunctional muscle habits exacerbate the process
but are not the initial cause.
On occasion, gnathic lesions presenting as primary
chronic osteomyelitis occur in patients with other `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 145
signiﬁcant systemic manifestations. As the name
implies, CRMO includes involvement of multiple bones
that is thought by many to represent a widespread
variant of primary chronic osteomyelitis. As previously
discussed, SAPHO syndrome is an acronym for a
complex clinical presentation that includes synovitis,
acne, pustulosis, hyperostosis, and osteitis in which the
osseous lesions mirror those of primary chronic osteo-
myelitis and CRMO. The cause of SAPHO is unknown,
but it is thought to arise in genetically predisposed
individuals who develop an autoimmune disturbance
secondary to exposure to dermatologic bacteria.
Although not found consistently, an increased preva-
lence of histocompatibility antigen 27 (HLA 27) in
patients with SAPHO has been noted by several in-
vestigators. Researchers theorize that an abnormal
immune response to the microorganism cross-reacts
with normal bone or joint structures, leading to the
variety of clinical manifestations. Other immunologic
factors have been suggested to cause chronic osteomy-
elitis and CRMO, but again this theory currently is
unproven.
CLINICAL AND RADIOGRAPHIC
FEATURES
DIFFUSE SCLEROSING OSTEOMYELITIS
Diffuse sclerosing osteomyelitis is similar to the local-
ized variant (condensing osteitis; see page 147); how-
ever, the disorder is also very different. It arises almost
exclusively in adulthood, does not exhibit a sex pre-
dominance, and primarily occurs in the mandible.
An increased radiodensity develops around sites of
chronic infection (e.g., periodontitis, pericoronitis,
apical inﬂammatory disease) in a manner very similar
to the increased radiodensity that may be seen sur-
rounding areas of chronic suppurative osteomyelitis.
Typically, the altered area is restricted to a single site
but may be multifocal or extend to ﬁll an entire
quadrant.
The sclerosis centers on the crestal portions of the
tooth-bearing alveolar ridge and does not appear to
originate in the areas of attachment of the masseter or
digastric muscle (Fig. 3-50). The radiodensities do not
develop from previously radiolucent ﬁbro-osseous
lesions and do not exhibit the predilection for black
females, as is found in those patients with ﬂorid
cemento-osseous dysplasia. Pain and swelling are not
typical.
PRIMARY CHRONIC OSTEOMYELITIS
Primary chronic osteomyelitis is most commonly dis-
covered as an isolated process that typically is localized
to the mandible. Extragnathic evidence of SAPHO syn-
drome or CRMO is seen much less frequently. The
onset of symptoms tends to demonstrate two peaks,
one in adolescence and the other in adults after the
ﬁfth decade of life. Affected patients have recurrent
episodes of pain, swelling, local induration, and limited
mouth opening that is not associated with any obvious
dental infection. During periods of disease activity,
regional lymphadenopathy and reduced sensation in
the distribution of the inferior alveolar nerve may be
present. Absence of fever, purulence, sequestration,
and sinus formation are characteristic. The lack of an
obvious association with an odontogenic infection and
the nonsuppurative presentation clearly separate this
condition from chronic suppurative osteomyelitis.
In the early stages of primary chronic osteomyelitis,
radiographs tend to demonstrate a mixed pattern, with
areas of radiolucent osteolysis intermingled with zones
of sclerosis. In contrast to the pattern noted in CT
images of suppurative osteomyelitis, the osteolytic
areas are not continuous and alternate with zones of
sclerosis. The affected area of the bone typically is
thickened and demonstrates a periosteal proliferation
that is more solid than the typical laminated prolifera-
tive periostitis of inﬂammatory origin. Facial asymme-
try is not uncommon and often takes years to resolve
secondary to slow remodeling. Over time, the affected
area becomes predominantly sclerotic, but during sub-
sequent periods of disease activity, new foci of osteoly-
sis and cortical bone destruction appear. These newly
affected areas subsequently undergo sclerosis, awaiting
the next cycle of disease activity. With disease progres-
sion, the clinical symptoms typically diminish and the
affected bone demonstrates progressive sclerosis and a
reduction in the volume. Radiolucent osteolytic areas
may remain, but they tend to be relatively small and
widely scattered. Overall, the predominant radio-
graphic alteration of primary chronic osteomyelitis is
Fig. 3-50 Diffuse sclerosing osteomyelitis. Diffuse area of
increased radiodensity of the right body of the mandible in
the tooth-bearing area. No other quadrants were involved.
(Courtesy of Dr. Louis M. Beto.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

146 ORAL AND MAXILLOFACIAL PATHOLOGY
medullary sclerosis, a pattern that is noted invariably
in affected patients. Skeletal scintigraphy demonstrates
signiﬁcant uptake in the affected areas and should be
performed in all patients in an effort to rule out extra-
gnathic involvement.
CHRONIC TENDOPERIOSTITIS
Although the mean age of occurrence is 40 years,
chronic tendoperiostitis may occur in people of all
ages. There is no sex predilection. Recurrent pain,
swelling of the cheek, and trismus are classic symp-
toms. Suppuration and an associated infectious cause
are not found. Microbiologic cultures are typically neg-
ative, with the lesions failing to respond to appropriate
antibiotic medications. Uncommon spontaneous reso-
lution with development of radiographic normalcy has
been noted.
In most instances, the sclerosis is limited to a single
quadrant and centers on the anterior region of the
mandibular angle and posterior portion of the man-
dibular body (i.e., attachment of the masseter muscle).
Occasionally, the cuspid and premolar region and the
anterior mandible (i.e., attachment of the digastric
muscle) may be involved. Relatively radiolucent zones
are apparent within the areas of radiodensity, but his-
topathologic examination reveals only dense bone, for-
mation of reactive bone, and relatively few signs of
inﬂammation. The inferior border of the mandibular
body is typically affected, and signiﬁcant erosion of the
inferior border appears just anterior to the angle of the
mandible.
SAPHO SYNDROME
Patients with SAPHO syndrome are usually younger
than 60 years old and have chronic multifocal osteo-
myelitis that is typically associated with negative micro-
biologic cultures and is nonresponsive to antibiotic
therapy. In contrast to bacterial osteomyelitis, the
osteolytic areas are scattered randomly within areas of
sclerotic bone. Periosteal new bone formation is
common but not related to cortical bone perforation.
Investigation of the entire skeleton by bone scintigra-
phy classically reveals involvement of multiple sites.
The most frequently involved location is the anterior
chest wall, with the sternum, clavicles, and ribs being
affected individually or together. Other bones occa-
sionally involved include the spine, pelvis, and long
bones.
In early gnathic lesions, diffuse osteolytic zones are
more prominent than sclerosis; the affected bone is
enlarged because of signiﬁcant production of perios-
teal new bone. With time, the bone becomes more
sclerotic and decreases in size because of diminished
periosteal apposition, while the osteolytic zones be-
come smaller and fewer. External bone resorption and
deformity of the mandible are characteristic in older
lesions.
In some instances, multiple bone lesions are present
without associated skin involvement. In these cases the
osseous abnormalities have been termed CRMO. Scin-
tigraphy and radiographs will demonstrate synchro-
nous or metachronous involvement of multiple bones
such as the clavicle, humerus, radius, femur, or tibia.
Mandibular involvement in CRMO occurs in less than
10% of reported cases. Dermatologic involvement may
be absent, appear after some delay, or be so subtle as
to escape detection. The interval between initial recog-
nition of bone lesions and ultimate development of
skin alterations has been as long as 20 years. Com-
monly associated skin lesions include palmoplantar
pustulosis, pustular or plain psoriasis, acne conglobata
or ulcerans, and hidradenitis suppurativa.
HISTOPATHOLOGIC FEATURES
DIFFUSE SCLEROSING OSTEOMYELITIS
Diffuse sclerosing osteomyelitis demonstrates sclerosis
and remodeling of bone. The haversian canals are scat-
tered widely and little marrow tissue can be found.
Although the sclerosis occurs adjacent to areas of inﬂam-
mation, the bone is not typically intermixed with a sig-
niﬁcant inﬂammatory soft tissue component. If the
adjacent inﬂammatory process extends into the sclerotic
bone, then necrosis often occurs. The necrotic bone sep-
arates from the adjacent vital tissue and becomes sur-
rounded by subacutely inﬂamed granulation tissue.
Secondary bacterial colonization often is visible.
PRIMARY CHRONIC OSTEOMYELITIS
Similar histopathologic features are seen in primary
chronic osteomyelitis, SAPHO syndrome, and CRMO.
In the areas of sclerosis, numerous irregular trabeculae
of pagetoid bone are present and demonstrate exten-
sive evidence of remodeling with prominent reversal
lines, osteoblastic rimming, and focal areas of osteo-
clastic activity (Fig. 3-51). Intertrabecular ﬁbrosis is
present, with scattered lymphocytes and plasma cells.
Present in many, but not all examples, are foci of micro-
abscess formation, hyalinization around small blood
vessels, and subperiosteal bone formation. The micro-
abscesses have been correlated with the osteolytic foci
noted during active phases of the disease. In obvious
contrast to chronic suppurative osteomyelitis, bone
necrosis, bacterial colonization, and frank purulence
are absent.
CHRONIC TENDOPERIOSTITIS
Chronic tendoperiostitis demonstrates sclerosis and
remodeling of the cortical and subcortical bone with a
resultant increase in bone volume. If chronic inﬂam- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 147
matory cells are present, then they are located in corti-
cal resorption defects and the subcortical bone adjacent
to sites of muscle insertion.
TREATMENT AND PROGNOSIS
DIFFUSE SCLEROSING OSTEOMYELITIS
Diffuse sclerosing osteomyelitis is treated best through
resolution of the adjacent foci of chronic infection.
After resolution of the infection, the sclerosis remodels
in some patients but remains in others. The persistent
sclerotic bone is hypovascular, does not exhibit typical
remodeling, and is very sensitive to inﬂammation. The
patient and the clinician should work together to avoid
future problems with periodontitis or apical inﬂamma-
tory disease. With long-term alveolar resorption after
denture placement, the altered bone does not exhibit
typical resorption and exposure with secondary osteo-
myelitis can develop. These secondary lesions can be
treated in the same way as a primary acute or chronic
osteomyelitis (see page 143).
PRIMARY CHRONIC OSTEOMYELITIS
Even with signiﬁcant surgical and medical interven-
tion, the disease course is characterized by ﬂares sepa-
rated by partial remissions. Most treatments directed
toward elimination of infection have been proven inef-
fective. Long-term antibiotic treatment with or without
hyperbaric oxygen therapy has not produced consis-
tent long-term success. Surgical decortication has
decreased the intensity and frequency of symptoms but
has failed to resolve the process totally. Because of
inconsistent results from surgical intervention, exten-
sive surgery is contraindicated, especially in young,
growing patients. Corticosteroid medications, NSAIDs,
and calcitonin have been reported to relieve symptoms
but usually are associated with incomplete resolution.
In a limited number of publications, IV administration
of bisphosphonates has shown signiﬁcant therapeutic
beneﬁts. Of the bisphosphonates that have been evalu-
ated (alendronate, disodium clodronate, and pamidro-
nate), a single infusion of alendronate produced the
most remarkable response, resulting in complete dis-
appearance of pain within 24 hours, dramatic sup-
pression of bone turnover as conﬁrmed by skeletal
scintigraphy, and long-term remission.
CHRONIC TENDOPERIOSTITIS
Treatment of chronic tendoperiostitis as a form of
osteomyelitis has been most unsatisfactory. Large series
of patients have been treated with antibiotic medica-
tions, explorations, intraoral decortication, implanta-
tion of gentamicin beads, hyperbaric oxygen, and
corticosteroid drugs with no signiﬁcant effect. Treat-
ment directed toward resolution of muscle overuse has
resulted in signiﬁcantly decreased symptoms in most
patients and total resolution in a minority. Therapeutic
approaches include the following:
●Muscular relaxation instructions (soft diet, avoid-
ance of parafunctional habits)
● Rotation exercises
●Occlusal splint therapy
● Myofeedback
●Muscle relaxant drugs (e.g., diazepam, mefe-
noxalon)
CONDENSING OSTEITIS (FOCAL
SCLEROSING OSTEOMYELITIS)
Localized areas of bone sclerosis associated with the
apices of teeth with pulpitis (from large carious lesions
or deep coronal restorations) or pulpal necrosis are
termed condensing osteitis. The association with an
area of inﬂammation is critical, because these lesions
can resemble several other intrabony processes that
produce a somewhat similar pattern.
CLINICAL AND RADIOGRAPHIC
FEATURES
This secondary sclerosis of bone is seen most frequently
in children and young adults but also can occur in
older adults. The classic alteration consists of a local-
ized, usually uniform zone of increased radiodensity
adjacent to the apex of a tooth that exhibits a thickened
periodontal ligament space or an apical inﬂammatory
lesion (Fig. 3-52). Clinical expansion should not be
present. Most cases occur in the premolar and molar
areas of the mandible, and the dental pulp of the
Fig. 3-51 Primary chronic osteomyelitis. Trabeculae of
sclerotic, pagetoid bone showing numerous resting and
reversal lines. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

148 ORAL AND MAXILLOFACIAL PATHOLOGY
involved tooth demonstrates pulpitis or necrosis. The
lesion does not exhibit a radiolucent border, as is seen
in cases of focal cemento-osseous dysplasia (see
page 640), although an adjacent radiolucent inﬂamma-
tory lesion may be present. In addition, the radiopacity
is not separated from the apex as would be seen in
idiopathic osteosclerosis (see page 620).
TREATMENT AND PROGNOSIS
Treatment of the patient with condensing osteitis con-
sists of resolution of the odontogenic focus of infection.
After extraction or appropriate endodontic therapy of
the involved tooth, approximately 85% of cases of con-
densing osteitis will regress, either partially or totally.
Typically, resolution of the lesion is associated with
normalization of the associated periodontal mem-
brane. If the lesion persists and the periodontal mem-
brane remains wide, then reevaluation of the
endodontic therapy should be considered. A residual
area of condensing osteitis that remains after resolu-
tion of the inﬂammatory focus is termed a bone scar
(Fig. 3-53).
OSTEOMYELITIS WITH
PROLIFERATIVE PERIOSTITIS
(PERIOSTITIS OSSIFICANS)
Bone formation within a periosteal reaction is a
common ﬁnding that occurs in a wide variety of intraos-
seous pathoses and in all age groups. Causes of perios-
teal new bone formation include osteomyelitis, trauma,
cysts, infantile cortical hyperostosis, ﬂuorosis, avita-
minosis C, hypertrophic osteoarthropathy, congenital
syphilis, and neoplasms such as Ewing sarcoma, Lang-
erhans cell histiocytosis, and osteogenic sarcoma. Of
these, osteomyelitis and malignant neoplasms are asso-
ciated most frequently with formation of bone within
a periosteal reaction.
In 1893 a Swiss physician, Carl Garrè, reported in
the German literature on patterns of acute osteomyeli-
tis. Since that time, numerous articles have been written
that associate Garrè’s report with a form of inﬂamma-
tory periosteal hyperplasia demonstrating an onion-
skin-like reduplication of the cortical plate. (In these
subsequent articles, Garrè’s name was misspelled con-
sistently as Garré, with an improper accent.) However,
Garrè did not have any pathologic specimens for
microscopic examination, and Roentgen did not dis-
cover x-rays until 2 years after Garrè’s publication.
Nowhere in the original publication is there any
mention of periostitis, periosteal duplication, or “onion-
skinning.” Although the term Garrè’s osteomyelitis often
is used synonymously for this condition, it is an
improper designation that should be disassociated with
the entity described in the text that follows.
CLINICAL AND RADIOGRAPHIC
FEATURES
Proliferative periostitis represents a periosteal reac-
tion to the presence of inﬂammation. The affected peri-
osteum forms several rows of reactive vital bone that
parallel each other and expand the surface of the
altered bone. Affected patients tend to be primarily
children and young adults, with a mean age of 13 years.
No sex predominance is noted.
As expected, the most frequent cause is dental caries
with associated periapical inﬂammatory disease,
although lesions have been reported secondary to peri-
odontal infections, fractures, buccal bifurcation cysts,
and nonodontogenic infections. Most cases arise in the
Fig. 3-52 Condensing osteitis. Increased areas of
radiodensity surrounding the apices of the nonvital
mandibular ﬁrst molar.
Fig. 3-53 Bone scar. Residual area of increased
radiodensity in the area of extraction of the mandibular ﬁrst
molar. (Courtesy of Dr. Walter Blevins.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 149
premolar and molar area of the mandible. The hyper-
plasia is located most frequently along the lower border
of the mandible, but buccal cortical involvement also
is common. Isolated lingual cortical enlargement is
infrequent. Most cases are unifocal, although multiple
quadrants may be affected.
Appropriate radiographs demonstrate radiopaque
laminations of bone that roughly parallel each other
and the underlying cortical surface (Fig. 3-54). The
laminations vary from 1 to 12 in number, and radiolu-
cent separations often are present between the new
bone and the original cortex. Less frequently, the new
bone formation exhibits consolidation and contains
numerous ﬁne bony projections that radiate perpen-
dicular from the underlying and intact periosteum.
Within the new bone, areas of small sequestra or osteo-
lytic radiolucencies may be found.
Because of difﬁculty in proper angulation and prob-
lems related to superimposition of the underlying bone,
CT scanning has proved to be consistently superior to
conventional radiography in demonstrating prolifera-
tive periostitis. On plain ﬁlms, the alterations are typi-
cally seen best on a panoramic or lateral oblique
radiograph. The latter type often is favored because of
ﬁner detail of the ﬁnal image. If lateral oblique radio-
graphs fail to demonstrate the lesion, then occlusal
views and, less frequently, posteroanterior radiographs
may be successful.
A
C
B
Fig. 3-54 Proliferative periostitis. A, Firm swelling of the lateral and inferior border of the
right mandible that arose after traumatic injury. B, Computed tomography (CT) image
demonstrating new periosteal bone growth with onionskin laminations. C, Panoramic
radiograph exhibiting new periosteal bone formation along the right inferior border of the
mandible. (Courtesy of Drs. Sherif Mekhail and Benjamin Lin.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

150 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Usually, biopsy is not required unless the clinical diag-
nosis is in question. Specimens often reveal parallel
rows of highly cellular and reactive woven bone in
which the individual trabeculae are frequently ori-
ented perpendicular to the surface. The trabeculae
sometimes form an interconnecting meshwork of bone
or are scattered more widely, resembling the pattern
seen in immature ﬁbrous dysplasia (Fig. 3-55). Between
the cellular trabeculae, relatively uninﬂamed ﬁbrous
connective tissue is evident. Sequestra, if included,
demonstrate the typical features of bone necrosis (see
Osteomyelitis, page 141).
TREATMENT AND PROGNOSIS
Most cases of proliferative periostitis of the jaws are
associated with periapical inﬂammatory lesions, and
treatment in these cases (either extraction of the offend-
ing tooth or appropriate endodontic therapy) is directed
toward eliminating the source of the infection. After
the focus of infection has been eliminated and inﬂam-
mation has resolved, the layers of bone will consolidate
in 6 to 12 months as the overlying muscle action helps
to remodel the bone to its original state.
If a unifocal periosteal reaction similar to prolifera-
tive periostitis appears in the absence of an obvious
source of inﬂammation, biopsy is recommended
because several neoplastic conditions can result in a
similar pattern. On occasion, periosteal hyperplasia
has been found in patients without any detectable
cause except for the close proximity of an unerupted
tooth surrounded by its dental follicle. The cause of
the periosteal hyperplasia in these instances is
unclear.
ALVEOLAR OSTEITIS (DRY SOCKET;
FIBRINOLYTIC ALVEOLITIS)
After extraction of a tooth, a blood clot is formed at the
site, with eventual organization of the clot by granula-
tion tissue, gradual replacement by coarse ﬁbrillar
bone, and, ﬁnally, replacement by mature bone.
Destruction of the initial clot prevents appropriate
healing and causes the clinical condition known as
alveolar osteitis.
Extensive investigations have shown that the clot is
lost secondary to transformation of plasminogen to
plasmin, with subsequent lysis of ﬁbrin and formation
of kinins (ﬁbrinolytic alveolitis); these are potent
pain mediators. Local trauma, estrogens, and bacterial
pyrogens are known to stimulate ﬁbrinolysins. This
knowledge correlates well with the increased fre-
quency of alveolar osteitis in association with deeply
impacted mandibular third molars, poor oral hygiene,
inexperienced surgeons, traumatic extractions, oral
contraceptive use, and presurgical infections. In addi-
tion, inadequate irrigation at surgery and the use of
tobacco products have been related to the develop-
ment of the problem. In fact, studies have shown that
the prevalence of alveolar osteitis is 20% in patients
who smoke more than one pack of cigarettes per day
and increases to 40% for those who smoke on the day
of surgery or within 24 hours after surgery. Heavy
sucking or spitting by the patient after surgery also has
been implicated in dislodgement and loss of the alveo-
lar clot.
CLINICAL FEATURES
The frequency of alveolar osteitis is higher in the man-
dible and the posterior areas. After oral contraceptive
use is taken into account, there does not appear to be
a signiﬁcant sex predilection. The prevalence is
between 1% and 3% of all extractions, but it increases
to 25% to 30% for impacted mandibular third molars.
The frequency appears to be decreased when impacted
teeth are removed prophylactically rather than for
therapeutic reasons after development of chronic
inﬂammation of pericoronal tissues. The overall preva-
lence is highest between 20 and 40 years of age (when
the majority of teeth are extracted), although the likeli-
hood of developing alveolar osteitis appears greatest
for extractions in the 40- to 45-year-old age group.
The affected extraction site is ﬁlled initially with a
dirty gray clot that is lost and leaves a bare bony socket
(dry socket). The detection of the bare socket may be
hindered by partial retention of the clot or by overlying
inﬂamed tissue that covers the site. The diagnosis is
conﬁrmed by probing of the socket, which reveals
exposed and extremely sensitive bone. Typically, severe
Fig. 3-55 Proliferative periostitis. Interconnecting
trabeculae of new bone formation (top left) extending from
the original cortical surface (delineated by arrows). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 3 PULPAL AND PERIAPICAL DISEASE 151
pain, foul odor, and (less frequently) swelling and
lymphadenopathy develop 3 to 4 days after extraction
of the tooth. On occasion, the pain radiates from the
socket to the ipsilateral ear, temporal region, or eye.
Rarely, trismus also may be noted. The signs and symp-
toms may last from 10 to 40 days.
TREATMENT AND PROGNOSIS
On evaluation of the patient complaining of postextrac-
tion pain, a radiograph should be taken of the affected
area to rule out the possibility of a retained root tip or
a foreign body. All sutures should be removed. The
socket is irrigated with warm saline, followed by thor-
ough clinical inspection of the socket for any unex-
pected pathosis. Curettage of the socket is not
recommended, because this typically increases the
associated pain. Potent oral analgesics should be pre-
scribed, and the patient should be given a plastic
syringe with instructions to keep the socket clean via
home irrigation with a chlorhexidine or saline solution.
This irrigation should continue until debris no longer
collects within the healing socket (usually 3 to 4
weeks).
Use of an obtundent and antiseptic dressing such as
iodoform gauze containing eugenol is controversial.
Although the dressing may reduce the symptoms and
help keep out food debris, many believe the dressing
acts as foreign material and delays healing of the extrac-
tion socket. If a dressing is used, then it should be
changed every 24 hours for the ﬁrst 3 days, then every
2 to 3 days until granulation tissue covers the exposed
bone. The dressing should be discontinued as soon as
the patient is pain free. After that time, the patient
should be given a plastic syringe with instructions for
home irrigation.
Many investigators have studied preventive mea-
sures for alveolar osteitis. For female patients using oral
contraceptives, the extractions could be scheduled on
days without estrogen supplementation (typically days
23 to 28 of the menstrual cycle). Before the formation
of the initial blood clot, thorough irrigation of the surgi-
cal site with sterile saline to remove any small frag-
ments of debris, tooth, and bone appears beneﬁcial.
One popular method for prevention of alveolar osteitis
that is associated with a low chance of an adverse reac-
tion is gentle rinsing with chlorhexidine on the day of
the surgery and for several days after the surgical pro-
cedure. Placement of a prophylactic dressing into the
extraction socket is thought by many to increase the
chance of possible side effects and add unnecessary
additional cost to the procedure. In spite of this,
some clinicians use systemic or topical antiﬁbrinolyt-
ics, topical antibiotic medications, or systemic antibi-
otic drugs. Of the used intraalveolar antibiotic
medications, tetracycline is chosen most frequently,
but lincomycin, clindamycin, and metronidazole also
show favorable results. The antibiotic should not be in
an ointment form, because such use has resulted in
chronic foreign body reactions (e.g., myospherulosis)
(see page 324). As mentioned, many surgeons are hesi-
tant to place medicaments into an extraction socket;
those who do often restrict their use to certain “high-
risk” patients, such as those who:
●Take oral contraceptives
● Smoke
●Have existing signs of pericoronitis
●Have traumatic extractions
●Have a history of alveolar osteitis
BIBLIOGRAPHY
General References
Cohen S, Hargreaves KM: Pathways of the pulp, ed 9, St Louis,
2005, Mosby.
Ingle JI, Bakland LK: Endodontics, ed 5, Hamilton, Ontario, 2002,
BC Decker.
Pulpitis
Banchs F, Trope M: Revascularization of immature permanent
teeth with apical periodontitis: new treatment protocol? J
Endod 30:196-200, 2004.
Barrieshi-Nusair KM, Qudeimat MA: A prospective clinical study
of mineral trioxide aggregate for partial pulpotomy in cari-
ously exposed permanent teeth, J Endod 32:731-735, 2006.
Çals¸kan MK, Öztop F, Çals¸kan G: Histological evaluation of teeth
with hyperplastic pulpitis caused by trauma or caries: case
reports, Int Endod J 36:64-70, 2002.
Heyeraas KJ, Sveen OB, Mjör IA: Pulp-dentin biology in restor-
ative dentistry. Part 3: pulpal inﬂammation and its sequelae,
Quintessence Int 32:611-625, 2001.
Holland GR: Pulpalgia, the Pimpernel of pain, Tex Dent J 120:239-
247, 2003.
Hyman JL, Cohn ME: The predictive value of endodontic diag-
nostic tests, Oral Surg Oral Med Oral Pathol 58:343-346,
1984.
Michaelson PL, Holland GR: Is pulpitis painful? Int J Endod
35:829-832, 2002.
Modaresi J, Dianat O, Mozayeni MA: The efﬁcacy comparison of
ibuprofen, acetaminophen-codeine, and placebo premedica-
tion therapy on the depth of anesthesia during treatment of
inﬂamed teeth, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 102:339-403, 2006.
Rafter M: Apexiﬁcation: a review, Dent Traumatol 21:1-8, 2005.
Witherspoon DE, Small JC, Harris GZ: Mineral trioxide aggre-
gate pulpotomies. A case series outcome assessment, J Am
Dent Assoc 137:610-618, 2006.
Secondary and Tertiary Dentin
Amir FA, Gutmann JL, Witherspoon DE: Calciﬁc metamorpho-
sis: a challenge in endodontic diagnosis and treatment, Quin-
tessence Int 32:447-455, 2001.
Mjör IA, Ferrari M: Pulp-dentin biology in restorative dentistry.
Part 6: reactions to restorative materials, tooth-restoration
interfaces, and adhesive techniques, Quintessence Int 33:35-
63, 2002. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

152 ORAL AND MAXILLOFACIAL PATHOLOGY
Mjör IA, Sveen OB, Heyeraas KJ et al: Pulp-dentin biology in
restorative dentistry. Part 1: normal structure and physiology,
Quintessence Int 32:427-46, 2001.
Morse DR: Age-related changes of the dental pulp complex and
their relationship to systemic aging, Oral Surg Oral Med Oral
Pathol 72:721-745, 1991.
Paewinsky E, Pfeiffer H, Brinkmann B: Quantiﬁcation of second-
ary dentine formation from orthopantomograms—a contribu-
tion to forensic age estimation methods in adults, Int J Legal
Med 119:27-30, 2005.
Pashley DH, Pashley EL, Carvalho RM et al: The effects of dentin
permeability on restorative dentistry, Dent Clin North Am
46:211-245, 2002.
Smith AJ, Murray PE, Lumley PJ: Preserving the vital pulp in
operative dentistry: I. A biological approach, Dent Update
29:64-69, 2002.
Solheim T: Amount of secondary dentin as an indicator of age,
Scand J Dent Res 100:193-199, 1992.
West JD: The aesthetics and endodontic dilemmas of calciﬁc
metamorphosis, Pract Periodontics Aesthet Dent 9:286-293,
1997.
Woods MA, Robinson QC, Harris EF: Age-progressive changes
in pulp widths and root lengths during adulthood: a study of
American blacks and whites, Gerodontology 9:41-50, 1990.
Pulpal Calciﬁcations
Al-Hadi Hamasha A, Darwazeh A: Prevalence of pulp stones in
Jordanian adults, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 86:730-732, 1998.
Comer TL, Ground TG: Hereditary pattern for dentinal dysplasia
type Id: a case report, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 94:51-53, 2002.
Morse DR: Age-related changes of the dental pulp complex and
their relationship to systemic aging, Oral Surg Oral Med Oral
Pathol 72:721-745, 1991.
Moss-Salentijn L, Hendricks-Klyvert M: Calciﬁed structures in
human dental pulps, J Endod 14:184-189, 1988.
Parekh S, Kyriazidou A, Bloch-Zupan A et al: Multiple pulp
stones and shortened roots of unknown etiology, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 101:e139-142, 2006.
Rao SR, Witkop CJ, Yamane GM: Pulpal dysplasia, Oral Surg Oral
Med Oral Pathol 30:682-689, 1970.
Selden HS: Radiographic pulpal calciﬁcations: normal or abnor-
mal—a paradox, J Endod 17:34-37, 1991.
Trowbridge HO: Pulp biology: progress during the past 25 years,
Aust Endod J 29:5-12, 2003.
Periapical Inﬂammatory Disease (Granuloma; Cyst; Abscess)
Bhaskar SN: Periapical lesions—types, incidence, and clinical
features, Oral Surg Oral Med Oral Pathol 21:657-671, 1966.
Çals¸kan MK: Prognosis of large cyst-like periapical lesions fol-
lowing nonsurgical root canal treatment: a clinical review, Int
Endod J 37:408-416, 2004.
Chen S-Y, Fantasia JE, Miller AS: Hyaline bodies in the connec-
tive tissue wall of odontogenic cysts, J Oral Pathol 10:147-157,
1981.
Dahlén G: Microbiology and treatment of dental abscesses and
periodontal-endodontic lesions, Periodontol 2000 28:206-
239, 2002.
Gao Z, Flaitz CM, Mackenzie IC: Expression of keratinocyte
growth factor in periapical lesions, J Dent Res 75:1658-1663,
1996.
Harn WM, Chen MC, Chen YHM: Effect of occlusal trauma on
healing of periapical pathoses: report of two cases, Int Endod
J 34:554-561, 2001.
High AS, Hirschmann PN: Age changes in residual radicular
cysts, J Oral Pathol 15:524-528, 1986.
Kuriyama T, Absi EG, Williams DW et al: An outcome audit of
the treatment of acute dentoalveolar infection: impact of
penicillin, Br Dent J 198:759-763, 2005.
Matthews DC, Sutherland S, Basrani B: Emergency management
of acute apical abscesses in the permanent dentition: a sys-
tematic review of the literature, J Can Dent Assoc 69:660-60i,
661, 2003.
Nair PNR: New perspectives on radicular cysts: do they heal? Int
Endod J 31:155-160, 1998.
Nair PNR: On the causes of persistent apical periodontitis: a
review, Int Endod J 39:249-281, 2006.
Nair PNR, Pajarola G, Schroeder HE: Types and incidence of
human periapical lesions obtained with extracted teeth, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 81:93-102,
1993.
Ricucci D, Mannocci F, Pitt TR: A study of periapical lesions
correlating the presence of a radiopaque lamina with histo-
logical ﬁndings, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 101:389-394, 2006.
Slots J, Nowzari H, Sabeti M: Cytomegalovirus infection in
symptomatic periapical pathosis, Int Endod J 37:519-524,
2004.
Stockdale CR, Chandler NP: The nature of the periapical lesion—
a review of 1108 cases, J Dent 16:123-129, 1988.
Sutherland S, Matthews DC: Emergency management of acute
apical periodontitis in the permanent dentition: a systematic
review of the literature, J Can Dent Assoc 69:160-160i, 161,
2003.
Tronstad L: Recent development in endodontic research, Scand
J Dent Res 100:52-59, 1992.
Trowbridge HO, Stevens BH: Microbiologic and pathologic
aspects of pulpal and periapical disease, Curr Opin Dent 2:85-
92, 1992.
Cellulitis
Baqain ZH, Newman L, Hyde N: How serious are oral infections?
J Laryngol Otol 118:561-565, 2004.
Busch RF, Shah D: Ludwig’s angina: improved treatment, Otolar-
yngol Head Neck Surg 117:S172-S175, 1997.
Dolan RW, Chowdhury K: Diagnosis and treatment of intracra-
nial complications of paranasal sinus infections, J Oral Maxil-
lofac Surg 53:1080-1087, 1995.
Hutchinson IL, James DR: New treatment for Ludwig’s angina,
Br J Oral Maxillofac Surg 27:83-84, 1989.
Iwu CO: Ludwig’s angina: report of seven cases and review of the
current concepts in management, Br J Oral Maxillofac Surg
28:189-193, 1990.
Lazow SK: Orofacial infection in the 21st century, N Y State Dent
J 71:36-41, 2005.
Moreland LW, Corey J, McKenzie R: Ludwig’s angina: report of
a case and review of the literature, Arch Intern Med 148:461-
466, 1988.
Ogundiya DA, Keith DA, Mirowski J: Cavernous sinus thrombo-
sis and blindness as complication of an odontogenic infection,
J Oral Maxillofac Surg 47:1317-1321, 1989.
Pynn BR, Sands T, Pharoah MJ: Odontogenic infections: part 1.
Anatomy and radiology, Oral Health 85:7-21, 1995.
Sands T, Pynn BRT, Katsikeris N: Odontogenic infections: part 2.
Microbiology, antibiotics and management, Oral Health
85:11-28, 1995.
Osteomyelitis
Adekeye EO, Cornah J: Osteomyelitis of the jaws: a review of 141
cases, Br J Oral Maxillofac Surg 23:24-35, 1985.
Daramola JO, Ajagbe HA: Chronic osteomyelitis of the mandible
in adults: a clinical study of 34 cases, Br J Oral Surg 20:58-62,
1982. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 3 PULPAL AND PERIAPICAL DISEASE 153
Harvey BR, Ephros H, DeFalco RJ: Tetracycline bone labeling in
surgical management of chronic osteomyelitis: a case report,
J Oral Maxillofac Surg 62:752-754, 2004.
Koorbusch GF, Fotos P, Terhark K: Retrospective assessment of
osteomyelitis: etiology, demographics, risk factors, and man-
agement in 35 cases, Oral Surg Oral Med Oral Pathol 74:149-
154, 1992.
Marx RE: Chronic osteomyelitis of the jaws, Oral Maxillofac Clin
North Am 3:367-381, 1991.
Rohlin M: Diagnostic value of bone scintigraphy in osteomyelitis
of the mandible, Oral Surg Oral Med Oral Pathol 75:650-655,
1993.
Schuknecht B, Valavanis A: Osteomyelitis of the mandible, Neu-
roimaging Clin North Am 13:605-618, 2003.
van Merkesteyn JPR, Bakker DJ, van der Waal I et al: Hyperbaric
oxygen treatment of chronic osteomyelitis of the jaws, Int J
Oral Surg 13:386-395, 1984.
van Merkesteyn JPR, Groot RH, van der Akker HP et al: Treat-
ment of chronic suppurative osteomyelitis of the mandible,
Int J Oral Maxillofac Surg 26:450-454, 1997.
Diffuse Sclerosing Osteomyelitis
Groot RH, van Merkesteyn JP, Bras J: Diffuse sclerosing osteo-
myelitis and ﬂorid osseous dysplasia, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 81:333-342, 1996.
Baltensperger M, Grätz K, Bruder E et al: Is primary chronic
osteomyelitis a uniform disease? Proposal of a classiﬁcation
based on a retrospective analysis of patients treated in the
past 30 years, J Craniomaxillofac Surg 32:43-50, 2004.
Eyrich GKH, Baltensperger MM, Bruder E et al: Primary chronic
osteomyelitis in childhood and adolescence: a retrospective
analysis of 11 cases and review of the literature, J Oral Maxil-
lofac Surg 61:561-573, 2003.
Groot RH, Ongerboer de Visser BW, van Merkesteyn JP et al:
Changes in masseter inhibitory reﬂex responses in patients
with diffuse sclerosing osteomyelitis of the mandible, Oral
Surg Oral Med Oral Pathol 74:727-732, 1992.
Groot RH, van Merkesteyn JP, van Soest JJ et al: Diffuse scleros-
ing osteomyelitis (chronic tendoperiostitis) of the mandible:
an 11-year follow-up report, Oral Surg Oral Med Oral Pathol
74:557-560, 1992.
Heggie AA, Shand JM, Aldred MJ et al: Juvenile mandibular
chronic osteomyelitis: a distinct clinical entity, Int J Oral Max-
illofac Surg 32:459-468, 2003.
Hino S, Murase R, Terakado N et al: Response of diffuse scleros-
ing osteomyelitis of the mandible to alendronate: follow-up
study by
99m
Tc scintigraphy, Int J Oral Maxillofac Surg 34:576-
578, 2005.
Montonen M, Kalso E, Pylkkären L et al: Disodium clodronate
in the treatment of diffuse sclerosing osteomyelitis (DSO) of
the mandible, Int J Oral Maxillofac Surg 30:313-317, 2001.
Soubrier M, Dubost JJ, Ristori JM et al: Pamidronate in the treat-
ment of diffuse sclerosing osteomyelitis of the mandible, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 92:637-640,
2001.
Suei Y, Taguchi A, Tanimoto K: Diagnostic point and possible
origin of osteomyelitis in synovitis, acne, pustulosis, hyperos-
tosis and osteitis (SAPHO) syndrome: a radiographic study of
77 mandibular osteomyelitis cases, J Rheumatol 42:1398-
1403, 2003.
Suei Y, Taguchi A, Tanimoto K: Diagnosis and classiﬁcation of
mandibular osteomyelitis, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 100:207-214, 2005.
van Merkesteyn JPR, Groot RH, Bras J et al: Diffuse sclerosing
osteomyelitis of the mandible: a new concept of its etiology,
Oral Surg Oral Med Oral Pathol 70:414-419, 1990.
Condensing Osteitis
Boyne PJ: Incidence of osteosclerotic areas in the mandible and
maxilla, J Oral Surg Anesth Hosp Dent Serv 18:486-491, 1960.
Eliasson S, Halvarsson C, Ljungheimer C: Periapical condensing
osteitis and endodontic treatment, Oral Surg Oral Med Oral
Pathol 57:195-199, 1984.
Eversole LR, Stone CE, Strub D: Focal sclerosing osteomyelitis/
focal periapical osteopetrosis: radiographic patterns, Oral
Surg Oral Med Oral Pathol 58:456-460, 1984.
Farman AG, de V Joubert JJ, Nortjé C: Focal osteosclerosis and
apical periodontal pathoses in “European” and Cape Coloured
dental outpatients, Int J Oral Surg 7:549-557, 1978.
Hedin M, Polhagen L: Follow-up study of periradicular bone
condensation, Scand J Dent Res 79:436-440, 1979.
Osteomyelitis with Proliferative Periostitis
Eversole LR, Leider AS, Corwin JO et al: Proliferative periostitis
of Garré: its differentiation from other neoperiostoses, J Oral
Surg 37:725-731, 1979.
Jacobson HLJ, Baumgartner JC, Marshall JG et al: Proliferative
periostitis of Garré: report of a case, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 94:111-114, 2002.
Kannan SK, Sandhya G, Selvarani R: Periostitis ossiﬁcans (Garrè’s
osteomyelitis) radiographic study of two cases, Int J Paediatr
Dent 16:59-64, 2006.
Kawai T, Hiranuma H, Kishino M et al: Gross periostitis ossiﬁ-
cans in mandibular osteomyelitis. Review of the English lan-
guage literature and radiographic variation, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 86:376-381, 1998.
Kawai T, Murakami S, Sakuda M et al: Radiographic investiga-
tion of mandibular periostitis ossiﬁcans in 55 cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 82:704-712, 1996.
Nortjé CJ, Wood RE, Grotepass F: Periostitis ossiﬁcans versus
Garrè’s osteomyelitis: part II. Radiologic analysis of 93 cases
in the jaws, Oral Surg Oral Med Oral Pathol 66:249-260,
1988.
Wood RE, Nortjé CJ, Grotepass F et al: Periostitis ossiﬁcans
versus Garrè’s osteomyelitis: part I. What did Garrè really
say? Oral Surg Oral Med Oral Pathol 65:773-777, 1988.
Alveolar Osteitis
Awang MN: The aetiology of dry socket: a review, Int Dent J
39:236-240, 1989.
Birn H: Etiology and pathogenesis of ﬁbrinolytic alveolitis (“dry
socket”), Int J Oral Surg 2:215-263, 1973.
Blum IR: Contemporary views on dry socket (alveolar osteitis): a
clinical appraisal of standardization, aetiopathogenesis and
management: a critical review, Int J Oral Maxillofac Surg
31:309-317, 2003.
Caso A, Hung, L-K, Beirne OR: Prevention of alveolar osteitis
with chlorhexidine: a meta-analytic review, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 99:155-159, 2005.
Catellani JE: Review of factors contributing to dry socket through
enhanced ﬁbrinolysis, J Oral Surg 37:42-46, 1979.
Fazakerley M, Field EA: Dry socket: a painful post-extraction
complication (a review), Dent Update 18(1):31-34, 1991.
Garcia AG, Grana PM, Sampedro FG et al: Does oral contracep-
tive use affect the incidence of complications after extraction
of a mandibular third molar? Br Dent J 194:453-455, 2003.
Houston JP, McCollum J, Pietz D et al: Alveolar osteitis: a review
of its etiology, prevention, and treatment modalities, Gen Dent
50:457-463, 2002.
Larsen PE: Alveolar osteitis after surgical removal of impacted
mandibular third molars: identiﬁcation of the patient at risk,
Oral Surg Oral Med Oral Pathol 73:393-397, 1992.
Swanson AE: Prevention of dry socket: an overview, Oral Surg
Oral Med Oral Pathol 70:131-136, 1990. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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154
4
Periodontal Diseases
CHAPTER OUTLINE
Gingivitis
Necrotizing Ulcerative Gingivitis
Plasma Cell Gingivitis
Granulomatous Gingivitis
Desquamative Gingivitis
Drug-Related Gingival Hyperplasia
Gingival Fibromatosis
Periodontitis
Chronic Periodontitis
Necrotizing Ulcerative Periodontitis
Periodontal Abscess
Pericoronitis
Aggressive Periodontitis
Localized Aggressive Periodontitis
Generalized Aggressive Periodontitis
Papillon-Lefévre Syndrome
CLINICAL FEATURES
Most cases of gingivitis occur from lack of proper oral
hygiene, which leads to the accumulation of dental
plaque and calculus; however, many other factors can
affect the gingiva’s susceptibility to the oral ﬂora. The
frequency of gingivitis is high in all age groups, but its
true prevalence is difﬁcult to determine because of the
lack of a standardized method of measurement. Clini-
cally detectable inﬂammatory changes of the gingiva
begin in childhood and increase with age. With similar
amounts of dental plaque, the severity of gingivitis is
greater in adults than in prepubertal children. Around
the time of puberty, there is a period of increased sus-
ceptibility to gingivitis (puberty gingivitis), with the
peak prevalence of involvement occurring between the
ages of 9 and 14 years (Fig. 4-1). Between the ages of
11 and 17 years, the frequency declines; then a slow
increase is seen until the prevalence approaches 100%
in the sixth decade of life.
In most age groups, females demonstrate a lower
frequency of gingivitis than do males (although females
have periods of increased susceptibility). This may be
due more to better oral hygiene in females than to a
physiologic difference between the sexes. In addition
to the years of puberty, females exhibit a greater sus-
ceptibility to gingivitis when they are exposed to the
high levels of progesterone associated with pregnancy
In this textbook of oral and maxillofacial pathology, the
discussion of periodontal diseases is limited appropri-
ately in scope. However, several ﬁne textbooks are
available on periodontology and can provide the reader
with more information on the background, microbiol-
ogy, clinical presentations, diagnostic procedures, and
current therapies used to treat these diseases.
GINGIVITIS
Gingivitis refers to inﬂammation limited to the soft
tissues that surround the teeth. It does not include the
inﬂammatory processes that may extend into the
underlying alveolar ridge, periodontal ligament, or
cementum. The primary types of gingivitis are listed in
Box 4-1. This part of the text concentrates on the
plaque-related types. Necrotizing ulcerative gingivi-
tis (NUG), medication-inﬂuenced gingivitis, and a
speciﬁc type of allergic gingivitis (plasma cell gingivi-
tis) are presented later in this chapter. Additional
forms of allergic gingivitis are discussed in Chapter 9.
The gingivitis associated with speciﬁc infections (e.g.,
herpes simplex, human immunodeﬁciency virus [HIV])
is discussed in Chapters 5 and 7. The gingiva is a fre-
quent site of involvement in several of the dermato-
logic vesiculoerosive diseases; these are well described
in Chapter 16. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 4 PERIODONTAL DISEASES 155
individual traits seem to determine the severity of gin-
givitis, independent of the degree of plaque accumula-
tion. Even after removal of the causative plaque and
resolution of the associated gingivitis, individuals iden-
tiﬁed as being susceptible to gingivitis exhibit measur-
able differences in gingival crevicular ﬂuid volume
from patients who have demonstrated resistance to
plaque-related gingivitis. In addition, evidence sug-
gests that susceptibility to gingivitis appears linked to
susceptibility to future development of periodontitis. In
the future, such research may allow identiﬁcation of
patients who are susceptible to gingivitis and ultimately
periodontitis, and appropriate interventions could be
instituted.
Box 4-1
Types of Gingivitis
● Plaque-related gingivitis
●Necrotizing ulcerative gingivitis (NUG)
● Medication-inﬂuenced gingivitis
● Allergic gingivitis
● Speciﬁc infection-related gingivitis
● Dermatosis-related gingivitis
Box 4-2
Systemic Factors Associated
with Gingivitis
1. Hormonal changes
● Puberty
● Pregnancy
●Oral contraceptive use
2.Stress
3.Substance abuse
4.Poor nutrition
●Ascorbate (vitamin C) deﬁciency (see page 826)
5. Certain medications (see page 163)
● Phenytoin
●Calcium channel blockers
● Cyclosporine
6.Diabetes mellitus (see page 842)
7.Down syndrome
8.Immune dysfunction
9.Heavy-metal poisoning (see page 313)
Fig. 4-1 Puberty gingivitis. Erythematous gingivitis that
arose at time of initial menses and was slow to respond to
local therapy.
Box 4-3
Local Factors Associated with Gingivitis
1.Local trauma
2.Tooth crowding with overlapping
3.Dental anomalies
●Enamel pearls (see page 93)
●Enamel and radicular grooves
4.Tooth fracture
5.Dental caries
6.Gingival recession
7.High frenum attachments
8.Iatrogenic factors
● Overhanging restorations
● Removable prostheses
● Orthodontic appliances
9. Inadequate lip closure
10. Mouth breathing
or some forms of oral contraceptives. Progesterone
appears to increase the permeability of gingival blood
vessels, thereby rendering the area more sensitive to
bacterial, physical, and chemical irritants.
A number of other systemic factors have been shown
to increase the frequency of gingivitis and are listed in
Box 4-2. In contrast, smoking and use of many antibi-
otic drugs, corticosteroid medications, and nonsteroi-
dal antiinﬂammatory drugs (NSAIDs) have been
correlated with a reduced gingival response to plaque.
Various local factors that can be related to gingivitis are
shown in Box 4-3.
Injury to the gingiva from mastication, oral hygiene
techniques, or other habits may result in a breach of
the oral mucosa, with secondary infection from the
local ﬂora. Most such injuries result in transient areas
of erythema. However, if the trauma follows a chronic
pattern, then areas of persistently swollen, erythema-
tous gingiva may result. Patients who are mouth breath-
ers or demonstrate incomplete lip closure can display
a unique pattern of gingivitis in which the anterior
facial gingiva is smooth, swollen, and red (Fig. 4-2).
In a large group of patients that was controlled for
the local and systemic factors, a variety of severity in
gingivitis was seen. Susceptibility to plaque-related gin-
givitis appears to vary within the population, and the `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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156 ORAL AND MAXILLOFACIAL PATHOLOGY
Inﬂammation of the gingiva may be localized or
generalized. The involved area may be diffuse or con-
ﬁned to the free gingival margins (marginal gingivi-
tis) (Fig. 4-3) or the interdental papillae (papillary
gingivitis). The earliest signs of gingivitis include a loss
of stippling, plus bleeding on gentle probing. Healthy
gingiva is coral pink; with inﬂammation, the involved
gingiva becomes light red. With progression, the area
becomes redder and edematous. As the process
becomes entrenched, the involved gingiva becomes
brighter red or magenta; the gingiva often demon-
strates margins that may be blunted, receded, or hyper-
plastic (Fig. 4-4). When chronic inﬂammation causes
signiﬁcant enlargement because of edema or ﬁbrosis,
the process is termed chronic hyperplastic gingivitis
(Fig. 4-5). Bleeding occurs easily, and exudate can be
seen in the gingival sulcus. A localized tumorlike pro-
liferation of subacutely inﬂamed granulation tissue,
known as a pyogenic granuloma (see page 517), can
develop on the gingiva of patients with severe gingivitis
(Fig. 4-6).
Fig. 4-3 Marginal gingivitis. Diffuse erythematous
alteration of the free gingival margins.
Fig. 4-4 Chronic gingivitis. Bright-red gingiva is blunted,
receded, and hyperplastic secondary to a total lack of oral
hygiene. Note the extensive calculus buildup.
Fig. 4-5 Chronic hyperplastic gingivitis. Diffuse erythema
and enlargement of marginal and papillary gingiva.
Fig. 4-6 Hyperplastic gingivitis with pyogenic granuloma.
Diffuse erythematous enlargement of marginal and papillary
gingiva with hemorrhagic, tumorlike proliferation (which
arose during pregnancy) between the maxillary bicuspid and
ﬁrst molar.
Fig. 4-2 Mouth breathing–related gingivitis. Slick, swollen,
and red gingivitis of the anterior facial gingiva secondary to
chronic mouth breathing. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 4 PERIODONTAL DISEASES 157
HISTOPATHOLOGIC FEATURES
Incipient gingivitis demonstrates a light inﬂammatory
inﬁltrate consisting of polymorphonuclear leukocytes
that accumulate in the connective tissue adjacent to
the sulcular epithelium. With progression, the inﬁl-
trate becomes more intense and demonstrates a
mixture of lymphocytes, plasma cells, and acute inﬂam-
matory cells (Fig. 4-7). Areas of ﬁbrosis, hyperemia,
edema, and hemorrhage may be present.
TREATMENT AND PROGNOSIS
Although periodontitis always is preceded by gingivitis,
most areas of gingivitis remain stable for years, and the
number of affected sites that convert to periodontitis is
small. In spite of this, optimal gingival health should be
the goal of all clinicians and their patients. In a 26-year
study of a cohort receiving state-of-the-art dental care,
the prevalence of localized tooth loss increased 46
times in areas associated with gingiva that consistently
bled on probing during routine examinations. Even
when attachment loss is not evident and the alterations
appear restricted to the gingival soft tissues, proactive
interventions are recommended to eliminate these
areas of persistent pathosis during the early stages of
disease.
Treatment of gingivitis consists of elimination (if
possible) of any known cause of increased susceptibil-
ity and improvement in oral hygiene to decrease the
dental plaque responsible for the inﬂammatory altera-
tions. Most self-administered plaque control programs
are ineffective unless periodic professional reinforce-
ment also is provided. A further discussion of dental
plaque and its relationship to gingival inﬂammation is
presented in the discussion of periodontitis (see page
168). Research has shown that few individuals have
the physical skills and motivation necessary to obtain
and maintain ultimate oral hygiene. Mechanical
removal of dental plaque can be aided by the use of
numerous chemical agents, such as mouth rinses with
chlorhexidine or essential oils, or dentifrices contain-
ing triclosan with 2.0% Gantrez copolymer. In this vein,
studies have evaluated the addition of these chemopre-
ventative agents to typical oral hygiene efforts and
shown a statistically signiﬁcant positive response to
these products in controlling plaque and gingivitis. On
occasion, hyperplastic and ﬁbrotic gingiva may have to
be recontoured surgically to allow total resolution of
the pathosis after improvements in hygiene have been
made. If the gingivitis does not resolve after improved
plaque control and elimination of obvious contributing
factors, then the patient should be evaluated for under-
lying systemic disorders that could be contributing to
the process.
NECROTIZING ULCERATIVE
GINGIVITIS (VINCENT’S INFECTION;
TRENCH MOUTH)
Necrotizing ulcerative gingivitis (NUG) has a dis-
tinctive pattern of gingival pathologic changes that
have been recognized for hundreds of years. Until
recently, the name of this process has been preceded
by the term acute (i.e., ANUG); however, several inves-
tigators have discontinued the use of this word because
there is no chronic form of the disease. In the 1890s
the French physician Jean Hyacinthe Vincent identi-
ﬁed a fusiform bacterium, Bacillus fusiformis (currently
Fusobacterium nucleatum), and a spirochete, Borrelia vin-
centii, after microscopic examination of plaque samples
from affected sites. Vincent believed that the fusiform
bacteria were principally responsible for the condition,
and the spirochetes mainly were saprophytic oppor-
tunists. The spirochete and fusiform bacterium associa-
tion remains true today, but more sophisticated
techniques have implicated Fusobacterium nucleatum,
Prevotella intermedia, Porphyromonas gingivalis, Trepo-
nema spp., and Selenomonas spp. Although the associa-
tion with bacteria is strong, controversial research has
suggested that viruses such as cytomegalovirus, Epstein-
Barr virus, and herpes simplex may contribute to the
onset and progression of the process.
The infection frequently occurs in the presence of
psychologic stress. People in military service exhibit an
increased frequency of NUG; the disorder was so
common in the battleﬁeld trenches during World War
I that the nickname trench mouth became well known.
Stress-related corticosteroid hormones are thought to
alter T4/T8 lymphocyte ratios and may cause the
Fig. 4-7 Chronic gingivitis. Sulcular epithelium with
exocytosis overlying connective tissue that contains
inﬂammatory inﬁltrate consisting of lymphocytes, plasma
cells, and polymorphonuclear leukocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

158 ORAL AND MAXILLOFACIAL PATHOLOGY
decreased neutrophilic chemotaxis and phagocytic
response seen in patients with NUG. Stress-related epi-
nephrine may result in localized ischemia, which pre-
disposes the gingiva to NUG.
In addition to stress, other factors have been related
to an increased frequency of NUG:
● Immunosuppression
● Smoking
● Local trauma
●Poor nutritional status
●Poor oral hygiene
● Inadequate sleep
● Recent illness
Immunocompromised status, especially that seen in
association with acquired immunodeﬁciency syndrome
(AIDS) (see page 264) and infectious mononucleosis
(see page 253), has been related to the development of
NUG. The list of predisposing factors clearly supports
the association between a depressed systemic immu-
nity and the appearance of the disorder.
CLINICAL FEATURES
NUG may occur at any age; however, when encoun-
tered in the United States or Europe, it is seen most
frequently in young and middle-aged adults. Several
publications have reported a higher frequency in
whites. The prevalence in the normal population is less
than 0.1%; however, in stressed populations (e.g., mili-
tary recruits) the frequency increases up to 7%. In
developing countries, NUG typically occurs in very
young children suffering from malnutrition. Seasonal
variations in prevalence have been reported by a
number of investigators but have been inconsistent in
different areas of the world.
In a classic case of NUG, the interdental papillae are
highly inﬂamed, edematous, and hemorrhagic. Typi-
cally, the affected papillae are blunted and demon-
strate areas of “punched-out,” craterlike necrosis that
are covered with a gray pseudomembrane (Fig. 4-8).
Early cases may be missed easily because the ulcer-
ation initially involves only the tip of the interdental
papilla. A fetid odor, exquisite pain, spontaneous hem-
orrhage, and accumulations of necrotic debris usually
are noted. Although a bad odor is not always noted, its
absence in a patient without predisposing factors
should raise concern for other pathoses such as gonor-
rhea (see page 193). Occasional ancillary clinical fea-
tures include lymphadenopathy, fever, and malaise.
The process sometimes can lead to a loss of attachment
and the development of associated periodontitis (nec-
rotizing ulcerative periodontitis) or spread to adja-
cent soft tissue (necrotizing ulcerative mucositis,
necrotizing stomatitis) (Fig. 4-9). If the necrotizing
infection extends through the mucosa to the skin of the
face, then it is typically termed noma (cancrum oris)
(see page 201).
Several investigators have suggested that NUG,
necrotizing ulcerative periodontitis, and necrotizing
stomatitis are one disease process termed necrotizing
gingivostomatitis. Evidence presented by numerous
authors has shown the diseases to be similar clinically,
histopathologically, and bacteriologically, with the only
differences being underlying systemic factors and ana-
tomic extension of the necrosis.
HISTOPATHOLOGIC FEATURES
The histopathologic features of NUG are not speciﬁc.
Typically, affected gingival papillae demonstrate
surface ulceration that is covered by a thickened ﬁbri-
nopurulent membrane. The underlying lamina propria
demonstrates an intense acute or mixed inﬂammatory
Fig. 4-8 Necrotizing ulcerative gingivitis (NUG). Gingiva is
friable and hemorrhagic with necrosis of the interdental
papillae.
Fig. 4-9 Necrotizing ulcerative mucositis. Gingiva exhibits
epithelial necrosis that has extended between the adjacent
interdental papillae and apically to the alveolar mucosa
junction. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 159
inﬁltrate and extensive hyperemia. In nonulcerated
affected epithelium, often a loss of the typical surface
keratinization occurs. Necrotic material and extensive
bacterial colonization often are included in the mate-
rial submitted for microscopic examination.
TREATMENT AND PROGNOSIS
In contrast to most forms of periodontal disease, NUG
typically demonstrates quick resolution after removal
of the bacterial challenge. Even with conservative
therapy, regeneration of the affected gingiva is nor-
mally seen. The affected area is treated best with
débridement by scaling, curettage, or ultrasonic
instrumentation (except when contraindicated, as
in HIV-positive patients). Topical or local anesthetic
often is required before the clinician can débride the
tissues adequately. Frequent rinses with chlorhexidine,
warm saltwater, or diluted hydrogen peroxide are
beneﬁcial in increasing the therapeutic response.
Antibiotic medications (metronidazole and penicillin
have been suggested as the drugs of choice) are a useful
adjunct, especially in the presence of fever or
lymphadenopathy.
Treatment should include instructions on oral
hygiene and patient motivation; identiﬁcation and res-
olution of any predisposing factors also are advanta-
geous. Supportive therapy (e.g., rest, appropriate ﬂuid
intake, soft nutritious diet) often improves the clinical
response. Follow-up appointments are necessary to
reinforce the home care instructions and to rule out a
recurrence of the process. In cases resistant to treat-
ment, further evaluation to rule out HIV infection or
infectious mononucleosis is prudent.
The clinician must be ever vigilant in the search for
other signs and symptoms of immunosuppression.
Subtle palatal candidiasis or HIV-related oral hairy leu-
koplakia (see page 268) can be overlooked easily in a
patient with NUG. Appropriate attention must be
directed toward the oral soft tissue examination, espe-
cially in patients with infections such as NUG that are
related to immunosuppression. In addition, a thorough
investigation of underlying causes of immunosuppres-
sion should be performed on patients whose condi-
tions are resistant to normal therapy.
PLASMA CELL GINGIVITIS (ATYPICAL
GINGIVOSTOMATITIS)
A distinctive pattern of gingival inﬂammation, plasma
cell gingivitis, was brought to the attention of health
care practitioners during the late 1960s and early
1970s. A rash of cases occurred during that time, and
most appear to have been related to a hypersensitivity
to a component of chewing gum. Since that time, the
number of cases has dwindled, but similar gingival
alterations are reported occasionally.
Although the association with chewing gum has
decreased, allergy still is responsible for many reported
cases. A brand of herbal toothpaste, a speciﬁc type of
mint candy, and peppers used for cooking have all
been implicated in more recent reports. The list of
allergens appears to be variable, and a thorough evalu-
ation often is required to rule out an allergic cause.
CLINICAL FEATURES
Patients with plasma cell gingivitis experience a rapid
onset of sore mouth, which often is intensiﬁed by den-
tifrices and hot or spicy foods. The entire free and
attached gingiva demonstrates a diffuse enlargement
with bright erythema and loss of normal stippling (Fig.
4-10). Extension onto the palate can occur, and eden-
tulous areas typically exhibit less intense changes. On
A B
Fig. 4-10 Plasma cell gingivitis. A, Diffuse, bright-red enlargement of the free and attached
gingiva. B, Same patient as depicted in A after elimination of the inciting allergen. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

160 ORAL AND MAXILLOFACIAL PATHOLOGY
occasion, a similar localized gingival and vestibular
alteration can occur from topical placement of a mate-
rial that elicits a similar plasmacytic inﬂammatory
reaction.
Additional sites of involvement may be seen, or the
changes may be localized to the gingiva. In the chewing
gum–related cases of the early 1970s, involvement of
the lips and tongue was typical. The lips were dry,
atrophic, occasionally ﬁssured, and angular cheilitis
was frequent. Tongue involvement resulted in ery-
thematous enlargement with furrows, mild crenation,
and loss of the typical dorsal coating.
More recent reports have described lesions often
isolated to the gingiva without the classic lip and tongue
involvement seen in the past. A larger percentage of
these cases are idiopathic, and occasional extraoral
involvement of sites such as the supraglottic region
occurs.
HISTOPATHOLOGIC FEATURES
The cases of classic plasma cell gingivitis of the 1970s
demonstrated psoriasiform hyperplasia and spongiosis
of the surface epithelium, with intense exocytosis and
neutrophilic microabscesses. The underlying lamina
propria contains numerous dilated vascular channels
and an extremely dense chronic inﬂammatory inﬁl-
trate that is composed predominantly of plasma
cells (Fig. 4-11). The more recent cases are similar
but often demonstrate less involvement of the surface
epithelium and a less dense underlying plasmacytic
inﬁltrate.
Investigation of the clonality of the plasma cell inﬁl-
trate may be necessary to rule out the possibility of a
monoclonal plasma cell neoplasm. All allergic and
idiopathic cases of plasma cell gingivitis demonstrate a
polyclonal mixture of plasma cells and a normal proﬁle
on plasma immunoelectrophoresis.
TREATMENT AND PROGNOSIS
All patients with plasma cell gingivitis should be
instructed to keep a complete dietary history, with
records of everything taken into the mouth (e.g., foods,
dentifrice, mouthwash, tobacco, alcohol, chewing gum,
candy, medications). Possible allergens should be elim-
inated in an attempt to discover the underlying cause.
If an easy answer is not apparent, then extensive allergy
testing and an elimination diet can be undertaken.
Many patients in whom no underlying cause could
be discovered have been treated with topical or sys-
temic immunosuppressive medications, with variable
results. Betamethasone rinses, ﬂuocinonide gel, topical
triamcinolone, and topical fusidic acid are several of
the reported choices. In spite of all the evaluations
and therapeutic interventions, some patients do not
respond to treatment and no cause for the disease can
be identiﬁed.
GRANULOMATOUS GINGIVITIS
The discovery of unexplained granulomatous inﬂam-
mation in a gingival biopsy specimen is termed granu-
lomatous gingivitis and represents a diagnostic
challenge for the pathologist, referring clinician, and
patient. The pathologist must rule out histologically
distinctive granulomatous diseases and speciﬁc granu-
lomatous infectious processes (e.g., foreign material,
deep fungal infections, acid-fast bacteria) (see Chapters
5 and 6). The clinician must search for signs and symp-
toms of local and systemic granulomatous diseases
(e.g., Crohn’s disease, sarcoidosis, chronic granuloma-
tous disease, Wegener’s granulomatosis) (see Chapters
9 and 17), and the patient must endure and pay for
these evaluations. Even after a costly workup, some
patients who have localized areas of granulomatous
inﬂammation of the gingiva have no signs or symptoms
of any of the previously mentioned disorders.
Several investigators have reported granulomatous
gingival lesions caused by the introduction of dental
materials into the connective tissue deep to the sulcu-
lar epithelium. As more cases have been reported, it
has become evident that the associated inﬂammatory
reaction often is not granulomatous and may mimic
gingival lichen planus or create a nonspeciﬁc pattern
of chronic or subacute mucositis. These lesions have
been termed foreign body gingivitis and are thought
to arise when damage to the sulcular epithelium during
restorative or oral hygiene procedures allows the intro-
duction of foreign material into the gingival tissues.
When the material is obvious on light microscopy, the
Fig. 4-11 Plasma cell gingivitis. High-power
photomicrograph exhibiting a dense inﬂammatory inﬁltrate
consisting predominantly of plasma cells with scattered
lymphocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 161
association between the gingival pathosis and the mate-
rial can be made easily. Often the material is smaller
than 1 μm in diameter and is so ﬁne that it could be
overlooked.
In a review of 85 cases of foreign body gingivitis,
energy-dispersive radiographic microanalysis revealed
21 different elements embedded with the gingival soft
tissues. The most common elements were silver, alumi-
num, silicon, tin, sulfur, copper, calcium, phosphorus,
and iron. Elements compatible with ﬁne particles of
amalgam dust were identiﬁed most often. Particles
consistent with corundum or silica also were common
(sandpaper disks, polishing paste, toothpaste, and pos-
sibly restorative ﬁlling material). Materials implicated
less frequently include dust from tungsten carbide
burs, composite material, endodontic sealer compo-
nents, and temporary cement. This investigation dem-
onstrates that the presumed causative agents are
diverse and can originate from a wide variety of dental
materials.
CLINICAL FEATURES
Both foreign body gingivitis and nonspeciﬁc granulo-
matous gingivitis may occur at any age; however, they
are most frequently encountered in adulthood. The
lesions may be solitary or multifocal, typically with a
diameter less than 2 cm. The affected areas appear as
red or red-and-white macules, which most frequently
involve the interdental papillae but also may occur
along the marginal gingiva (Figs. 4-12 and 4-13). Pain
or sensitivity is a common ﬁnding, and the lesions
persist despite conventional therapy and rigorous oral
hygiene. The process can be seen adjacent to clinically
normal teeth or next to teeth with restorations.
Frequently, foreign body gingivitis creates areas of
erythematous and atrophic mucositis that closely
resemble gingival lichen planus. In many cases the
causative foreign material is not obvious during review
of submitted biopsy specimens. A good clinicopatho-
logic correlation often is beneﬁcial in arriving at the
correct diagnosis. A diagnosis of gingival lichen planus
should be viewed with suspicion in a patient who does
not have extragingival involvement or if the gingival
changes are somewhat localized and nonmigrating. In
such cases a request to the pathologist for a thorough
search for foreign material is prudent.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of granulomatous gingivitis demon-
strates focal collections of histiocytes intermixed with
an intense lymphocytic inﬁltrate (Fig. 4-14). On occa-
sion, well-formed histiocytic granulomas with multi-
nucleated giant cells are seen. Special stains for
organisms should be negative. If foreign material is
detected, then the clinician can render a diagnosis of
a foreign body reaction (rather than the more nonspe-
ciﬁc term, granulomatous gingivitis). In some cases,
however, the foreign material may be too ﬁne to be
detected.
In the previously mentioned review of 85 cases of
foreign body gingivitis, granulomatous inﬂammation
was present in approximately 20%. In the remainder,
the inﬂammatory inﬁltrate was dominated by lympho-
cytes, intermixed with plasma cells and macrophages
(Fig. 4-15). In some cases, neutrophils were noted
along with the chronic inﬂammatory cellular inﬁltrate.
In a small number of cases, prominent ﬁbrosis was
associated with the foreign material. Not infrequently,
the mucositis was lichenoid, with degeneration of the
basal cell layer of the epithelium and a superﬁcial
bandlike inﬂammatory cell inﬁltrate in the superﬁcial
Fig. 4-12 Granulomatous gingivitis. Localized enlarged
and erythematous gingiva associated with the maxillary left
central incisor. The alterations developed shortly after
placement of a porcelain-fused-to-metal (PFM) full crown and
were not responsive to conservative local therapy. (Courtesy of
Dr. Timothy L. Gutierrez.)
Fig. 4-13 Foreign body gingivitis. Isolated area of marginal
gingivitis. (Courtesy of Dr. Ronald Godat.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

162 ORAL AND MAXILLOFACIAL PATHOLOGY
lamina propria. Because the immune reaction in lichen
planus tends to be composed primarily of lymphocytes,
the presence of signiﬁcant numbers of plasma cells,
histiocytes, or neutrophils in the absence of plaque-
related gingivitis should suggest a thorough search for
subtle foreign material.
In the majority of cases, the foreign material appears
as black or brown-black granules. In many cases, color-
less, translucent crystal structures are noted and may
be intermixed with black granules. These crystals often
are difﬁcult to detect unless viewed under polarized
light. To ensure that any foreign material is not an
artifact introduced during processing, it should be
present in multiple sections.
TREATMENT AND PROGNOSIS
When all the histopathologic and clinical investiga-
tions have been performed, the ﬁnal differential diag-
nosis of granulomatous gingivitis is usually narrowed
down to a localized form of orofacial granulomatosis
(see page 341) or a foreign body reaction. Without
deﬁnitive demonstration of foreign material, a com-
plete physical evaluation for diseases known to be asso-
ciated with orofacial granulomatosis is mandatory. On
occasion, patients with orofacial granulomatosis ini-
tially have gingival lesions but eventually develop more
widespread manifestations such as cheilitis granulo-
matosa, cobblestone buccal mucosa, or vestibular
linear hyperplastic folds.
Surgical excision of the affected tissue is the therapy
of choice for those cases related to foreign material. In
persistently atrophic or erosive areas of foreign body
gingivitis, overlaying the damaged area with a graft
from a healthy gingival donor site may be a better
option than complete excision. In an attempt to prevent
future introduction of iatrogenic foreign material, it
appears appropriate to follow certain guidelines:
●The clinician should use extreme care when trim-
ming restorations or using abrasive instruments close
to gingival margins.
● Air abrasion (i.e., sandblasting) should be used
cautiously.
●Dental prophylaxis should be delayed for 2
days after scaling, root planing, and curettage
procedures.
Patients who do not respond to surgical removal and
have recurrences of granulomatous gingivitis despite
cautious dental care probably should be classiﬁed
as having orofacial granulomatosis and managed
accordingly.
DESQUAMATIVE GINGIVITIS
Most clinicians use the term desquamative gingivitis
to describe gingival epithelium that spontaneously
sloughs or can be removed with minor manipulation.
The process most likely represents a manifestation of
one of several different vesiculoerosive diseases. Histo-
pathologic and immunologic investigations of this con-
dition reveal that most patients exhibit features that are
diagnostic of pemphigoid or lichen planus. Other diag-
noses that are made less frequently include linear
IgA disease, pemphigus vulgaris, epidermolysis bullosa
acquisita, systemic lupus erythematosus (SLE), chronic
Fig. 4-14 Granulomatous gingivitis. Focal collection of
histiocytes, lymphocytes, and multinucleated giant cells
within the superﬁcial lamina propria of the gingiva.
Fig. 4-15 Foreign body gingivitis. Particles of pigmented
foreign material (arrow) intermixed with lymphocytes and
plasma cells. This biopsy was obtained from the patient
depicted in Fig. 4-13. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 163
ulcerative stomatitis, and paraneoplastic pemphigus.
The gingival manifestations of these mucosal and
dermatologic diseases are described in greater detail
in Chapter 16, so further discussion here is not
warranted.
DRUG-RELATED GINGIVAL
HYPERPLASIA (DRUG-RELATED
GINGIVAL OVERGROWTH)
Drug-related gingival hyperplasia refers to an abnor-
mal growth of the gingival tissues secondary to use of
a systemic medication. The term is a misnomer because
neither the epithelium nor the cells within the connec-
tive tissue exhibit either hyperplasia or hypertrophy.
The increased gingival size is due to an increased
amount of extracellular matrix, predominantly colla-
gen. Therefore, several authors designate the alteration
as medication-associated gingival enlargement or
gingival overgrowth. These designations are further
supported by investigators who have suggested the gin-
gival changes arise from interference with normal
intracellular collagen degradation. It is known that gin-
gival collagen constantly undergoes physiologic remod-
eling, and the process must be tightly controlled to
maintain a constant volume of the gingival tissues.
Investigators have suggested that cyclosporine, phe-
nytoin, and nifedipine are all associated with calcium
deregulation, which disrupts the normal collagen
phagocytosis and remodeling process. If this is true,
then the increased collagen does not occur from hyper-
plasia but from impaired collagen degradation and
remodeling.
A list of medications reported to be associated with
gingival hyperplasia is provided in Box 4-4. Of these
medications, a strong association has been noted only
with cyclosporine (Fig. 4-16), phenytoin, and nifedi-
pine (Fig. 4-17). In the remainder, the prevalence is
much lower or the association is weak or anecdotal. As
new drugs have been developed, the list of offending
medications has grown. When cyclosporine and nifed-
ipine are used concurrently, the severity of the associ-
ated hyperplasia often is increased (Fig. 4-18).
Fig. 4-16 Cyclosporine-related gingival hyperplasia.
Diffuse, erythematous, and ﬁbrotic gingival hyperplasia.
Fig. 4-17 Nifedipine-related gingival hyperplasia. Diffuse,
ﬁbrotic gingival hyperplasia after 1 month of intensive oral
hygiene. Signiﬁcant erythema, edema, and increased
enlargement were present before intervention.
Box 4-4
Medications Reported to be Associated
with Gingival Hyperplasia
Anticonvulsants
● Carbamazepine
● Ethosuximide
● Ethotoin
● Felbamate
● Mephenytoin
● Methsuximide
● Phenobarbital
● Phensuximide
● Phenytoin
● Primidone
● Sodium valproate
● Vigabatrin
Calcium channel blockers
● Amlodipine
● Bepridil
● Diltiazem
● Felodipine
● Nicardipine
● Nifedipine
● Nimodipine
● Nitrendipine
● Verapamil
Cyclosporine
Erythromycin
Oral contraceptives `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

164 ORAL AND MAXILLOFACIAL PATHOLOGY
The prevalence of these hyperplasias varies widely;
however, as reported in one critical review of the litera-
ture, the prevalence related to use of phenytoin is
approximately 50%. Cyclosporine and nifedipine each
produce signiﬁcant changes in about 25% of patients
treated. Whether there is a relationship between the
particular dose and the risk or severity of the hyperpla-
sia is a controversial issue. Investigators have suggested
that susceptibility to cyclosporine gingival hyperplasia
is associated with certain histocompatibility antigen
(HLA) types, whereas other HLA types appear to protect
against hyperplasia. Whether similar correlations exist
for the other forms of medication-associated gingival
hyperplasia is unknown.
The degree of gingival enlargement appears to be
related signiﬁcantly to the patient’s susceptibility and
the level of oral hygiene. In observations of patients with
excellent oral hygiene, gingival overgrowth (as ascer-
tained by pseudopocket formation) is reduced dramati-
cally or not present. Even with good oral hygiene,
however, some degree of gingival enlargement can be
discovered in susceptible individuals, although in many
cases the changes are difﬁcult to detect. Rigorous oral
hygiene often can limit the severity to clinically insig-
niﬁcant levels. Of the medications discussed, cyclospo-
rine appears to be the least responsive to the institution
of a rigorous program of oral hygiene; even with this
medication, however, the elimination of gingival inﬂam-
mation results in noticeable clinical improvement. In
addition, the degree of drug-associated gingival hyper-
plasia appears to be markedly higher in smokers.
CLINICAL FEATURES
Because young patients use phenytoin most often, the
gingival hyperplasia it induces is primarily a problem
in people younger than age 25. Cases related to the
calcium channel blockers occur mainly in middle-aged
or older adults. Cyclosporine is used over a broad age
range, and this correlates with the age of reported
hyperplasia. A greater risk for gingival hyperplasia
occurs when the drug is used in children, especially
adolescents. No sex or race predilection is present.
After 1 to 3 months of drug use, the enlargements
originate in the interdental papillae and spread across
the tooth surfaces (Fig. 4-19). The anterior and facial
segments are the most frequently involved areas. In
extensive cases, the hyperplastic gingiva can cover a
portion (or all) of the crowns of many of the involved
teeth (Figs. 4-20 and 4-21). Extension lingually and
occlusally can interfere with speech and mastication.
In one report, signiﬁcant lingual expansion of the
gingiva resulted in tongue displacement and respira-
tory distress. Edentulous areas are generally not
affected, but signiﬁcant hyperplasia under poorly
Fig. 4-18 Cyclosporine- and nifedipine-related gingival
hyperplasia. Dramatic gingival hyperplasia in a patient using
two drugs associated with gingival enlargement.
Fig. 4-19 Mild phenytoin-related gingival hyperplasia.
Gingival enlargement present predominantly in the
interdental papillae.
Fig. 4-20 Phenytoin-related gingival hyperplasia.
Signiﬁcant erythematous gingival hyperplasia is covering
portions of the crowns of numerous teeth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 165
maintained dentures and around implants has been
noted (Fig. 4-22).
Nongingival soft tissue growths that resemble pyo-
genic granulomas have been reported in allogenic
bone marrow transplant recipients who are receiving
cyclosporine for graft-versus-host disease (GVHD) (Fig.
4-23). It is thought that cyclosporine triggers the pro-
liferations in areas chronically inﬂamed by GVHD.
In the absence of inﬂammation, the enlarged gingiva
is normal in color and ﬁrm, with a surface that may be
smooth, stippled, or granular. With inﬂammation, the
affected gingiva often becomes dark red and edema-
tous, with a surface that is friable, bleeds easily, and
occasionally is ulcerated. Pyogenic granuloma-like
enlargements occasionally are seen in the presence of
heavy inﬂammation.
HISTOPATHOLOGIC FEATURES
The exact histopathologic changes that occur in people
with drug-induced gingival hyperplasia are difﬁcult to
ascertain because of variations in the techniques of
investigation. In spite of this, most controlled micro-
scopic examinations of hyperplastic gingival tissues
removed from lesions caused by phenytoin or the dihy-
dropyridines reveal redundant tissue of apparently
normal composition. Those cases related to cyclospo-
rine use demonstrate an increased amount of collagen
per unit volume, with a normal density of ﬁbroblasts.
The overlying surface epithelium may demonstrate
elongation of the rete ridges, with long extensions into
the underlying lamina propria. In patients with sec-
ondary inﬂammation, there is increased vascularity
and a chronic inﬂammatory cellular inﬁltrate that most
frequently consists of lymphocytes and plasma cells. In
patients with pyogenic granuloma-like overgrowths,
the proliferations often demonstrate an increased vas-
cularity and signiﬁcant subacute inﬂammation.
TREATMENT AND PROGNOSIS
Discontinuation of the offending medication by the
attending physician often results in cessation, and pos-
sibly some regression, of the gingival enlargement;
even substitution of one medication for another may
be beneﬁcial. If the patient’s response allows drug sub-
stitution, then cyclosporine can be replaced with tacro-
limus; phenytoin with carbamazepine, lamotrigine,
gabapentin, sulthiame, topiramate, or valproic acid;
and nifedipine with isradipine or atenolol. Often the
response to medication substitution is not immediate.
Fig. 4-21 Phenytoin-related gingival hyperplasia.
Signiﬁcant gingival hyperplasia almost totally covers the
crowns of the posterior maxillary dentition. (Courtesy of Dr. Ann
Drummond and Dr. Timothy Johnson.)
Fig. 4-22 Phenytoin-related palatal hyperplasia. Extensive
hyperplasia of palatal mucosa in an edentulous patient with
poor denture hygiene.
Fig. 4-23 Nongingival cyclosporine hyperplasia. Exophytic
and granulomatous-appearing mass of the dorsal surface of
the tongue that arose in a bone marrow transplant patient
who was receiving cyclosporine for graft-versus-host disease
(GVHD). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

166 ORAL AND MAXILLOFACIAL PATHOLOGY
Unless the degree of hyperplasia dramatically affects
aesthetics and function, allowing at least 6 to 12 months
between discontinuation of the offending medication
and the decision whether to proceed with surgical
therapy is recommended. If the drug use is mandatory,
then professional cleaning, frequent reevaluations, and
home plaque control are important. Antiplaque agents,
such as chlorhexidine, have been beneﬁcial in the pre-
vention of plaque buildup and the associated gingival
hyperplasia.
Systemic or topical folic acid has been shown to
ameliorate the gingival hyperplasia in some cases. In
addition, several authors have documented signiﬁcant
resolution of cyclosporine-related gingival hyperplasia
after a short course of metronidazole or azithromycin.
Although the mechanism is not clear, it appears these
antibiotic medications can inhibit proliferation of col-
lagen ﬁbers along with their antimicrobial abilities.
Azithromycin also may be beneﬁcial in resolving gin-
gival hyperplasia related to nifedipine and phenytoin.
Although gingival hyperplasia is associated with
increased probing depths, some investigators do not
believe this necessarily leads to exaggerated attach-
ment loss or an increased loss of teeth. Therefore, some
clinicians exercise watchful waiting and do not perform
invasive therapy without evidence of attachment loss,
inappropriate aesthetics, or disruption of speech or
mastication. When objectionable alterations are noted
and all other interventions fail to achieve signiﬁcant
resolution, eradication of the excess gingival tissues
remains the treatment of choice. This can be achieved
by surgical removal, by chemosurgical techniques, by
means of electrosurgery, or by use of a carbon dioxide
laser. Histopathologic examination of all excised tissue
is mandatory to conﬁrm the diagnosis. Recurrence is
not uncommon, especially in patients with inadequate
oral hygiene. Although recurrences may arise in as
little as 3 months, most surgical results are maintained
for at least 12 months.
GINGIVAL FIBROMATOSIS
(FIBROMATOSIS GINGIVAE;
ELEPHANTIASIS GINGIVAE)
Gingival ﬁbromatosis is a slowly progressive gingival
enlargement caused by a collagenous overgrowth of
the gingival ﬁbrous connective tissue. In spite of the
name, this disorder bears no relationship to the hyper-
cellular and neoplastic ﬁbromatoses that can occur in
soft tissue and bone (see pages 515 and 658).
Gingival ﬁbromatosis may be familial or idiopathic.
Other ﬁndings sometimes seen in conjunction with
gingival ﬁbromatosis include hypertrichosis (Fig.
4-24), generalized aggressive periodontitis, epilepsy,
mental retardation, sensorineural deafness, hypothy-
roidism, chondrodystrophia, and growth hormone
deﬁciency. The familial variations may occur as an iso-
lated ﬁnding or in association with one of several
hereditary syndromes (e.g., Zimmermann-Laband,
Murray-Puretic-Drescher, Rutherfurd, multiple
hamartoma [see page 760], Cross, Ramon, Jones,
prune belly).
In most cases of isolated gingival ﬁbromatosis, an
autosomal dominant pattern of inheritance is seen;
however, autosomal recessive examples also have been
noted. Incomplete penetrance and variable expressiv-
ity are seen. Even in cases with similar patterns of
inheritance, genetic heterogeneity of gingival ﬁbroma-
tosis has been noted and conﬁrms that this alteration
represents a group of clinically similar disorders. In the
autosomal dominant pattern of isolated gingival ﬁbro-
matosis, one of three different mutations, GINGF
(HGF1), GINGF2 (HGF2), and GINGF3 (HGF3), have
been documented and correlates respectively to chro-
mosomes 2p21, 5q13-q22, and 2p22.3-p23.3. Of the
three deﬁned loci, only the SOS1 (son of sevenless-1)
gene associated with the GINGF locus has been identi-
ﬁed. In studies of another kindred with hereditary gin-
gival ﬁbromatosis and hypertrichosis, this presentation
Fig. 4-24 Hypertrichosis in association with gingival
ﬁbromatosis. Dramatically increased body hair of the back
and buttocks in a patient with gingival ﬁbromatosis. (Courtesy
of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 167
was not linked to either mutation known at that time
(GINGF or GINGF1), further conﬁrming the genetic
heterogeneity in this hereditary gingival ﬁbromatosis.
CLINICAL FEATURES
In most instances, the enlargement begins before age
20 and often is correlated with the eruption of the
deciduous or permanent teeth (Fig. 4-25). Most inves-
tigators believe that the presence of teeth probably is
necessary for the condition to occur. After the process
has begun, it can overgrow the associated teeth and
even interfere with lip closure. Failure or delay in erup-
tion of subsequent teeth may be evident (Fig. 4-26). In
some instances, a tooth may have erupted into a normal
position, but the ﬁbrous connective tissue continues to
cover the crown and prevent visualization.
The gingival changes may be generalized or local-
ized to one or more quadrants. Either jaw may be
involved, but the maxilla is affected more frequently
and demonstrates a greater degree of enlargement.
Palatal surfaces are typically increased in thickness
more than the buccal side. Typically, extension past the
alveolar mucosal junction into the mucobuccal fold is
not seen, but palatal extensions can cause signiﬁcant
distortion of the contour of the palate and, at times,
almost can meet in the midline.
In localized cases, the hyperplasia may involve a
group of teeth and remain stable or, at a later date, may
extend to other segments of one or both jaws. One
distinctive and not uncommon pattern involves the
posterior maxillary alveolar ridge. In this pattern, the
hyperplastic tissue forms bilaterally symmetrical en-
largements that extend posteriorly and palatally from
the posterior alveolar ridges (Fig. 4-27). Less com-
monly, the overgrowth also may be isolated to the facial
gingiva of the lower molars.
The gingiva is ﬁrm, normal in color, and covered by
a surface that is smooth or ﬁnely stippled. In older
patients, the surface may develop numerous papillary
projections. The frenular attachments may appear to
divide the gingival tissues of the alveolar ridge into
lobules. Associated clinical problems include poor aes-
thetics, prolonged retention of deciduous teeth, abnor-
mal occlusion, inadequate lip closure, and difﬁculty in
eating and speaking.
HISTOPATHOLOGIC FEATURES
The enlargements of gingival ﬁbromatosis consist of
dense hypocellular, hypovascular collagenous tissue,
which forms numerous interlacing bundles that appear
to run in all directions. The surface epithelium often
Fig. 4-25 Gingival ﬁbromatosis. A young child with cheeks
retracted by the parent. Note erythematous gingival
hyperplasia arising in association with erupting deciduous
dentition. (Courtesy of Dr. George Blozis.)
Fig. 4-26 Gingival ﬁbromatosis. Signiﬁcant ﬁbrotic gingival
hyperplasia with resultant delayed eruption of numerous
teeth. (From Neville BW, Damm DD, White DK, Waldron CA: Color atlas
of clinical oral pathology, Philadelphia, 1991, Lea & Febiger.)
Fig. 4-27 Localized gingival ﬁbromatosis. Bilateral and
symmetrical ﬁbrotic enlargements of the palatal surfaces of
the posterior maxillary alveolar ridges. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

168 ORAL AND MAXILLOFACIAL PATHOLOGY
exhibits long, thin rete ridges that extend deeply into
the underlying ﬁbrous connective tissue (Fig. 4-28).
Inﬂammation is absent to mild. On occasion, scattered
islands of odontogenic epithelium, foci of dystrophic
calciﬁcation, or areas of osseous metaplasia may be
seen. Electron microscopic examination demonstrates
a mixture of both ﬁbroblasts and myoﬁbroblast-like
cells.
TREATMENT AND PROGNOSIS
Conservative treatment consists of gingivectomy in
conjunction with a rigorous program of oral hygiene.
Follow-up is recommended because there is a ten-
dency for recurrence within a few years. Investigators
have suggested that the frequency of recurrence is less
if gingivectomy is delayed until after full eruption of
the permanent dentition. In severe cases, selective
extraction of teeth (and gingivectomy) often is required
to achieve a normal gingival morphology.
PERIODONTITIS
Periodontitis refers to an inﬂammation of the gingival
tissues in association with some loss of both the attach-
ment of the periodontal ligament and bony support.
With progressive loss of attachment, signiﬁcant destruc-
tion of the periodontal ligament and adjacent alveolar
bone can occur. Apical migration of the crevicular epi-
thelium along the root surface results in the formation
of periodontal pockets. Loosening and eventual loss of
teeth are possible.
For more than a century, the presence of the disease
has been correlated with the accumulation of dental
plaque on the tooth and under the gingiva. Despite this,
current evidence suggests that dental plaque is part of
the natural human microﬂora. In some patients with
extensive dental plaque, destructive lesions of the peri-
odontium do not develop. Many investigators now
believe that periodontitis occurs not from the mere
presence of dental plaque but as a result of shifts in the
proportions of bacterial species in the plaque, possibly
related to changes in the dentogingival environment
(e.g., a soft diet or a highly fermentable carbohydrate
content diet).
Dramatic differences exist in the content of dental
plaque in areas of healthy and diseased periodontium.
Healthy sites are colonized primarily by facultative
gram-positive organisms, such as actinomycetes and
streptococci; plaque within areas of active periodontitis
contains anaerobic and microaerophilic gram-negative
ﬂora. Of the more than 500 types of bacteria that may
reside in the oral cavity, only a few have been related
to periodontitis, and the speciﬁc types often correlate
with the clinical patterns of periodontitis. Chronic
periodontitis is associated strongly with Actinobacillus
actinomycetemcomitans, Tannerella forsythensis (formerly
Bacteroides forsythus), and Porphyromonas gingivalis.
Additional organisms frequently thought to be involved
include Prevotella intermedia, Campylobacter rectus, Trepo-
nema denticola, and Fusobacterium nucleatum. Although
controversial, some investigators also have suggested
that human cytomegalovirus and other herpesviruses
could play a contributing role.
The pathogenic organisms exist in an organized
community termed a bioﬁlm. Bacteria growing in bio-
ﬁlms are relatively protected from normal host defenses
and exhibit an increased resistance to locally or sys-
temically administered antibiotic medications. Lipo-
polysaccharides released from the bioﬁlms are thought
to trigger release of catabolic inﬂammatory mediators
that lead to the loss of attachment. Mechanical disrup-
tion of this organized bacterial bioﬁlm may be an
important factor associated with successful treatment
of periodontitis.
The presence of pathogenic bacteria is essential but
insufﬁcient to produce periodontitis. Although mild-to-
moderate periodontitis is present in the majority of
adults, only 10% to 15% of the population develops
severe, generalized disease. The variation of suscepti-
bility to periodontitis appears related to genetic inﬂu-
ences on host response, with 50% of the risk for chronic
periodontitis attributed to heredity, 20% to tobacco
abuse, and another 20% to colonization by speciﬁc
pathogenic bacteria.
The classiﬁcation of periodontitis, as delineated by
the American Academy of Periodontology, is listed in
Box 4-5. In 1999 this classiﬁcation underwent signiﬁ-
cant revision, with consolidation of many previously
distinct disorders. The concept of “early-onset peri-
odontitis” and all of its subdivisions has been reclassi-
Fig. 4-28 Gingival ﬁbromatosis. Surface stratiﬁed
squamous epithelium exhibiting long, thin rete ridges and
underlying dense, ﬁbrous connective tissue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 169
ﬁed as aggressive periodontitis. The following text
concentrates on the chronic form of periodontitis; a
later section discusses the aggressive forms of peri-
odontitis. From this list it should be clear that peri-
odontitis represents a heterogeneous group of
disorders.
Periodontitis associated with systemic disease is
not rare, and Box 4-6 lists many of the disorders that
may be associated with a premature loss of periodontal
attachment. Necrotizing ulcerative periodontitis
(NUP) represents the loss of attachment that often
occurs in association with necrotizing ulcerative gingiv-
itis (NUG) (see page 157). This form has been corre-
lated with aggressive invasion by a number of
spirochetes and Prevotella intermedia.
CLINICAL AND RADIOGRAPHIC
FEATURES
CHRONIC PERIODONTITIS
With the decline in caries, chronic periodontitis has
become the primary cause of tooth loss in patients
older than 35 years of age. A national survey found that
44% of adults in the United States had attachment loss
of 3 mm or more in at least one site. The disorder
demonstrates an increased prevalence in males,
although researchers believe that much of this effect is
related to poorer oral hygiene and dental-visit behav-
ior. In addition, an increased prevalence of chronic
periodontitis is associated with the following:
● Advancing age
● Smoking
● Diabetes mellitus
● Osteoporosis
● HIV infection
●Lower socioeconomic level
Local factors also may predispose patients to iso-
lated periodontal defects; these include tooth shape
and alignment, presence and quality of dental restora-
tions, poor interdental contact, calculus formation,
subgingival dental caries, traumatic occlusion, and
abnormal alveolar bone or gingival anatomy.
Conversely, it appears that the presence of signiﬁ-
cant periodontitis may place patients at risk for an
increased prevalence or greater severity of certain
medical disorders. Although controversial, increasing
evidence links periodontitis with an elevated risk for
coronary artery disease, stroke, progressive diabetes
mellitus, respiratory diseases, and delivery of low–birth
weight babies. If true, then it is unclear if these associa-
tions are due to dissemination of triggering host inﬂam-
matory mediators or the spread of bacteria or their
related toxins. Although strong direct associations have
been documented, the epidemiology is difﬁcult to
Box 4-5
Classiﬁcation of Periodontitis
1. Chronic periodontitis
● Localized
● Generalized
2. Aggressive periodontitis
● Localized
● Generalized
3. Periodontitis as a manifestation of systemic diseases
●Associated with hematologic disorders
●Associated with genetic disorders
●Not otherwise speciﬁed
4. Necrotizing periodontal diseases
●Necrotizing ulcerative gingivitis (NUG)
●Necrotizing ulcerative periodontitis (NUP)
5. Abscesses of the periodontium
● Gingival abscess
● Periodontal abscess
●Pericoronal abscess (in association with
pericoronitis)
6. Periodontitis associated with endodontic lesions
Box 4-6
Systemic Disorders with Premature
Attachment Loss
1.Acatalasia
2.Acrodynia
3.Acquired immunodeﬁciency syndrome (AIDS)
4.Blood dyscrasias
● Leukemia
● Agranulocytosis
● Cyclic neutropenia
5. Chédiak-Higashi syndrome
6. Cohen syndrome
7. Crohn’s disease
8. Diabetes mellitus
9. Dyskeratosis congenita
10. Ehlers-Danlos syndrome, types IV and VIII
11. Glycogen storage disease
12. Haim-Munk syndrome
13. Hemochromatosis
14. Hypophosphatasia
15. Kindler syndrome
16. Langerhans cell disease
17. Leukocyte dysfunctions with associated extraoral
infections
18.Oxalosis
19.Papillon-Lefèvre syndrome
20.Sarcoidosis
21.Trisomy 21 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

170 ORAL AND MAXILLOFACIAL PATHOLOGY
interpret because of the additional risk factors associ-
ated with both conditions. For example, cardiovascular
disease has been related to periodontitis, but the nature
of this association is cloudy because both are strongly
associated with smoking. Numerous interventional
studies are ongoing to investigate the possible reduc-
tion in these medical disorders secondary to elimina-
tion and control of periodontitis.
In chronic periodontitis, no abnormalities of the
immune system are found. Periodontitis begins in
youth and early adulthood, takes years to decades to
progress, and includes cyclic patterns of exacerbation
and remission. The assumption that periodontitis is a
disease of aging has been challenged, and most believe
the increased periodontal destruction observed in
older adults reﬂects a lifetime of disease accumulation
rather than an age-speciﬁc disease.
In patients with periodontitis, gingivitis is present
and precedes the development of signiﬁcant periodon-
tal lesions. Although many sites may demonstrate gin-
givitis and few progress to attachment loss, lifelong
local measures directed against sites of gingivitis rep-
resent an effective approach for prevention of chronic
periodontitis. As loss of attachment occurs, blunting
and apical positioning of the gingival margins typically
are present (Fig. 4-29). Periodontal disease is present
when a loss of attachment can be demonstrated through
the use of a periodontal probe. In the absence of sig-
niﬁcant gingival hyperplasia, a measurement of pocket
depths greater than 3 to 4 mm indicates destruction of
the periodontal ligament and resorption of adjacent
alveolar bone; however, clinical attachment loss is the
best measurement of accumulated periodontal destruc-
tion and represents the diagnostic gold standard. High-
quality dental radiographs exhibit a decreased vertical
height of the bone surrounding the affected teeth (Fig.
4-30). With advanced bone loss, tooth mobility is
present.
NECROTIZING ULCERATIVE PERIODONTITIS
NUP presents similarly to NUG (see page 157), but it
also demonstrates loss of clinical attachment and alveo-
lar bone. This destructive form of periodontitis may
arise within a zone of preexisting periodontitis, or it
may represent a sequela of a single or multiple episodes
of NUG. Many believe that NUG and NUP represent
different stages of the same infection. Patients affected
with this pattern frequently are younger than most
patients affected with chronic periodontitis and often
demonstrate immunosuppression or malnutrition.
PERIODONTAL ABSCESS
A periodontal abscess (Figs. 4-31 and 4-32) is a local-
ized purulent infection of the gingiva with involvement
of the adjacent periodontal attachment and alveolar
Fig. 4-29 Adult periodontitis. Diffuse gingival erythema
with blunting and apical positioning of the gingival margins.
(Courtesy of Dr. Samuel Jasper.)
Fig. 4-30 Advanced adult periodontitis. Generalized
horizontal bone loss with an isolated vertical defect involving
the mesial root of the ﬁrst molar.
Fig. 4-31 Periodontal abscess. Localized erythematous
gingival enlargement with central purulent drainage. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 171
bone. On occasion, an abscess may be localized to the
marginal or interdental gingiva without involvement of
the adjacent periodontal ligament or alveolar bone.
This lesion is termed a gingival abscess and often is
secondary to plaque or foreign material that has
become entrapped in the gingival sulcus.
A periodontal abscess often arises in a preexisting
periodontal lesion and usually is precipitated by altera-
tions in the subgingival ﬂora, host resistance, or both.
Factors frequently associated with abscess formation
are closure of the entrance into a periodontal pocket,
furcation involvement, or diabetes. Many cases arise in
patients actively undergoing periodontal therapy,
perhaps because of incomplete removal of deep calcu-
lus with microbial penetration of the soft tissue sur-
rounding the pocket or premature sealing of the coronal
opening to the pocket. Other factors involved less fre-
quently are trauma and anatomic dental anomalies,
such as enamel pearls (see page 93) and dens invagina-
tus (see page 90). Most cases arise in adults; periodontal
abscesses in children are rare and most frequently the
result of a foreign body that has been introduced into
previously healthy periodontal tissues.
A periodontal abscess appears as a zone of gingival
enlargement along the lateral aspect of a tooth. The
involved gingiva may be erythematous and edematous,
with a slick, red surface, or it may be hemorrhagic, with
a dark-red coloration (Fig. 4-33). Common symptoms
include the following:
● Throbbing pain
● Extreme sensitivity to palpation of the affected
gingiva
●Sensitivity, mobility, or extrusion of the adjacent
tooth
● Foul taste
● Lymphadenopathy
●Fever, leukocytosis, and malaise (occasionally)
Probing or gentle pressure on the affected gingiva
often results in the expression of pus from the sulcus.
The abscess may drain through an overlying sinus tract.
With drainage, the abscess becomes asymptomatic but
can demonstrate acute exacerbations if the mucosa
heals over and the pressure builds again. Radiographs
often demonstrate bone loss associated with the previ-
ous periodontal defect or additional radiolucency sec-
ondary to the current acute process. In some cases, the
infection can spread into the periapical region and
create a combined periodontal-endodontic lesion.
PERICORONITIS
Pericoronitis is an inﬂammatory process that arises
within the tissues surrounding the crown of a partially
erupted tooth. The inﬂammatory reaction often arises
when food debris and bacteria are present beneath the
gingival ﬂap overlying the crown. Other predisposing
factors include stress and upper respiratory infections,
especially tonsillitis or pharyngitis.
These gingival ﬂaps can exhibit long periods of
chronic inﬂammation without symptoms. If the debris
and bacteria become entrapped deep within the gingi-
val ﬂap, then abscess formation develops. Abscess
development is seen most frequently in association
with the mandibular third molars, and the predomi-
nant symptoms are extreme pain in the area, a foul
taste, and inability to close the jaws. The pain may
Fig. 4-32 Periodontal abscess. Same patient as depicted
in Fig. 4-31. Note extensive loss of bone support associated
with the maxillary cuspid.
Fig. 4-33 Periodontal abscess. Dark-red and hemorrhagic
enlargement of the interdental papilla between the maxillary
right lateral incisor and cuspid. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

172 ORAL AND MAXILLOFACIAL PATHOLOGY
radiate to the throat, ear, or ﬂoor of the mouth. The
affected area is erythematous and edematous, and the
patient often has lymphadenopathy, fever, leukocyto-
sis, and malaise (Fig. 4-34). NUG-like necrosis may
develop in areas of persistent pericoronitis.
HISTOPATHOLOGIC FEATURES
When soft tissue from areas of periodontitis is exam-
ined microscopically, gingivitis is present and the cre-
vicular epithelium lining the pocket is hyperplastic,
with extensive exocytosis of acute inﬂammatory cells.
The adjacent connective tissue exhibits an increased
vascularity and contains an inﬂammatory cellular inﬁl-
trate consisting predominantly of lymphocytes and
plasma cells, but with a variable number of polymor-
phonuclear leukocytes. Frequently, large colonies of
microorganisms, representing plaque and calculus, are
noted.
TREATMENT AND PROGNOSIS
PERIODONTITIS
Initial attention must be directed toward elimination
of any existing risk factors. Even with appropriate treat-
ment and improved oral hygiene, many patients fail to
respond to therapy unless certain factors (e.g., smoking,
inadequately controlled diabetes) are eliminated. Once
these inﬂuences have been managed, the treatment of
periodontitis is directed toward stopping the loss of
attachment. The foremost goal of this process is the
elimination of the pathogenic bacterial plaque. Scaling,
root planing, and curettage can be used to treat early
periodontal lesions. In deeper pockets, a surgical ﬂap
may be required to gain access to the tooth for neces-
sary débridement. At this time, the underlying bone
may be recontoured (if necessary) to aid in the resolu-
tion of the periodontal pocket.
In some bony defects, regeneration of the attach-
ment can be attempted through interdental denuda-
tion or the placement of autogenous bone grafts,
allografts, or alloplastic materials. Often these grafts
are used in conjunction with materials such as polytet-
raﬂuoroethylene in an attempt to achieve guided tissue
regeneration in moderate-to-advanced periodontal
defects.
Because of the chronic nature of periodontitis, anti-
biotic medications are not generally used except in
patients who do not respond to conventional therapy.
Inappropriate use of antibiotic agents can lead to over-
growth of potentially pathogenic organisms and devel-
opment of bacterial drug resistance. When required,
tetracycline or metronidazole are used most frequently.
The choice of antibiotic medication always should be
guided by microbiologic analysis with susceptibility
testing. Several studies also suggest that NSAIDs may
help slow the progression of bone loss in some cases of
destructive periodontitis.
Several forms of local antibiotic delivery have been
developed. The antibiotic drugs are placed directly into
sites of refractory periodontitis and consist of gels, oint-
ments, nonresorbable ﬁbers, and resorbable polymers.
These antibiotic agents represent an adjunct to scaling
and root planing and should be limited to sites that are
resistant to conventional therapy alone. Although short-
term beneﬁts have been demonstrated, many investi-
gations have revealed limited long-term positive effects
when compared with scaling and root planing without
antibiotic medications.
In many cases the prognosis for chronic periodonti-
tis correlates directly with the patient’s desire to main-
tain oral health. Long-term studies show that periodontal
health can be maintained after appropriate periodon-
tal therapy if a program of rigorous oral hygiene and
professional care is established. Professional scaling
and root planing modify the composition of the plaque
microﬂora so that pathogenic plaques are converted to
those with bacterial types normally found in healthy
mouths. Bacterial morphotypes return to pretreatment
levels 42 days after professional prophylaxis, but patho-
genic complexes capable of inducing attachment loss
require approximately 3 months to be reestablished
functionally. In patients with less-than-optimal oral
hygiene or with isolated defects that cannot be self-
cleaned, a loss of attachment can be prevented if pro-
fessional scaling and root planing are performed at
3-month intervals.
Many clinicians believe that the average individual
is neither motivated nor sufﬁciently effective in main-
taining the level of plaque control necessary to prevent
Fig. 4-34 Pericoronitis. Painful erythematous enlargement
of the soft tissues overlying the crown of the partially erupted
right mandibular third molar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 173
periodontal disease. In these cases, supplementing
normal hygiene techniques with regular professional
cleaning and interventions such as counterrotational
electric toothbrushes with automatic timers, antimi-
crobial mouth rinses (e.g., essential oils, chlorhexidine),
and toothpastes containing triclosan with 2% Gantrez
copolymer may prove beneﬁcial. Other interventions
occasionally recommended include medications to
temper the host response (e.g., NSAIDs, doxycycline at
subantimicrobial dose).
Destructive periodontal disease that is nonrespon-
sive to normal therapy in compliant patients is termed
refractory periodontitis. In such cases the patient
should be reevaluated closely for any predisposing risk
factors (such as smoking) or systemic diseases known
to be associated with an increased prevalence of peri-
odontitis. Subgingival microbial cultures can be
obtained to assist in selection of an appropriate antibi-
otic intervention. Antimicrobial therapy may be com-
bined with more frequent periodontal maintenance
therapy and stronger reinforcement of the patient’s
oral hygiene techniques.
Investigators are beginning to discover genetic
markers for those patients who are at risk for develop-
ing severe, progressive periodontitis. Many envision a
future in which patients are evaluated for the presence
of these markers, with susceptible individuals moni-
tored closely for early colonization by periodontal
pathogens. If colonization is detected, then it could be
eliminated easily and inexpensively. Attempts at
vaccine development have been hindered by the mul-
tifactorial nature of periodontitis combined with the
complexity of the bacterial bioﬁlms.
NECROTIZING ULCERATIVE PERIODONTITIS
Once any underlying inﬂuence (e.g., immunosuppres-
sion, malnutrition) has been resolved, NUP often
responds well to irrigation, débridement of the necrotic
areas, effective oral hygiene measures, and administra-
tion of systemic antibiotic medications. Failure to
respond to standard therapy mandates a thorough
physical evaluation to rule out the possibility of an
underlying disease.
PERIODONTAL ABSCESS
A gingival or periodontal abscess is treated by drainage
through the sulcus or by an incision through the overly-
ing mucosa. Thorough cleansing of the area with
removal of all foreign material, plaque, and calculus
should be performed. Penicillin or other antibiotic
drugs are prescribed when a fever is present. Analgesic
agents are prescribed, and the patient receives a soft
diet, is told to use warm saltwater rinses, and is
instructed to return each day until the symptoms have
resolved. After the acute phase has passed, the patient
is treated for any underlying chronic pathologic peri-
odontal condition.
PERICORONITIS
Acute pericoronitis is treated with gentle antiseptic
lavage under the gingival ﬂap to remove gross food
debris and bacteria. Systemic antibiotic agents are used
if a fever or general symptoms are noted. The patient
is instructed to use warm saltwater rinses and to return
in 24 hours. Once the acute phase has subsided, the
tooth can be extracted if long-term maintenance is con-
traindicated. If tooth retention is desirable, then the
overlying gingival ﬂap is removed surgically, followed
by elimination of all food debris and bacterial colonies
by thorough curettage.
AGGRESSIVE PERIODONTITIS
Although periodontitis is much more frequent in older
adults, it also can be a signiﬁcant problem in children
and young adults. Before the 1999 reclassiﬁcation by
the American Academy of Periodontology, destructive
periodontal disease in younger patients was termed
early-onset periodontitis and subdivided into prepu-
bertal, localized juvenile, generalized juvenile, and
rapidly progressing forms of periodontitis. The “early-
onset” designation was discontinued during the 1999
workshop because the term was deemed too restric-
tive. Many argued that this pattern of periodontitis can
occur at any age and is not restricted to patients younger
than 35 years old. It was agreed that an appropriate
classiﬁcation system should not be based on age but
should consider primarily the clinical, radiographic,
historical, and laboratory ﬁndings.
The 1999 workshop concluded that the most logical
classiﬁcation system should not be age dependent or
require knowledge of rates of progression. In general,
the new designation of localized aggressive peri-
odontitis replaces the older term, localized juvenile
periodontitis, whereas generalized aggressive peri-
odontitis supersedes generalized juvenile periodon-
titis. The pattern previously designated as prepubertal
periodontitis has been associated with a systemic leu-
kocyte dysfunction termed leukocyte adhesion syndrome.
This disease currently is classiﬁed as one of the forms
of periodontitis presenting as a manifestation of a sys-
temic disease.
By deﬁnition, aggressive periodontitis occurs in oth-
erwise healthy people; there should be no association
with a systemic disease process. In keeping with this
deﬁnition, the diagnosis is one of exclusion, and all
systemic disorders known to be related to premature
loss of attachment (see Box 4-6) should be ruled out
before the deﬁnitive diagnosis is made. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

174 ORAL AND MAXILLOFACIAL PATHOLOGY
In contrast to chronic disease, aggressive periodon-
titis appears to be correlated with one or more deﬁ-
ciencies in the immune response, rather than with
inappropriate accumulations of plaque and calculus.
Researchers believe that aggressive periodontitis rep-
resents a number of different pathoses that have been
grouped together because of similar clinical presenta-
tions. Suspected pathogens that are commonly found
in these diseases include Actinobacillus actinomycetem-
comitans, Prevotella intermedia, Porphyromonas gingivalis,
and a variety of other less common organisms. The
response to therapy often hinges on the successful
elimination of these organisms. As mentioned in the
discussion of periodontitis (see page 168), an associa-
tion with a number of viruses has been suggested but
disputed by others.
The majority of patients with aggressive periodonti-
tis have a demonstrable neutrophil dysfunction but
without systemic manifestations. In the localized
variant, a number of affected patients demonstrate
a speciﬁc defect of bactericidal activity toward A.
actinomycetemcomitans. Although this is a controver-
sial topic, several investigators have suggested that
aggressive periodontitis requires speciﬁc bacterial
ﬂora and the presence of a selective immune dysfunc-
tion that allows these pathogens to ﬂourish. This
unique pattern of immune alteration may explain the
failure to defend appropriately against certain peri-
odontal pathogens without exhibiting systemic signs of
immunodeﬁciency.
Familial aggregation of patients with aggressive
periodontitis is noted and suggests an underlying
genetic foundation, which may be transmitted in some
families as an autosomal dominant trait with reduced
penetrance (some patients can harbor mutation without
clinical evidence of disease). In all likelihood, aggres-
sive periodontitis is genetically heterogeneous, meaning
the mutation of any one of several different gene loci
can result in the disease; however, only one of these
causative mutations is identiﬁed within a kindred.
With this knowledge, it would not be surprising to
encounter variations in inheritance patterns in differ-
ent geographic locations and ethnic groups.
CLINICAL AND RADIOGRAPHIC
FEATURES
LOCALIZED AGGRESSIVE PERIODONTITIS
As previously stated, aggressive periodontitis can be
localized or generalized. One large study of children
aged 5 to 17 years in the United States demonstrated
a prevalence of 0.53% for the localized form and 0.13%
for the generalized variant. Localized aggressive
periodontitis typically begins around the ages of 11 to
13 years and has a strong familial tendency. The fol-
lowing speciﬁc features have been delineated by the
American Academy of Periodontology:
● Circumpubertal onset
● Robust serum antibody response to infecting
agents
●Attachment loss localized to the ﬁrst molars and
incisors, with involvement of no more than two
teeth other than the ﬁrst molars and incisors
This form may appear to localize around the ﬁrst
molars and the incisors, possibly because these teeth
have been erupted for the longest duration (Fig. 4-35).
In numerous clinical studies, minimal supragingival
plaque or calculus has been documented; however,
A B
Fig. 4-35 Localized aggressive periodontitis. A, Loss of bone support in the area of the ﬁrst
molars and incisors of both maxillary and mandibular right quadrants in a 14-year-old patient.
B, Left quadrants of the same patient depicted in A. Note the similar pattern of bone loss in the
area of the ﬁrst molars and incisors. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 175
this ﬁnding has been disputed. The rate of bone destruc-
tion is three to ﬁve times faster than that seen in chronic
periodontitis.
In the ﬁrst molar regions, radiographs reveal verti-
cal bone resorption that often is bilateral and symmet-
rical. In classic cases an arc-shaped zone of bone loss
extends from the distal aspect of the second bicuspid
to the mesial aspect of the second molar. Similar
involvement is apparent around the anterior teeth.
Tooth migration and mobility are common. If untreated,
then the process often continues until the teeth are
exfoliated. In about one third of patients affected with
localized aggressive periodontitis, progression to more
generalized disease occurs.
Of all the pathogens in dental plaque, A. actinomy-
cetemcomitans appears to be predominant in localized
aggressive periodontitis. This bacterium is present
in disease sites in more than 90% of cases. Its ability
to invade gingival tissue has created difﬁculties in
mechanical eradication. Knowledge of its importance
to the disease process has led to remarkable advances
in therapy.
GENERALIZED AGGRESSIVE PERIODONTITIS
Generalized aggressive periodontitis may not rep-
resent a distinct disease entity but, rather, may occur
in a collection of young adults with advanced periodon-
tal disease. Many cases may represent localized aggres-
sive periodontitis that has become more generalized
with time; other cases initially demonstrate general-
ized disease. As with the localized variant, a signiﬁcant
percentage of cases demonstrate neutrophil dysfunc-
tion. The American Academy of Periodontology recog-
nizes the following features:
●Usually diagnosed in patients younger than 30 years
old but may occur at any age
●Poor serum antibody response to infecting agents
●Pronounced episodic destruction of periodontal
attachment and alveolar bone
●Generalized loss of attachment that must affect at
least three teeth other than the ﬁrst molars and
incisors
Most affected patients are between the ages of 12
and 32. In contrast to many examples of the localized
variant, heavy plaque, calculus, and marked gingival
inﬂammation may be present. Compared with the
localized variant, more teeth are affected and the bone
loss is not restricted to speciﬁc areas of the jaws.
Although the localized pattern is associated primar-
ily with A. actinomycetemcomitans, the pathogens active
in the generalized variant are more complex, more
closely aligned to chronic periodontitis, and also involve
organisms such as Prevotella intermedia, Porphyromonas
gingivalis, Tannerella forsythensis, Fusobacterium nuclea-
tum, Campylobacter rectus, and various spirochetes. In
patients whose disease progresses from the localized to
generalized pattern, the associated periodontal patho-
gens often become more diverse as the patient ages
and the disease becomes more widespread.
HISTOPATHOLOGIC FEATURES
The microscopic examination of granulation tissue
removed from sites of aggressive periodontitis does not
differ dramatically from that seen in chronic periodon-
titis. In spite of this, initial histopathologic examination
of the material removed from active sites of disease is
mandatory to rule out the possibility of other disease
processes, such as Langerhans cell disease (see page
590). Even when the attachment loss presents in a
classic localized pattern, systemic disease cannot be
eliminated without an examination of tissue. The deﬁn-
itive diagnosis centers on the clinical, radiographic,
histopathologic, and microbiologic ﬁndings, combined
with the family history and leukocyte function tests.
TREATMENT AND PROGNOSIS
Unlike the treatment used for patients with chronic
periodontitis, scaling and root planing alone do not
stop progression of aggressive periodontitis. The defects
in leukocyte function, in addition to the invasive capa-
bilities of the involved pathogenic organisms, mandate
the use of antibiotics in combination with mechanical
removal of subgingival plaque and inﬂamed periodon-
tal tissues. Although tetracycline, amoxicillin and cla-
vulanate potassium, minocycline, and erythromycin
can be used in selected patients, the combination of
high-dose (500 mg three times per day) amoxicillin
and metronidazole has been shown to be most effective
in controlling the involved periodontal pathogens,
especially A. actinomycetemcomitans. Therapy often is
predicated on microbiologic testing to ensure selection
of the most appropriate antimicrobial agent. Some
investigators have claimed better results if the scaling
and root planing are completed within a 24-hour
period, rather than treating a quadrant at a time over
an extended period. Reinfection of previously cleaned
areas by organisms from untreated sites is thought to
worsen the response to therapy.
A reevaluation with professional prophylaxis is per-
formed once a month for 6 months and then every 3
months thereafter. Specimens for anaerobic cultures
are obtained at each 3-month recall. Patients with
refractory disease or signiﬁcant colonization by patho-
genic organisms receive additional courses of appro-
priate antibiotics. Long-term follow-up is mandatory
because of the possibility of reinfection or incomplete `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

176 ORAL AND MAXILLOFACIAL PATHOLOGY
elimination of the organisms. The presence of deep
residual pockets is associated with disease progression.
In such circumstances, periodontal surgery often is
performed to eliminate these defects. This intervention
is directed at any pocket consistently deeper than
5 mm and typically is performed after 2 to 6 months
of nonsurgical therapy.
Dental practitioners should alert proband patients
with aggressive periodontitis of the possible genetic
transmission of the disease process. In general, patients
diagnosed with localized aggressive periodontitis typi-
cally exhibit relatively stable disease, whereas those
initially diagnosed with generalized involvement often
continue to lose periodontal attachment and teeth.
Patients who smoke and those who present for therapy
with advanced clinical attachment loss tend to demon-
strate a worse prognosis and respond less reliably to
therapy.
PAPILLON-LEFÈVRE SYNDROME
In 1924, Papillon and Lefèvre initially described the
syndrome that bears their names. This autosomal reces-
sive disorder predominantly demonstrates oral and
dermatologic manifestations; similar dermatologic
changes can be seen in the absence of oral ﬁndings
(keratoderma palmoplantar of Unna-Thost syn-
drome and Meleda disease). Because of the autoso-
mal recessive inheritance pattern, the parents typically
are not affected; consanguinity is noted in approxi-
mately one third of cases. The predominant oral ﬁnding
is accelerated periodontitis that appears to be caused
by defects in neutrophil function and multiple immune-
mediated mechanisms.
Genetic studies of patients with Papillon-Lefèvre
syndrome have mapped the major gene locus to chro-
mosome 11q14-q21 and revealed mutation and loss of
function of the cathepsin C gene. This gene is impor-
tant in the structural growth and development of the
skin and is critical for appropriate immune response of
myeloid and lymphoid cells. Researchers believe that
the loss of appropriate function of the cathepsin C gene
results in an altered immune response to infection. In
addition, the altered gene may affect the integrity of the
junctional epithelium surrounding the tooth.
A closely related disease, Haim-Munk syndrome,
also exhibits palmoplantar keratosis, progressive peri-
odontal disease, recurrent skin infections, and several
skeletal malformations. In this syndrome, the skin
manifestations are more severe and the periodontal
disease is milder. Studies have demonstrated that
Haim-Munk syndrome and many examples of prepu-
bertal periodontitis also exhibit mutation of the cathep-
sin C gene and represent allelic variants of the mutated
gene responsible for Papillon-Lefèvre syndrome.
CLINICAL AND RADIOGRAPHIC
FEATURES
Papillon-Lefèvre syndrome exhibits a prevalence of
one to four per million people in the population, and
carriers are thought to be present in two to four per
thousand persons. In most cases, the dermatologic
manifestations become clinically evident in the ﬁrst 3
years of life. Diffuse transgredient (ﬁrst occurs on the
palms and soles and then spreads to the dorsa of the
hands and feet) palmar-plantar keratosis develops,
with occasional reports of diffuse follicular hyperkera-
tosis, nail dystrophy, hyperhidrosis, and keratosis on
the elbows and knees (Fig. 4-36). Other less common
sites of involvement include the legs, thighs, dorsal
surface of the ﬁngers and toes, and (rarely) the trunk.
Although the appearance of the dermatologic manifes-
tations is variable, the lesions typically present as white,
light-yellow, brown, or red plaques and patches that
develop crusts, cracks, or deep ﬁssures. Some patients
describe worsening in the winter, and others describe
keratotic desquamation, which may be confused with
psoriasis.
The oral manifestations consist of dramatically
advanced periodontitis that is seen in both the decidu-
ous and the permanent dentitions and develops soon
after the eruption of the teeth. Extensive hyperplastic
and hemorrhagic gingivitis is seen (Fig. 4-37). A rapid
loss of attachment occurs, with the teeth soon lacking
osseous support and radiographically appearing to
Fig. 4-36 Papillon-Lefèvre syndrome. Plantar keratosis of
the foot. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 177
ﬂoat in the soft tissue (Fig. 4-38). Without aggressive
therapy, the loss of the dentition is inevitable. Mobility
and migration of the teeth are observed consistently,
and mastication often is painful because of the lack of
support. The teeth spontaneously exfoliate or are
removed because of sensitivity during function. This
process prematurely eliminates the deciduous denti-
tion; with eruption of the permanent teeth, the destruc-
tive pattern is duplicated. When the teeth are absent,
the alveolar mucosa is normal in appearance.
Although other pathogenic bacteria have been iso-
lated from sites of active disease, Actinobacillus actino-
mycetemcomitans has been related directly to the
periodontal destruction. Although a hereditary compo-
nent exists and leukocyte dysfunction can be demon-
strated, it appears that an infection with a speciﬁc,
potent bacterium, such as A. actinomycetemcomitans,
must be present for the periodontal component to
develop. Interestingly, one investigation documented
the development of appropriate peripheral leukocyte
function after successful resolution of the pathogenic
organisms responsible for the periodontitis. This indi-
cates that the leukocyte dysfunction may be induced
by infection with A. actinomycetemcomitans (possibly
secondary to generated leukotoxins).
In addition to the dermatologic and oral manifesta-
tions, numerous investigators have documented less
frequent ﬁndings. Retardation of somatic development
and ectopic calciﬁcations of the falx cerebri and choroid
plexus have been reported, in addition to an increased
susceptibility to infections beyond the oral cavity. Pyo-
derma, furunculosis, pneumonia, hepatic abscesses,
and other infections have been documented.
HISTOPATHOLOGIC FEATURES
Once again, the histopathologic features of Papillon-
Lefèvre syndrome resemble those seen in chronic
periodontitis and are not speciﬁc. Submitted tissue
often contains hyperplastic crevicular epithelium with
exocytosis. The underlying connective tissue exhibits
increased vascularity and a mixed inﬂammatory cellu-
lar inﬁltrate consisting predominantly of polymorpho-
nuclear leukocytes, lymphocytes, histiocytes, and
plasma cells. Initially, histopathologic examination is
recommended to rule out other pathologic causes of
the periodontal destruction.
TREATMENT AND PROGNOSIS
The most successful treatment of the skin lesions has
been retinoid (e.g., etretinate) administration, which
has resulted in remarkable improvement with com-
plete clearance in the majority of patients. Surprisingly,
a few authors have reported improvement of the asso-
ciated periodontal disease during periods of retinoid
use, but others have disputed this claim. Possible
adverse reactions caused by retinoid administration
include angular cheilitis, dry lips, hair loss, arthralgia,
tendinous and ligamentous calciﬁcations, and teratoge-
nicity. In an attempt to avoid these drug-related adverse
reactions, patients with mild dermatologic manifesta-
tions often are treated with topical lubricants, kerato-
lytic agents (salicylic or lactic acid), corticosteroid
agents, or antibiotics medications.
Attempts at resolution of the periodontal disease
often have been frustrating. In spite of extensive
periodontal therapy and antibiotic agents, in many
patients the disease progresses until all teeth are lost.
However, several investigators have reported a cessa-
tion of attachment loss, and two different treatment
approaches have been used.
Fig. 4-37 Papillon-Lefèvre syndrome. Generalized
erythematous gingivitis.
Fig. 4-38 Papillon-Lefèvre syndrome. Multifocal sites of
bone loss in all four quadrants. (From Giansanti JS, Hrabak RP,
Waldron CA: Palmoplantar hyperkeratosis and concomitant periodontal
destruction [Papillon-Lefèvre syndrome], Oral Surg Oral Med Oral Pathol
36:40, 1973.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

178 ORAL AND MAXILLOFACIAL PATHOLOGY
Despite the use of numerous antibiotic medications,
several reports document a difﬁculty in resolution of
the infection associated with teeth that already exhibit
attachment loss. In some of the cases, all of the peri-
odontally involved deciduous teeth were extracted, fol-
lowed by a period of edentulousness with antibiotic
treatment in an attempt to remove the causative patho-
gens. Tetracycline was successful in preventing the
redevelopment of periodontitis in the permanent teeth
after the extractions, as well as in the resolution of the
infection in the deciduous dentition. However, penicil-
lin, erythromycin, metronidazole, and tetracycline
were all unsuccessful in resolving active sites of
periodontitis.
The second approach revolves around direct attack
against A. actinomycetemcomitans. In numerous studies
of patients with destructive periodontitis associated
with A. actinomycetemcomitans, therapy with high-dose
amoxicillin and metronidazole has proven effective
when combined with high patient compliance and
strong supportive periodontal therapy. A variety of
other regimens have been used with variable success
in different geographic regions, suggesting the possibil-
ity of inconsistent effectiveness related to local patterns
of antibiotic resistance. It appears clear that elimina-
tion of A. actinomycetemcomitans and continued control
of plaque and calculus are mandatory, but the antibi-
otic agent best suited for this task can vary.
Through the use of mechanical plaque control and
appropriate antibiotic medications directed toward
A. actinomycetemcomitans, the course of the disease
might be altered. The progression of attachment loss is
slowed dramatically, and the teeth that erupt after the
initiation of therapy do not develop periodontal
destruction. Rigorous oral hygiene, chlorhexidine
mouth rinses, frequent professional prophylaxis, and
periodic appropriate antibiotic therapy are necessary
for long-term maintenance.
BIBLIOGRAPHY
General Reference
Newman MG, Takei H, Carranza FA et al: Clinical periodontology,
ed 10, Philadelphia, 2006, WB Saunders.
Gingivitis
American Academy of Periodontology: Parameter on plaque-
induced gingivitis, J Periodontol 71(suppl):851-852, 2000.
American Academy of Periodontology: Treatment of plaque-
induced gingivitis, chronic periodontitis, and other clinical
conditions, J Periodontol 72:1790-1800, 2001.
Fransson C, Berglundh T, Lindhe J: The effects of age on the
development of gingivitis. Clinical, microbiological and his-
tological ﬁndings, J Clin Periodontol 23:379-385, 1996.
Gunsolley JC: A meta-analysis of six-month studies of antiplaque
and antigingivitis agents, J Am Dent Assoc 137:1649-1657,
2006.
Löe H, Theilade E, Jensen SB: Experimental gingivitis in man,
J Periodontol 36:177-187, 1965.
Löe H, Theilade E, Jensen SB et al: Experimental gingivitis in
man. 3. Inﬂuence of antibiotics on gingival plaque develop-
ment, J Periodontol Res 2:282-289, 1967.
Moskow BS, Polson AM: Histologic studies on the extension of
the inﬂammatory inﬁltrate in human periodontitis, J Clin Peri-
odontol 18:534-542, 1991.
Schätzle M, Löe H, Lang NP et al: The clinical course of chronic
periodontitis. IV. Gingival inﬂammation as a risk factor in
tooth mortality, J Clin Periodontol 31:1122-1127, 2004.
Tatakis DN, Trombelli L: Modulation of clinical expression of
plaque-induced gingivitis. I. Background review and ratio-
nale, J Clin Periodontol 31:229-238, 2004.
Theilade E, Wright WH, Jensen SB et al: Experimental gingivitis
in man. II. A longitudinal clinical and bacteriologically inves-
tigation, J Periodontol Res 1:1-13, 1966.
Trombelli L: Susceptibility to gingivitis: a way to predict peri-
odontal disease? Oral Health Prev Dent 2(suppl 1):265-269,
2004.
Trombelli L, Scapoli C, Orlandini E et al: Modualtion of clinical
expression of plaque-induced gingivitis. III. Response of “high
responders” and “low responders” to therapy, J Clin Periodon-
tol 31:253-259, 2004.
Necrotizing Ulcerative Gingivitis
American Academy of Periodontology: Parameter on acute peri-
odontal diseases, J Periodontol 71(suppl):863-866, 2000.
Arendorf TM, Bredekamp B, Cloete C-A: Seasonal variation of
acute necrotising ulcerative gingivitis in South Africans, Oral
Dis 7:150-154, 2001.
Contreras A, Falkler Jr WA, Enwonwu C et al: Human herpesviri-
dae in acute necrotizing ulcerative gingivitis in children in
Nigeria, Oral Microbiol Immuol 12:259-265, 1997.
Hartnett AC, Shiloah J: The treatment of acute necrotizing ulcer-
ative gingivitis, Quintessence Int 22:95-100, 1991.
Horning GM: Necrotizing gingivostomatitis-NUG to noma,
Compend Contin Educ Dent 17:951-962, 1996.
Horning GM, Cohen ME: Necrotizing ulcerative gingivitis, peri-
odontitis, and stomatitis: clinical staging and predisposing
factors, J Periodontol 66:990-998, 1995.
Jiménez LM, Duque FL, Baer PN et al: Necrotizing ulcerative
periodontal diseases in children and young adults in Medel-
lín, Columbia, 1965-2000, J Int Acad Periodontol 7:55-63,
2005.
Johnson BD, Engel D: Acute necrotizing ulcerative gingivitis: a
review of diagnosis, etiology and treatment, J Periodontol
57:141-150, 1986.
Rowland RW: Necrotizing ulcerative gingivitis, Ann Periodontol
4:65-73, 1999.
Wade DN, Kerns DG: Acute necrotizing ulcerative gingivitis-
periodontitis: a literature review, Mil Med 5:337-342,
1998.
Plasma Cell Gingivitis
Kerr DA, McClatchey KD, Regezi JA: Allergic gingivostomatitis
(due to gum chewing), J Periodontol 42:709-712, 1971.
Kerr DA, McClatchey KD, Regezi JA: Idiopathic gingivostomati-
tis: cheilitis, glossitis, gingivitis syndrome: atypical gingivosto-
matitis plasma-cell gingivitis, plasmacytosis of gingiva, Oral
Surg Oral Med Oral Pathol 32:402-423, 1971.
Lubow RM, Cooley RL, Hartman KS et al: Plasma-cell gingivo-
stomatitis: report of a case, J Periodontol 55:235-241, 1984.
MacLeod RL, Ellis JE: Plasma cell gingivitis related to the use of
herbal toothpaste, Br Dent J 166:375-376, 1989.
Mahler V, Hornstein OP: Plasma cell gingivitis: treatment with
2% fusidic acid, J Am Acad Dermatol 34:145-146, 1996. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 4 PERIODONTAL DISEASES 179
Marker P, Krogdahl A: Plasma cell gingivitis apparently related
to the use of khat: report of a case, Br Dent J 192:311-313,
2002.
Owings JR: An atypical gingivostomatitis: report of four cases, J
Periodontol 40:538-542, 1969.
Perry HO, Deffner NF, Sheridan PJ: Atypical gingivostomatitis:
nineteen cases, Arch Dermatol 107:872-878, 1973.
Serio FG, Siegel MA: Plasma cell gingivitis of unusual origin:
report of a case, J Periodontol 62:390-393, 1991.
Silverman S Jr, Lozada F: An epilogue to plasma-cell gingivosto-
matitis (allergic gingivostomatitis), Oral Surg Oral Med Oral
Pathol 43:211-217, 1977.
Sollecito TP, Greenberg MS: Plasma cell gingivitis: report of two
cases, Oral Surg Oral Med Oral Pathol 73:690-693, 1992.
Timms MS, Sloan P: Association of supraglottic and gingival idio-
pathic plasmacytosis, Oral Surg Oral Med Oral Pathol 71:451-
453, 1991.
Granulomatous Gingivitis
Daley TD, Wysocki GP: Foreign body gingivitis: an iatrogenic
disease? Oral Surg Oral Med Oral Pathol 69:708-712, 1990.
Gordon SC, Daley TD: Foreign body gingivitis: clinical and
microscopic features of 61 cases, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 83:562-570, 1997.
Gordon SC, Daley TD: Foreign body gingivitis: identiﬁcation of
the foreign material by energy-dispersive x-ray microanalysis,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:571-576,
1997.
Gravitis K, Daley TD, Lochhead MA: Management of patients
with foreign body gingivitis: report of 2 cases with histologic
ﬁndings, J Can Dent Assoc 71:105-109, 2005.
Koppang HS, Roushan A, Sraﬁlzadeh A et al: Foreign body gin-
gival lesions: distribution, morphology, identiﬁcation by x-ray
energy dispersive analysis and possible origin of foreign
material, J Oral Pathol Med 36:161-172, 2007.
Lombardi T, Kuffer R, Dubrez B: Polishing-paste-induced silica
granuloma of the gingiva, Dermatology 203:177-179, 2001.
Mignogna MD, Fedele S, LoRusso L et al: Orofacial granulomato-
sis with gingival onset, J Clin Periodontol 28:692-696, 2001.
Drug-Related Gingival Hyperplasia
American Academy of Periodontology: Informational paper.
Drug-associated gingival enlargement, J Periodontol 75:1424-
1431, 2004.
Botha PJ: Drug-induced gingival hyperplasia and its manage-
ment—a literature review, J Dent Assoc S Afr 52:659-664,
1997.
Brunet L, Miranda J, Farré M et al: Gingival enlargement induced
by drugs, Drug Saf 15:219-231, 1996.
Butler RT, Kalkwarf KL, Kaldahl WB: Drug-induced gingival
hyperplasia: phenytoin, cyclosporine, and nifedipine, J Am
Dent Assoc 114:56-60, 1987.
Camargo PM, Melnick PR, Pirih FQM et al: Treatment of drug-
induced gingival enlargement: aesthetic and functional con-
siderations, Periodontol 2000 27:131-138, 2001.
Desai P, Silver JG: Drug-induced gingival enlargements, J Can
Dent Assoc 64:263-268, 1998.
Dongari A, McDonnell HT, Langlais RP: Drug-induced gingival
overgrowth, Oral Surg Oral Med Oral Pathol 76:543-548,
1993.
Eggerath J, English H, Leichter JW: Drug-associated gingival
enlargement: case report and review of aetiology, manage-
ment and evidenced-based outcomes of treatment, J N Z Soc
Periodontol 88:7-14, 2005.
Hall EE: Prevention and treatment considerations in patients
with drug-induced gingival enlargement, Curr Opin Periodon-
tol 4:59-63, 1997.
Hassell TM, Hefti AF: Drug-induced gingival overgrowth: old
problem, new problem, Crit Rev Oral Biol Med 2:103-137,
1991.
McCulloch CA: Drug-induced ﬁbrosis: interference with intra-
cellular collagen degradation pathway, Curr Opin Drug Discov
Devel 7:720-724, 2004.
Meisel P, Schwahn C, John U et al: Calcium antagonists and deep
gingival pockets in the population-based SHIP study, Br J Clin
Pharmacol 60:552-559, 2005.
Woo S-B, Allen CM, Orden A et al: Non-gingival soft tissue over-
growths after allogeneic marrow transplantation, Bone Marrow
Transplant 17:1127-1132, 1996.
Gingival Fibromatosis
Coletta RD, Graner E: Hereditary gingival ﬁbromatosis: a sys-
tematic review, J Periodontol 77:753-764, 2006.
Hart TC, Zhang Y, Gorry MC et al: A mutation in the SOS1 gene
causes hereditary gingival ﬁbromatosis type 1, Am J Hum
Genet 70:943-954, 2002.
Jorgenson RJ, Cocker ME: Variation in the inheritance and
expression of gingival ﬁbromatosis, J Periodontol 45:472-477,
1974.
Mangino M, Pizzuti A, Dallapiccola B et al: Hereditary gingival
ﬁbromatosis (HGF) with hypertrichosis is unlinked to the
HGF1 and HGF2 loci, Am J Med Genet 116A:312-314,
2003.
Rushton MA: Hereditary or idiopathic hyperplasia of the gums,
Dent Pract Dent Rec 7:136-146, 1957.
Shashi V, Pallos D, Pettenati MJ et al: Genetic heterogeneity of
gingival ﬁbromatosis on chromosome 2p, J Med Genet 36:683-
686, 1999.
Takagi M, Yamamoto H, Mega H et al: Heterogeneity in the gin-
gival ﬁbromatoses, Cancer 68:2202-2212, 1991.
Xiao S, Bu L, Zhu L et al: A new locus for hereditary gingival
ﬁbromatosis (GINGF2) maps to 5q13-q22, Genomics 74:180-
185, 2001.
Ye X, Shi L, Cheng Y et al: A novel locus for autosomal dominant
hereditary gingival ﬁbromatosis, GINGF3, maps to chromo-
some 2q22.3-p23.3, Clin Genet 68:239-244, 2005.
Periodontitis
Albandar JM: Global risk factors and risk indicators for periodon-
tal diseases, Periodontol 2000 29:177-206, 2002.
American Academy of Periodontology: Position paper. Support-
ive periodontal therapy (SPT), J Periodontol 69:502-506,
1998.
American Academy of Periodontology: Parameter on acute peri-
odontal diseases, J Periodontol 71:863-866, 2000.
American Academy of Periodontology: Parameter on “refrac-
tory” periodontitis, J Periodontol 71:859-860, 2000.
American Academy of Periodontology: Informational paper.
Modulation of the host response in periodontal therapy, J
Periodontol 73:460-470, 2003.
American Academy of Periodontology: Position paper. Diagnosis
of periodontal diseases, J Periodontol 74:1237-1247, 2003.
American Academy of Periodontology: Informational paper.
Implications of genetic technology for the management of
periodontal diseases, J Periodontol 76:850-857, 2005.
American Academy of Periodontology: Position paper. Epidemi-
ology of periodontal diseases, J Periodontol 76:1406-1419,
2005.
Armitage G: Development of a classiﬁcation system for peri-
odontal diseases and conditions, Ann Periodontol 4:1-6,
1999.
Bataineh AB, Al Qudah MA: The predisposing factors of peri-
coronitis of mandibular third molars in a Jordanian popula-
tion, Quintessence Int 34:227-231, 2003. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
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180 ORAL AND MAXILLOFACIAL PATHOLOGY
Cappuyns I, Gugerli P, Mombelli A: Viruses in periodontal
disease—a review, Oral Dis 11:219-229, 2005.
Corbet EF: Diagnosis of acute periodontal lesions, Periodontol
2000 34:204-216, 2004.
Gaggl AJ, Rainer H, Grund E et al: Local oxygen therapy for
treating acute necrotizing periodontal disease in smokers, J
Periodontol 77:31-38, 2006.
Greenstein G: Periodontal response to mechanical non-surgical
therapy: a review, J Periodontol 63:118-130, 1992.
Dentino AR, Kassab MW, Renner EJ: Prevention of periodontal
diseases, Dent Clin North Am 49:573-594, 2005.
Ismail AI, Morrison EC, Burt BA et al: Natural history of peri-
odontal disease in adults: ﬁndings from the Tecumseh peri-
odontal disease study, 1959-87, J Dent Res 69:430-435,
1990.
Kinane DF, Hart TC: Genes and genetic polymorphisms associ-
ated with periodontal disease, Crit Rev Oral Biol Med 14:430-
449, 2003.
Lindhe J, Nyman S: Long-term maintenance of patients treated
for advanced periodontal disease, J Clin Periodontol 11:504-
514, 1984.
Loos BG, John RP, Laine ML: Identiﬁcation of genetic risk factors
for periodontitis and possible mechanisms of action, J Clin
Periodontol 32(suppl 6):159-179, 2005.
Meng HX: Periodontal abscess, Ann Periodontol 4:79-82, 1999.
Minsk L: Diagnosis and treatment of acute periodontal condi-
tions, Compend Contin Educ Dent 27:8-11, 2006.
Newman HN: Plaque and chronic inﬂammatory periodontal
disease: a question of ecology, J Clin Periodontol 17:533-541,
1990.
Novak MJ: Necrotizing ulcerative periodontitis, Ann Periodontol
4:74-77, 1999.
Preshaw PM, Seymour RA, Heasman PA: Current concepts in
periodontal pathogenesis, Dent Update 21:570-578, 2004.
Rees JS, Midda M: Update on periodontology: 1. Current con-
cepts in the histopathology of periodontal disease, Dent Update
18:418-422, 1991.
Scannapieco FA: Systemic effects of periodontal diseases, Den
Clin North Am 49:533-550, 2005.
Slots J: Herpesviruses in periodontal diseases, Periodontol 2000
38:33-62, 2005.
Tatakis DN, Kumar PS: Etiology and pathogenesis of periodontal
diseases, Dent Clin North Am 49:491-516, 2005.
Tonetti MS, D’Aiuto F, Nibali L et al: Treatment of periodontitis
and endothelial function, N Engl J Med 35:911-920, 2007.
Aggressive Periodontitis
Albandar JM, Brown LJ, Genco RJ et al: Clinical classiﬁcation of
periodontitis in adolescents and young adults, J Periodontol
68:545-555, 1997.
American Academy of Periodontology: Parameter on aggressive
periodontitis, J Periodontol 71:867-869, 2000.
American Academy of Periodontology: Position paper. Periodon-
tal diseases of children and adolescents, J Periodontol 74:1696-
1704, 2003.
Armitage GC: Development of a classiﬁcation system for peri-
odontal diseases and conditions, Ann Periodontol 4:1-6,
1999.
Donly KJ, Ashkenazi M: Juvenile periodontitis: a review of patho-
genesis, diagnosis and treatment, J Clin Pediatr Dent 16:73-78,
1992.
Guerrero A, Grifﬁths GS, Nibali L et al: Adjunctive beneﬁts of
systemic amoxicillin and metronidazole in non-surgical treat-
ment of generalized aggressive periodontitis: a randomized
placebo-controlled clinical trial, J Clin Periodontol 32:1096-
1107, 2005.
Hughes FJ, Syed M, Koshy B et al: Prognostic factors in the treat-
ment of generalized aggressive periodontitis: I. Clinical fea-
tures and initial outcome, J Clin Periodontol 33:663-670,
2006.
Kamma JJ, Slots J: Herpesviral-bacterial interactions in aggres-
sive periodontitis, J Clin Periodontol 30:420-426, 2003.
Kinane DF, Hart TC: Genes and genetic polymorphisms associ-
ated with periodontal disease, Crit Rev Oral Biol Med 14:430-
449, 2003.
Lindhe J, Liljenberg B: Treatment of localized juvenile periodon-
titis: results after 5 years, J Clin Periodontol 11:399-410,
1984.
Löe H, Brown LJ: Early onset periodontitis in the United States
of America, J Periodontol 62:608-616, 1991.
Mongardini C, van Steenberghe D, Dekeyser C et al: One stage
full- versus partial-mouth disinfection in the treatment of
chronic adult or generalized early-onset periodontitis. I.
Long-term clinical observations, J Periodontol 70:632-645,
1999.
Novak MJ, Novak KF: Early-onset periodontitis, Curr Opin Peri-
odontol 3:45-58, 1996.
Tonetti MS, Mombelli A: Early-onset periodontitis, Ann Periodon-
tol 4:39-52, 1999.
Xajigeorgiou C, Sakellari D, Slini T et al: Clinical and microbio-
logical effects of different antimicrobials on generalized
aggressive periodontitis, J Clin Periodontol 33:254-264,
2006.
Papillon-Lefèvre Syndrome
Ahuja V, Shin RH, Mudgil A et al: Papillon-Lefèvre syndrome: a
successful outcome, J Periodontol 76:1996-2001, 2005.
Gorlin RJ, Sedano H, Anderson VE: The syndrome of palmar-
plantar hyperkeratosis and premature destruction of the
teeth: a clinical and genetic analysis of the Papillon-Lefèvre
syndrome, J Pediatr 65:895-908, 1964.
Hart TC, Hart PS, Bowden DW et al: Mutations of the cathepsin
C gene are responsible for Papillon-Lefèvre syndrome, J Med
Genet 36:881-887, 1999.
Hart TC, Hart PS, Michalec M et al: Haim-Munk syndrome and
Papillon-Lefèvre syndrome are allelic mutations in cathepsin
C, J Med Genet 37:88-94, 2000.
Hattab FN, Amin WM: Papillon-Lefèvre syndrome with albi-
nism: a review of the literature and report of 2 brothers, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 100:709-716,
2005.
Hewitt C, McCormick D, Linden G: The role of cathepsin C in
Papillon-Lefèvre syndrome, prepubertal periodontitis, and
aggressive periodontitis, Hum Mutat 23:222-228, 2004.
Lundgren T, Crossner C-G, Twetman S et al: Systemic retinoid
medication and periodontal health in patients with Papillon-
Lefèvre syndrome, J Clin Periodontol 23:176-179, 1996.
Noack B, Görgens H, Hoffmann TH et al: Novel mutations in the
cathepsin C gene in patients with pre-pubertal aggressive peri-
odontitis and Papillon-Lefèvre syndrome, J Dent Res 83:368-
370, 2004.
Pacheco JJ, Coelho C, Salazar F et al: Treatment of Papillon-
Lefèvre syndrome periodontitis, J Clin Periodontol 29:370-
374, 2002.
Wiebe CB, Häkkinen L, Putnins EE et al: Successful periodontal
maintenance of a case with Papillon-Lefèvre syndrome: 12-
year follow-up and review of the literature, J Periodontol
72:824-830, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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181
5
Bacterial Infections
CHAPTER OUTLINE
Impetigo
Erysipelas
Streptococcal Tonsillitis and Pharyngitis
Scarlet Fever
Tonsillar Concretions and Tonsillolithiasis
Diphtheria
Syphilis
ously damaged sites such as scratches or abrasions.
Often, facial lesions will have a linear pattern that cor-
responds to previous ﬁngernail scratches. The infec-
tion is more prevalent in school-aged children but
also may be seen in adults. The peak occurrence is
during the summer or early fall in hot, moist climates.
Impetigo is contagious and easily spread in crowded or
unsanitary living conditions.
Nonbullous impetigo initially appears as red macules
or papules, with the subsequent development of fragile
vesicles. These vesicles quickly rupture and become
covered with a thick, amber crust (Fig. 5-1). The crusts
are adherent and have been described as “cornﬂakes
glued to the surface.” Some cases may be confused with
exfoliative cheilitis (see page 304) or recurrent herpes
simplex (see page 243). Pruritus is common, and
scratching often causes the lesions to spread (Fig. 5-2).
Lymphangitis, cellulitis, fever, anorexia, and malaise
are uncommon, although leukocytosis occurs in about
half of affected patients.
Bullous impetigo usually is caused by S. aureus and
also has been termed staphylococcal impetigo. Like
the nonbullous form, it most frequently affects the
extremities, trunk, and face. Infants and newborns are
infected most commonly, but the disease also may
occur in children and adults. The lesions are character-
ized by superﬁcial vesicles that rapidly enlarge to form
larger ﬂaccid bullae. Initially, the bullae are ﬁlled with
IMPETIGO
Impetigo is a superﬁcial infection of the skin that is
caused by Streptococcus pyogenes (group A streptococ-
cus) and Staphylococcus aureus, either separately or
together. The term impetigo is derived from a Latin
word meaning “attack,” because of its common presen-
tation as a scabbing eruption. Two clinically distinctive
patterns are seen, nonbullous impetigo and bullous
impetigo. Intact epithelium is normally protective
against infection; therefore, many cases arise in
damaged skin such as preexisting dermatitis, cuts,
abrasions, or insect bites. Secondary involvement of an
area of dermatitis has been termed impetiginized
dermatitis. An increased prevalence is associated with
debilitating systemic conditions such as human immu-
nodeﬁciency virus (HIV) infection, type 2 diabetes
mellitus, or dialysis.
CLINICAL FEATURES
Nonbullous impetigo (impetigo contagiosa) is the
more prevalent pattern and occurs most frequently on
the legs, with less common involvement noted on the
trunk, scalp, or face. The facial lesions usually develop
around the nose and mouth. In many patients with
facial involvement, the pathogenic bacteria are har-
bored in the nose and spread onto the skin into previ-
Gonorrhea
Tuberculosis
Leprosy
Noma
Actinomycosis
Cat-Scratch Disease
Sinusitis `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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182 ORAL AND MAXILLOFACIAL PATHOLOGY
clear serous ﬂuid, but the contents of the bullae quickly
become more turbid and eventually purulent. Although
the bullae may remain intact, they usually rupture and
develop a thin brown crust that some describe as
“lacquer.” Weakness, fever, and diarrhea may be seen.
Lymphadenopathy and cellulitis are unusual complica-
tions. Meningitis and pneumonia are very rare but may
lead to serious complications, even death.
DIAGNOSIS
A strong presumptive diagnosis can normally be made
from the clinical presentation. When the diagnosis is
not obvious clinically or the infection fails to respond
to standard therapy within 7 days, the deﬁnitive diag-
nosis requires isolation of S. pyogenes or S. aureus from
cultures of involved skin.
TREATMENT AND PROGNOSIS
For patients with nonbullous impetigo involving only a
small area with few lesions, topical mupirocin has been
shown to be effective. Fusidic acid (available in Europe,
not in the United States) also has been very effective;
however, increasing reports of resistance are diminish-
ing its use. Removal of the crusts with a clean cloth
soaked in warm soapy water is recommended before
application of topical therapy, rather than placing the
medication on inert, dried, exfoliating skin. For bullous
or more extensive lesions, topical antibiotic drugs often
are insufﬁcient; the treatment of choice is a 1-week
course of a systemic oral antibiotic. The best antibiotic
is one that is effective against both S. pyogenes and peni-
cillin-resistant S. aureus. Cephalexin, trimethoprim-
sulfamethoxazole, dicloxacillin, ﬂucloxacillin, and
amoxicillin-clavulanic acid represent good current
choices. Erythromycin or clindamycin can be used
in patients sensitive to penicillin, but resistance by
S. aureus to erythromycin has become an increasing
problem. If left untreated, then the lesions often enlarge
slowly and spread. Serious complications, such as acute
glomerulonephritis, are rare but possible in prolonged
cases. Inappropriate diagnosis and treatment with
topical corticosteroids may produce resolution of the
surface crusts, but infectious, red, raw lesions remain.
ERYSIPELAS
Erysipelas is a superﬁcial skin infection most
commonly associated with β-hemolytic streptococci
(usually group A, such as Streptococcus pyogenes, but
occasionally other groups such as group C, B, or G).
Other less common causative organisms include Staph-
ylococcus aureus, Streptococcus pneumoniae (i.e., pneumo-
coccus), Klebsiella pneumoniae, Yersinia enterocolitica, and
Haemophilus inﬂuenzae. The infection rapidly spreads
through the lymphatic channels, which become ﬁlled
with ﬁbrin, leukocytes, and streptococci. Although also
associated with ergotism, the term Saint Anthony’s ﬁre
has been used to describe erysipelas. Because the
French House of St. Anthony, an eleventh-century
hospital, had ﬁery red walls similar to the color of
erysipelas, the term Saint Anthony’s ﬁre was used to
describe this disease. Today, classical facial erysipelas
is a rare and often forgotten diagnosis. At times, the
appropriate diagnosis has been delayed because of
confusion with facial cellulitis from dental infections.
CLINICAL FEATURES
Erysipelas tends to occur primarily in young and older
adult patients or in those who are debilitated, diabetic,
immunosuppressed, obese, or alcoholic. Patients who
Fig. 5-1 Impetigo. Amber crusts of the skin and vermilion
border of the lips.
Fig. 5-2 Impetigo. Scaly and amber-colored crusts of the
perioral skin. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 183
have areas of chronic lymphedema or large surgical
scars (such as postmastectomy or saphenous venec-
tomy) also are susceptible to this disease. The infection
may occur anywhere on the skin, especially in areas of
previous trauma. The most commonly affected site is
the leg in areas affected by tinea pedis (athlete’s foot).
The face, arm, and upper thigh also frequently are
infected. In facial erysipelas, an increased prevalence
is noted in the winter and spring months, whereas
summer is the peak period of involvement of the lower
extremities.
When lesions occur on the face, they normally
appear on the cheeks, eyelids, and bridge of the nose,
at times producing a butterﬂy-shaped lesion that may
resemble lupus erythematosus (see page 794). If the
eyelids are involved, then they may become edematous
and shut, thereby resembling angioedema (see page
356). The affected area is painful, bright red, well cir-
cumscribed, swollen, indurated, and warm to the touch
(Fig. 5-3). Often the affected skin will demonstrate a
surface texture that resembles an orange peel (peau
d’orange). High fever and lymphadenopathy often are
present. Lymphangitis, leukocytosis, nausea, and vom-
iting occur infrequently. Diagnostic conﬁrmation is dif-
ﬁcult because cultures usually are not beneﬁcial.
TREATMENT AND PROGNOSIS
The treatment of choice is penicillin. Alternative anti-
biotic drugs include macrolides such as erythromycin,
cephalosporins such as cephalexin, and ﬂuoroquino-
lones such as ciproﬂoxacin. On initiation of therapy,
the area of skin involvement often enlarges, probably
secondary to the release of toxins from the dying strep-
tococci. A rapid resolution is noted within 48 hours.
Without appropriate therapy, possible complications
include abscess formation, gangrene, necrotizing fasci-
itis, toxic shock syndrome with possible multiple organ
failure, thrombophlebitis, acute glomerulonephritis,
septicemia, endocarditis, and death. Recurrences may
develop in the same area, most likely in a previous zone
of damaged lymphatics or untreated athlete’s foot.
With repeated recurrences, permanent and disﬁgur-
ing enlargements may result. In cases with multiple
recurrences, prophylaxis with oral penicillin has been
used.
STREPTOCOCCAL TONSILLITIS
AND PHARYNGITIS
Tonsillitis and pharyngitis are extremely common
and may be caused by many different organisms. The
most common causes are group A, β-hemolytic strep-
tococci, adenoviruses, enteroviruses, inﬂuenza, parain-
ﬂuenza, and Epstein-Barr virus. Although a virus causes
the majority of pharyngitis cases, infection with group
A streptococci is responsible for 15% to 30% of acute
pharyngitis cases in children and 5% to 10% of cases in
adults. Adults who are parents of school-aged children
or work in close association with children are at
increased risk for developing this infection. Spread is
typically by person-to-person contact through respira-
tory droplets or oral secretions, with a short incubation
period of 2 to 5 days. Uncommonly, outbreaks of strep-
tococcal pharyngitis have been associated with con-
taminated food, often inappropriately handled cold
salads containing foodstuffs such as eggs, mayonnaise,
tuna, potatoes, or cheese.
CLINICAL FEATURES
Although the infection can occur at any age, the great-
est prevalence occurs in children 5 to 15 years old,
with most cases in temperate climates arising in the
winter or early spring. The signs and symptoms of ton-
sillitis and pharyngitis vary from mild to intense.
Common ﬁndings include sudden onset of sore throat,
temperature of 101º to 104º F, dysphagia, tonsillar
hyperplasia, redness of the oropharynx and tonsils,
palatal petechiae, cervical lymphadenopathy, and a
yellowish tonsillar exudate that may be patchy or
Fig. 5-3 Erysipelas. Red, swollen area of the left cheek.
(Courtesy Dr. Arthur Gonty). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

184 ORAL AND MAXILLOFACIAL PATHOLOGY
conﬂuent (Fig. 5-4). Other occasional ﬁndings include
a “beefy” red and swollen uvula, excoriated nares, and
a scarlatiniform rash (see next topic). Systemic symp-
toms, such as headache, malaise, anorexia, abdominal
pain, and vomiting, may be noted, especially in younger
children. Conjunctivitis, coryza (rhinorrhea), cough,
hoarseness, discrete ulcerative lesions, anterior
stomatitis, absence of fever, a viral exanthem, and
diarrhea typically are associated with the viral infec-
tions and normally are not present in streptococcal
pharyngotonsillitis.
DIAGNOSIS
Although the vast majority of pharyngitis cases are
caused by a viral infection, reviews have shown that
about 70% of adults in the United States receive antibi-
otic therapy. In an attempt to minimize overuse, anti-
biotics should not be prescribed without conﬁrmation
of bacterial infection. Except for very rare infections
such as Corynebacterium diphtheriae (see page 186) and
Neisseria gonorrhoeae (see page 193), antibiotics are of
no beneﬁt for acute pharyngitis except for those related
to group A streptococci.
Patients exhibiting features strongly suggestive of a
viral infection (see previous section) should not receive
antibiotic therapy or microbiologic testing for strepto-
coccal infection. Because the clinical features of strep-
tococcal pharyngitis overlap those of viral origin, the
diagnosis cannot be based solely on clinical features;
however, laboratory testing of all patients with sore
throat cannot be justiﬁed. Diagnostic testing is recom-
mended only for those patients with clinical and epi-
demiologic ﬁndings that suggest streptococcal infection
or for those in close contact with a well-documented
case. Although less sensitive than throat culture, rapid
antigen detection testing provides quick results and
exhibits good sensitivity and speciﬁcity. If negative
results are obtained in children, then conﬁrmatory
throat cultures should be performed.
TREATMENT AND PROGNOSIS
Streptococcal pharyngitis usually is self-limited and
resolves spontaneously within 3 to 4 days after onset of
symptoms. In addition to reducing the localized morbid-
ity of the infection, the main goals of therapy are to
prevent development of acute rheumatic fever and com-
plications such as peritonsillar or retropharyngeal
abscess, deep tissue cellulitis, toxic shock–like syndrome,
bacteremia, arthralgia, and acute glomerulonephritis.
Initiation of appropriate therapy within the ﬁrst 9 days
after development of the pharyngitis will prevent rheu-
matic fever. Patients are considered noncontagious 24
hours after initiation of appropriate antibiotic therapy.
Group A streptococci are uniformly sensitive to
penicillin. Although oral penicillin remains the therapy
of choice, amoxicillin and cephalosporin drugs such as
cephalexin, cefadroxil, cefuroxime, and cefprozil also
are effective. Erythromycin is used in patients who
have a known sensitivity to penicillin. Newer macro-
lides (e.g., clarithromycin, azithromycin) have similar
effectiveness but cause less gastrointestinal distress
when compared with erythromycin.
No single regimen eliminates pharyngeal patho-
genic streptococci in 100% of treated patients. Post-
therapeutic laboratory testing is recommended in
patients with a family history of rheumatic fever, during
outbreaks of acute rheumatic fever or streptococcal glo-
merulonephritis, during outbreaks of streptococcal
pharyngitis in semiclosed communities, and when “ping
pong” spread is occurring within a family. In these cases,
clindamycin or amoxicillin-clavulanic acid often is able
to clear the organism in patients who continue to dem-
onstrate positive culture after penicillin therapy.
SCARLET FEVER (SCARLATINA)
Scarlet fever is a systemic infection produced by group
A, β-hemolytic streptococci. The disease begins as a
streptococcal tonsillitis with pharyngitis in which the
organisms elaborate an erythrogenic toxin that attacks
the blood vessels and produces the characteristic skin
rash. The condition occurs in susceptible patients who
do not have antitoxin antibodies. The incubation period
ranges from 1 to 7 days, and the signiﬁcant clinical
ﬁndings include fever, enanthem, and exanthem.
CLINICAL FEATURES
Scarlet fever is most common in children from the ages
of 3 to 12 years. The enanthem of the oral mucosa
involves the tonsils, pharynx, soft palate, and tongue
Fig. 5-4 Tonsillitis. Hyperplastic pharyngeal tonsils, with
yellowish exudate of crypts. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 185
(see discussion of streptococcal pharyngotonsillitis in
previous section). The tonsils, soft palate, and pharynx
become erythematous and edematous, and the tonsil-
lar crypts may be ﬁlled with a yellowish exudate. In
severe cases, the exudates may become conﬂuent and
can resemble diphtheria (see page 186).
Scattered petechiae may be seen on the soft palate.
During the ﬁrst 2 days, the dorsal surface of the tongue
demonstrates a white coating through which only the
fungiform papillae can be seen; this has been called
white strawberry tongue (Fig. 5-5). By the fourth or
ﬁfth day, red strawberry tongue develops when the
white coating desquamates to reveal an erythematous
dorsal surface with hyperplastic fungiform papillae.
Classically, in untreated cases, fever develops
abruptly around the second day. The patient’s tempera-
ture peaks at approximately 103º F and returns to
normal within 6 days. The exanthematous rash devel-
ops within the ﬁrst 2 days and becomes widespread
within 24 hours. The classic rash of scarlet fever is
distinctive and often is described as “a sunburn with
goose pimples.” Pinhead punctate areas that are normal
in color project through the erythema, giving the skin
of the trunk and extremities a sandpaper texture. The
rash is more intense in areas of pressure and skin folds.
Often, transverse red streaks, known as Pastia’s lines,
occur in the skin folds secondary to the capillary fragil-
ity in these zones of stress. In contrast, the skin of the
face usually is spared or may demonstrate erythema-
tous cheeks with circumoral pallor.
The rash usually clears within 1 week, and then a
period of desquamation of the skin occurs. This scaling
begins on the face at the end of the ﬁrst week and
spreads to the rest of the skin by the third week, with
the extremities being the last affected. The desquama-
tion of the face produces small ﬂakes; the skin of the
trunk comes off in thicker, larger ﬂakes. This period of
desquamation may last from 3 to 8 weeks.
DIAGNOSIS
A culture of throat secretions may be used to conﬁrm
the diagnosis of streptococcal infection, but this has
been replaced by several methods of rapid detection of
antigens that are speciﬁc for group A, β-hemolytic
streptococci. Failure to respond to appropriate antibi-
otics should alert the clinician that the detected strep-
tococci may represent an intercurrent carrier state,
and other causes of infection should be investigated.
TREATMENT AND PROGNOSIS
Treatment of scarlet fever and the associated strepto-
coccal pharyngitis is necessary to prevent the possi-
bility of complications, such as peritonsillar or
retropharyngeal abscess, sinusitis, or pneumonia. Late
complications are rare and include otitis media, acute
rheumatic fever, glomerulonephritis, arthralgia, men-
ingitis, and hepatitis. The treatment of choice is oral
penicillin, with erythromycin reserved for patients
who are allergic to penicillin. Ibuprofen can be used to
reduce the fever and relieve the associated discomfort.
The fever and symptoms show dramatic improvement
within 48 hours after the initiation of treatment. With
appropriate therapy, the prognosis is excellent.
TONSILLAR CONCRETIONS
AND TONSILLOLITHIASIS
Anatomically, the pharyngeal tonsils demonstrate
numerous deep, twisted, and epithelial-lined invagina-
tions. These tonsillar crypts function to increase the
surface area for interaction between the immune cells
within the lymphoid tissue and the oral environment.
These convoluted crypts commonly are ﬁlled with des-
quamated keratin and foreign material and second-
arily become colonized with bacteria, usually
Actinomyces spp. The contents of the invaginations often
become compacted and form a mass of foul-smelling
material known as a tonsillar concretion. Occasion-
ally, the condensed necrotic debris and bacteria
undergo dystrophic calciﬁcation and form a tonsillo-
lith. Recurrent tonsillar inﬂammation may promote
the development of these tonsillar concretions.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although tonsillar concretions and tonsilloliths are
not uncommon, published reports are rare, often
documenting unusually large examples. The affected
Fig. 5-5 Scarlet fever. Dorsal surface of the tongue
exhibiting white coating in association with numerous
enlarged and erythematous fungiform papillae (white
strawberry tongue). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

186 ORAL AND MAXILLOFACIAL PATHOLOGY
tonsil will demonstrate one or more enlarged crypts
ﬁlled with yellow debris that varies in consistency from
soft to friable to fully calciﬁed. In contrast to acute
tonsillitis, the surrounding tonsillar tissue is not acutely
painful, dramatically inﬂamed, or signiﬁcantly edema-
tous. Tonsilloliths can develop over a wide age range,
from childhood to old age, with a mean patient age in
the early 40s. Men are affected twice as frequently as
women. These calciﬁcations vary from small clinically
insigniﬁcant lesions to massive calciﬁcations more
than 14 cm in length. Tonsilloliths may be single or
multiple, and bilateral cases have been reported.
Many tonsillar concretions and tonsilloliths, espe-
cially the smaller examples, are asymptomatic.
However, these calciﬁcations can promote recurrent
tonsillar infections and may lead to pain, abscess for-
mation, ulceration, dysphagia, chronic sore throat, irri-
table cough, otalgia, or halitosis. Occasionally, patients
will report a dull ache or a sensation of a foreign object
in the throat that is relieved on removal of the tonsillar
plug. In patients with large stones, clinical examination
often reveals a hard, yellow submucosal mass of the
affected tonsil. In older adult patients, large tonsillo-
liths can be aspirated and produce signiﬁcant second-
ary pulmonary complications. Most frequently,
tonsilloliths are discovered on panoramic radiographs
as radiopaque objects superimposed on the midpor-
tion of the mandibular ramus (Fig. 5-6). On occasion,
calciﬁcations initially thought to be bilateral are proven
to be unilateral with a panoramic ghost image present
on the contralateral side.
DIAGNOSIS
A strong presumptive diagnosis can be made through
a combination of the clinical and radiographic features.
After detection on a panoramic radiograph, if further
diagnostic conﬁrmation of tonsilloliths is deemed
necessary, then their presence can be conﬁrmed
with computed tomography (CT), magnetic resonance
imaging (MRI), or the demonstration of the calculi on
removal of the affected tonsil.
TREATMENT AND PROGNOSIS
Tonsilloliths discovered incidentally during evaluation
of a panoramic radiograph often are not treated unless
associated with signiﬁcant tonsillar hyperplasia or clin-
ical symptoms. Affected individuals occasionally try
to remove tonsillar concretions with instruments such
as straws, toothpicks, and dental instruments. Such
therapy has the potential to damage the surrounding
tonsillar tissue and should be discouraged. Patients
should be educated to attempt removal by gargling
warm salt water or using pulsating jets of water.
Superﬁcial calculi can be enucleated or curetted;
deeper tonsilloliths require local excision. Redevelop-
ment of removed concretions is common. One group
successfully used laser cryptolysis to reduce the extent
of the tonsillar invaginations and stop the redevelop-
ment of the concretions. If evidence of associated
chronic tonsillitis is seen, then tonsillectomy provides
deﬁnitive therapy.
DIPHTHERIA
Diphtheria is a life-threatening infection produced
by Corynebacterium diphtheriae. The disease was ﬁrst
described in 1826, and C. diphtheriae (also termed
Klebs-Löfﬂer bacillus) was discovered initially by Klebs in
1883 and isolated in pure culture by Löfﬂer in 1884.
Humans are the sole reservoir, and the infection is
acquired through contact with an infected person or
carrier. The bacterium produces a lethal exotoxin
that causes tissue necrosis, thereby providing nutrients
for further growth and leading to peripheral spread.
However, an effective antitoxin has been available
since 1913, and immunization has been widespread in
North America since 1922.
In the ﬁrst edition of this textbook, it was stated that
diphtheria was included mainly for historical interest
because the world was on the threshold of virtual erad-
ication of this infection in developed countries.
However, a relatively recent epidemic in Russia reveals
how rapidly such advances can be reversed in the
absence of an effective immunization program. The
epidemic began in Moscow and spread to involve all of
the newly independent states of the former Soviet
Union. During this outbreak, more than 150,000 cases
were reported with approximately 4500 deaths. This
one epidemic represented more than 90% of all cases
reported between 1990 and 1995. The process was
Fig. 5-6 Tonsilloliths. Cluster of radiopacities in the
midportion of the ascending ramus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 187
ﬁnally controlled by administration of vaccine to all
children, adolescents, and adults (regardless of immu-
nization histories).
In addition to this epidemic, infections may occur in
people who are immunosuppressed or who have failed
to receive booster injections as required. Isolated out-
breaks still are reported in the urban poor and Native
American populations of North America. Occasional
reports from industrialized nations continue to docu-
ment individuals who have returned home after con-
tracting the infection while visiting a developing
country.
CLINICAL FEATURES
The signs and symptoms of diphtheria arise 1 to 5 days
after exposure to the organism. The initial systemic
symptoms, which include low-grade fever, headache,
malaise, anorexia, sore throat, and vomiting, arise grad-
ually and may be mild. Although skin wounds may be
involved, the infection predominantly affects mucosal
surfaces and may produce exudates of the nasal, tonsil-
lar, pharyngeal, laryngotracheal, conjunctival, or genital
areas. Involvement of the nasal cavity is often accom-
panied with prolonged mucoid or hemorrhagic dis-
charge. The oropharyngeal exudate begins on one or
both tonsils as a patchy, yellow-white, thin ﬁlm that
thickens to form an adherent gray covering. With time,
the membrane may develop patches of green or black
necrosis. The superﬁcial epithelium is an integral
portion of this exudate, and attempts at removal are
difﬁcult and may result in bleeding. The covering may
continue to involve the entire soft palate, uvula, larynx,
or trachea, resulting in stridor and respiratory difﬁcul-
ties. Palatal perforation has rarely been reported.
During the Russian epidemic, patients with lesions
isolated to the oral cavity were documented. In these
patients, scattered areas of necrosis were noted on the
buccal mucosa, upper and lower lips, hard and soft
palate, or tongue. Such localization is rare and makes
diagnosis more difﬁcult.
The severity of the infection correlates with the
spread of the membrane. Local obstruction of the
airway can be lethal. Involvement of the tonsils leads
to signiﬁcant cervical lymphadenopathy, which often
is associated with an edematous neck enlargement
known as bull neck. Toxin-related paralysis may affect
oculomotor, facial, pharyngeal, diaphragmatic, and
intercostal muscles. The soft palatal paralysis can lead
to nasal regurgitation during swallowing. Oral or nasal
involvement has been reported to spread to the adja-
cent skin of the face and lips.
Cutaneous diphtheria can occur anywhere on the
body and is characterized by chronic skin ulcers that
frequently are associated with infected insect bites and
also may harbor other pathogens such as Staphylococcus
aureus or Streptococcus pyogenes. These skin lesions can
arise even in vaccinated patients and typically are not
associated with systemic toxic manifestations. When
contracted by travelers from developed nations, the
diagnosis often is delayed because of the nonspeciﬁc
clinical presentation and a low index of suspicion. The
cutaneous lesions represent an important reservoir of
infection and can lead to more typical and lethal diph-
theria in unprotected contacts.
Although bacteremia is rare, circulating toxin can
result in systemic complications. Myocarditis and neu-
rologic difﬁculties are seen most frequently and are
usually discovered in patients with severe nasopharyn-
geal diphtheria. Myocarditis may exhibit as progressive
weakness and dyspnea or lead to acute congestive heart
failure. Neuropathy is not uncommon in patients with
severe diphtheria, and palatal paralysis is the most com-
monly seen manifestation. A peripheral polyneuritis
resembling Guillain-Barré syndrome also may occur.
DIAGNOSIS
Although the clinical presentation can be distinctive in
severe cases, laboratory conﬁrmation should be sought
in all instances. The specimen for culture should be
obtained from underneath the diphtheric membrane,
if possible, or from the surface of the membrane.
Culture material also should be obtained from the
nasal mucosa. Diphtheria also must be kept in mind
for any patient who has traveled to a disease-endemic
area and has chronic skin ulcerations. In these cases,
wound swab specimens should be examined for
C. diphtheriae.
TREATMENT AND PROGNOSIS
Treatment of the patient with diphtheria should
be initiated at the time of the clinical diagnosis and
should not be delayed until the results of the culture
are received. Antitoxin should be administered in
combination with antibiotics to prevent further toxin
production, to stop the local infection, and to prevent
transmission. Erythromycin, procaine penicillin, or
intravenous (IV) penicillin may be used. Most patients
are no longer infectious after 4 days of antibiotic
therapy, but some may retain vital organisms. The
patient is not considered to be cured until three con-
secutive negative culture specimens are obtained.
Before the development of the antitoxin, the mortal-
ity rate approached 50%, usually from cardiac or neu-
rologic complications. The current mortality rate is less
than 5%, but the outcome is unpredictable. Develop-
ment of myocarditis is an important predictor of
mortality. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

188 ORAL AND MAXILLOFACIAL PATHOLOGY
Deaths still occur in the United States because of
delays in therapy secondary to lack of suspicion. With
worldwide travel and visitors from across the globe,
prevention is paramount. Even in those vaccinated as
children, it must be remembered that a booster inocu-
lation is required every 10 years.
SYPHILIS (LUES)
Syphilis is a worldwide chronic infection produced by
Treponema pallidum. The organism is extremely vulner-
able to drying; therefore, the primary modes of trans-
mission are sexual contact or from mother to fetus.
Although the risk of infection from blood transfusion
is negligible because of serologic testing of donors,
transmission through exposure to infected blood is
theoretically possible because the organism may
survive up to 5 days in refrigerated blood. Humans are
the only proven natural host for syphilis.
After the advent of penicillin therapy in the 1940s,
the incidence of syphilis slowly decreased for many
years but often demonstrated peaks and troughs in
approximately 10-year cycles. In 2000 the United
States had the fewest reported cases of primary and
secondary syphilis since reporting began in 1941.
From 2001 to 2004, the rate increased primarily as a
result of increases among men who have sex with men
(MSM). In 2004, 84% of reported cases occurred in
men, and the Centers for Disease Control and Preven-
tion (CDC) estimates 64% of the total number was
among MSM. In women, the prevalence decreased
each year from 2000 to 2003 but leveled off and
remained stable in 2004. In 2004, men were affected
5.9 times more frequently than women.
Although the data vary from year to year, a signiﬁ-
cant and prolonged increased prevalence has been
seen in blacks, with the rate in 2004 being 5.6 times
greater than that among whites. Most of the recent
increases have been found in black men. Because of
the recent trends in the surveillance data, current
national health policy is stressing enhanced prevention
measures directed toward blacks and MSM.
Oral sex is thought to have played an increasingly
important contribution to the recent surge in a number
of sexually transmitted diseases in MSM. Because the
risk of HIV transmission through oral sex is lower than
the rate associated with vaginal or anal sex, many
falsely believed that unprotected oral sex was a safe or
no-risk sexual practice and represented a good replace-
ment for other higher-risk behaviors.
In patients with syphilis, the infection undergoes a
characteristic evolution that classically proceeds
through three stages. A syphilitic patient is highly infec-
tious only during the ﬁrst two stages, but pregnant
women also may transmit the infection to the fetus
during the latent stage. Maternal transmission during
the ﬁrst two stages of infection almost always results in
miscarriage, stillbirth, or an infant with congenital mal-
formations. The longer the mother has had the infec-
tion, the less the chance of fetal infection. Infection of
the fetus may occur at any time during pregnancy, but
the stigmata do not begin to develop until after the
fourth month of gestation. The clinical changes second-
ary to the fetal infection are known as congenital
syphilis. Between 1997 and 2002, a 63% reduction in
the prevalence of congenital syphilis was noted, a ﬁgure
that correlates closely with decreases in primary and
secondary syphilis rates among women during that
time. Continued national interventions attempt to
ensure that all pregnant women receive prenatal
care, including screening for syphilis early in the
pregnancy.
Oral syphilitic lesions are uncommon but may occur
in any stage. Many of the changes are secondary to
obliterative endarteritis, which occurs in areas of
infection.
CLINICAL FEATURES
PRIMARY SYPHILIS
Primary syphilis is characterized by the chancre that
develops at the site of inoculation, becoming clinically
evident 3 to 90 days after the initial exposure. The
majority of chancres are solitary, although multiple
lesions may be seen occasionally. The external genita-
lia and anus are the most common sites, and the
affected area begins as a papular lesion, which devel-
ops a central ulceration. Less than 2% of chancres occur
in other locations, but the oral cavity is the most
common extragenital site. Oral lesions are seen most
commonly on the lip, but other sites include the tongue,
palate, gingiva, and tonsils (Fig. 5-7). The upper lip is
affected more frequently in males, whereas lower lip
involvement is predominant in females. Some believe
this selective labial distribution may reﬂect the sur-
faces most actively involved during fellatio and cunni-
lingus. The oral lesion appears as a painless, clean-based
ulceration or, rarely, as a vascular proliferation resem-
bling a pyogenic granuloma. Regional lymphadenopa-
thy, which may be bilateral, is seen in most patients.
At this time the organism is spreading systemically
through the lymphatic channels, setting the stage for
future progression. If untreated, then the initial lesion
heals within 3 to 8 weeks.
SECONDARY SYPHILIS
The next stage is known as secondary (disseminated)
syphilis and is discovered clinically 4 to 10 weeks after
the initial infection. The lesions of secondary syphilis
may arise before the primary lesion has resolved com- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 5 BACTERIAL INFECTIONS 189
pletely. During secondary syphilis, systemic symptoms
often arise. The most common are painless lymphade-
nopathy, sore throat, malaise, headache, weight loss,
fever, and musculoskeletal pain. A consistent sign is
a diffuse, painless, maculopapular cutaneous rash,
which is widespread and can even affect the palmar
and plantar areas (Fig. 5-8). The rash also may involve
the oral cavity and appear as red, maculopapular
areas. Although the skin rash may result in areas of
scarring and hyperpigmentation or hypopigmentation,
it heals without scarring in the vast majority of
patients.
In addition, roughly 30% of patients have focal areas
of intense exocytosis and spongiosis of the oral mucosa,
leading to zones of sensitive whitish mucosa known as
mucous patches (Figs. 5-9 and 5-10). Occasionally,
several adjacent patches can fuse and form a serpen-
tine or snailtrack pattern. Subsequently, superﬁcial
epithelial necrosis may occur, leading to sloughing and
exposure of the underlying raw connective tissue.
These may appear on any mucosal surface but are
found commonly on the tongue, lip, buccal mucosa,
and palate. Elevated mucous patches also may be cen-
tered over the crease of the oral commissure and have
been termed split papules. Occasionally, papillary
lesions that may resemble viral papillomas arise during
this time and are known as condylomata lata.
Although these lesions typically occur in the genital or
anal regions, rare oral examples occur (Fig. 5-11). In
contrast to the isolated chancre noted in the primary
stage, multiple lesions are typical of secondary syphilis.
Spontaneous resolution usually occurs within 3 to 12
weeks; however, relapses may occur during the next
year.
Fig. 5-7 Chancre of primary syphilis. Ulceration of the
dorsal surface of the tongue on the left side. (From Neville BW,
Damm DD, White DK: Color atlas of clinical oral pathology, ed 2,
Hamilton, 1999, BC Decker.)
Fig. 5-8 Secondary syphilis. Erythematous rash of
secondary syphilis affecting the palms of the hands. (Courtesy of
Dr. John Maize.)
Fig. 5-9 Mucous patch of secondary syphilis.
Circumscribed white plaque on the lower labial mucosa.
(Courtesy of Dr. Pete Edmonds.)
Fig. 5-10 Mucous patch of secondary syphilis. Irregular
thickened white plaque of the right soft palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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190 ORAL AND MAXILLOFACIAL PATHOLOGY
On occasion, especially in the presence of a compro-
mised immune system, secondary syphilis can exhibit
an explosive and widespread form known as lues
maligna. This form has prodromal symptoms of fever,
headache, and myalgia, followed by the formation of
necrotic ulcerations, which commonly involve the face
and scalp. Oral lesions are present in more than 30%
of affected patients. Malaise, pain, and arthralgia are
seen occasionally. Several cases of lues maligna have
been reported in patients with acquired immunodeﬁ-
ciency syndrome (AIDS) (see page 264), and this pos-
sibility should be kept in mind whenever HIV-infected
patients have atypical ulcerations of the skin or oral
mucosa.
TERTIARY SYPHILIS
After the second stage, patients enter a period in which
they are free of lesions and symptoms, known as latent
syphilis. This period of latency may last from 1 to 30
years; then (in approximately 30% of patients) the third
stage, which is known as tertiary syphilis, develops. The
third stage of syphilis includes the most serious of all
complications. The vascular system can be affected sig-
niﬁcantly through the effects of the earlier arteritis.
Aneurysm of the ascending aorta, left ventricular
hypertrophy, aortic regurgitation, and congestive heart
failure may occur. Involvement of the central nervous
system (CNS) may result in tabes dorsalis, general
paralysis, psychosis, dementia, paresis, and death.
Ocular lesions such as iritis, choroidoretinitis, and
Argyll Robertson pupil (fails to react to light but
responds to accommodation) may occur. Less signiﬁ-
cant, but more characteristic, are scattered foci of gran-
ulomatous inﬂammation, which may affect the skin,
mucosa, soft tissue, bones, and internal organs. This
active site of granulomatous inﬂammation, known as a
gumma, appears as an indurated, nodular, or ulcer-
ated lesion that may produce extensive tissue destruc-
tion. Intraoral lesions usually affect the palate or tongue.
When the palate is involved, the ulceration frequently
perforates through to the nasal cavity (Fig. 5-12). The
tongue may be involved diffusely with gummata and
appear large, lobulated, and irregularly shaped. This
lobulated pattern is termed interstitial glossitis and
is thought to be the result of contracture of the lingual
musculature after healing of gummas. Diffuse atrophy
and loss of the dorsal tongue papillae produce a condi-
tion called luetic glossitis (Fig. 5-13). In the past, this
form of atrophic glossitis was thought to be precancer-
ous, but several more recent publications dispute this
concept.
CONGENITAL SYPHILIS
In 1858, Sir Jonathan Hutchinson described the
changes found in congenital syphilis and deﬁned the
following three pathognomonic diagnostic features,
known as Hutchinson’s triad:
● Hutchinson’s teeth
●Ocular interstitial keratitis
●Eighth nerve deafness
Like many diagnostic triads, few patients exhibit all
three features.
Infants infected with syphilis can display signs
within 2 to 3 weeks of birth. These early ﬁndings
include growth retardation, fever, jaundice, anemia,
hepatosplenomegaly, rhinitis, rhagades (circumoral
Fig. 5-11 Condyloma lata. Multiple indurated and slightly
papillary nodules on the dorsal tongue. (Courtesy of Dr. Karen
Novak.)
Fig. 5-12 Tertiary syphilis. Perforation of the hard palate.
(Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 191
radial skin ﬁssures), and desquamative maculopapular,
ulcerative, or vesiculobullous skin eruptions. Untreated
infants who survive often develop tertiary syphilis with
damage to the bones, teeth, eyes, ears, and brain. It is
these ﬁndings that were described well by Hutchinson.
The infection alters the formation of both the anterior
teeth (Hutchinson’s incisors) and the posterior denti-
tion (mulberry molars, Fournier’s molars, Moon’s
molars). Hutchinson’s incisors exhibit their greatest
mesiodistal width in the middle third of the crown. The
incisal third tapers to the incisal edge, and the resulting
tooth resembles a straightedge screwdriver (Fig. 5-14).
The incisal edge often exhibits a central hypoplastic
notch. Mulberry molars taper toward the occlusal
surface with a constricted grinding surface. The occlu-
sal anatomy is abnormal, with numerous disorganized
globular projections that resemble the surface of a mul-
berry (Fig. 5-15).
Interstitial keratitis of the eyes is not present at
birth but usually develops between the ages of 5 and
25 years. The affected eye has an opaciﬁed corneal
surface, with a resultant loss of vision. In addition to
Hutchinson’s triad, a number of other alterations such
as saddle-nose deformity, high-arched palate, frontal
bossing, hydrocephalus, mental retardation, gummas,
and neurosyphilis may be seen. Table 5-1 delineates
the prevalence rates of the stigmata of congenital syph-
ilis in a cohort of affected patients.
HISTOPATHOLOGIC FEATURES
The histopathologic picture of the oral lesions in the
syphilitic patient is not speciﬁc. During the ﬁrst two
stages, the pattern is similar. The surface epithelium is
ulcerated in primary lesions and may be ulcerated or
hyperplastic in the secondary stage. The underlying
lamina propria may demonstrate an increase in the
number of vascular channels, and an intense chronic
inﬂammatory reaction is present. The inﬁltrate is com-
posed predominantly of lymphocytes and plasma cells
and often demonstrates a perivascular pattern (Fig.
5-16). Although the presence of plasma cells within the
inﬁltrate may suggest the diagnosis of syphilis on the
skin, their presence in areas of oral ulceration is com-
monplace and therefore not necessarily of diagnostic
signiﬁcance. In secondary syphilis, ulceration may
not be present and the surface epithelium often
Fig. 5-13 Atrophic glossitis of tertiary syphilis. Dorsal
surface of the tongue exhibiting loss of ﬁliform papillae and
areas of epithelial atrophy and hyperkeratosis. (Courtesy of Dr.
Robert J. Gorlin.)
Fig. 5-14 Hutchinson’s incisors of congenital syphilis.
Dentition exhibiting crowns tapering toward the incisal
edges. (From Halstead CL, Blozis GG, Drinnan AJ et al: Physical
evaluation of the dental patient, St Louis, 1982, Mosby.)
Fig. 5-15 Mulberry molar of congenital syphilis. Maxillary
molar demonstrating occlusal surface with numerous globular
projections. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

192 ORAL AND MAXILLOFACIAL PATHOLOGY
demonstrates hyperplasia with signiﬁcant spongiosis
and exocytosis (Fig. 5-17). When noted in combination
with an underlying dense, deep, and perivascular plas-
macytic inﬁltrate, the index of suspicion often raises to
a level that supports a search for the organism. The use
of special silver impregnation techniques, such as
Warthin-Starry or Steiner stains, or immunoperoxi-
dase reactions directed against the organism often
show scattered corkscrewlike spirochetal organisms
that frequently are found most easily within the surface
epithelium (see Fig. 5-17, C). The organism also can be
detected in tissue through direct ﬂuorescent antibody
testing.
Oral tertiary lesions typically exhibit surface ulcer-
ation, with peripheral pseudoepitheliomatous hyper-
plasia. The underlying inﬂammatory inﬁltrate usually
Table 5-1 Stigmata of Congenital Syphilis
Stigmata of Congenital
Syphilis
a
Number of
Patients% Affected
Frontal bossing 235 86.7
Short maxilla 227 83.8
High-arched palate 207 76.4
Saddle nose 199 73.4
Mulberry molars 176 64.9
Hutchinson’s incisors 171 63.1
Higoumenaki’s sign
b
107 39.4
Relative prognathism of
mandible
70 25.8
Interstitial keratitis 24 8.8
Rhagades
c
19 7.0
Saber shin
d
11 4.1
Eighth nerve deafness 9 3.3
Scaphoid scapulae
e
2 0.7
Clutton’s joint
f
1 0.3
Modiﬁed from Fiumara NJ, Lessel S: Manifestations of late congenital
syphilis: an analysis of 271 patients, Arch Dermatol 102:78, 1970.
a
In a cohort of 271 patients.
b
Enlargement of clavicle adjacent to the sternum.
c
Premature perioral ﬁssuring.
d
Anterior bowing of tibia as a result of periostitis.
e
Concavity of vertebral border of the scapulae.
f
Painless synovitis and enlargement of joints, usually the knee.
Fig. 5-16 Primary syphilis. A chronic perivascular
inﬂammatory inﬁltrate of plasma cells and lymphocytes.
(Courtesy of Dr. John Metcalf.)
A
B
C
Fig. 5-17 Secondary syphilis, condyloma lata. A, Low-
power photomicrograph of biopsy from patient in Fig. 5-11,
which shows papillary epithelial hyperplasia and a heavy
plasmacytic inﬁltrate in the connective tissue. B, High-power
view showing intense exocytosis of neutrophils into the
epithelium. C, Immunoperoxidase reaction for Treponema
pallidum demonstrating numerous spirochetes in the
epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 193
demonstrates foci of granulomatous inﬂammation with
well-circumscribed collections of histiocytes and mul-
tinucleated giant cells. Even with special stains, the
organisms are hard to demonstrate in the third stage;
researchers believe the inﬂammatory response is an
immune reaction, rather than a direct response to
T. pallidum.
DIAGNOSIS
The diagnosis of syphilis can be conﬁrmed by demon-
strating the spiral organism by dark-ﬁeld examination
of a smear of the exudate of an active lesion. False-posi-
tive results are possible in the oral cavity because of
morphologically similar oral inhabitants, such as Trepo-
nema microdentium, T. macrodentium, and T. mucosum.
Demonstration of the organism on a smear or in biopsy
material should be conﬁrmed through the use of spe-
ciﬁc immunoﬂuorescent antibody or serologic tests.
Several nonspeciﬁc and not highly sensitive sero-
logic screening tests for syphilis are available. These
include the Venereal Disease Research Laboratory
(VDRL) and the rapid plasma reagin (RPR). After the
ﬁrst 3 weeks of infection, the screening tests are posi-
tive strongly throughout the ﬁrst two stages. After the
development of latency, the positivity generally sub-
sides with time. As part of appropriate prenatal care,
all pregnant women should receive one of the nonspe-
ciﬁc screening tests.
Speciﬁc and highly sensitive serologic tests for syph-
ilis also are available. These include the ﬂuorescent
treponemal antibody absorption (FTA-ABS), T. pallidum
hemagglutination assay (TPHA), T. pallidum particle
agglutination assay (TPPA), and microhemagglutina-
tion assay for antibody to T. pallidum (MHA-TP). These
test results become positive at the time of the develop-
ment of the ﬁrst lesion of primary syphilis and remain
positive for life. This lifelong persistence of positivity
limits their usefulness in the diagnosis of a second inci-
dence of infection. Therefore, in cases of possible rein-
fection, the organisms should be demonstrated within
the tissue or exudates.
TREATMENT AND PROGNOSIS
The treatment for syphilis necessitates an individual
evaluation and a customized therapeutic approach.
The treatment of choice is penicillin. The dose and
administration schedules vary according to the stage,
neurologic involvement, and immune status. For
primary, secondary, or early latent syphilis, a single
dose of parenteral long-acting benzathine penicillin G
is given. For late latent or tertiary syphilis, intramuscu-
lar penicillin is administered weekly for 3 weeks. For
the patient with a true penicillin allergy, doxycycline is
second-line therapy, although tetracycline, erythromy-
cin, and ceftriaxone also have demonstrated antitrepo-
nemal activity.
In 50% of patients with primary syphilis and 90%
of those with secondary syphilis, an unusual initial
response to therapy occurs known as the Jarisch-
Herxheimer reaction. This process occurs secondary
to release of endotoxin when antibiotics kill large
numbers of organisms. Clinical evidence of this reac-
tion occurs about 8 hours after the ﬁrst injection of
penicillin and most commonly includes mild fever,
malaise, headache, and an exacerbation of skin or
mucosal lesions. These signs and symptoms are very
temporary and rapidly fade.
Treatment failures occur in approximately 5% of
patients. When treating primary, secondary, or early
latent syphilis, some experts recommend serologic
follow-up at 6, 12, 18, and 24 months. Pregnant women
treated for syphilis should be retested at the twenty-
eighth week and again at delivery. Infants born to sero-
positive mothers are treated with IV penicillin.
Even in patients who obtain a clinical and serologic
“cure” with penicillin, it must be remembered that
T. pallidum can escape the lethal effects of the antibiotic
when the organism is located within the conﬁnes of
lymph nodes or the central nervous system. Therefore,
antibiotic therapy may not always result in a total cure
in patients with neurologic involvement but may arrest
only the clinical presentations of the infection. Patients
with immunosuppression, such as those with AIDS,
may not respond appropriately to standard antibiotic
regimens, and numerous reports have documented a
continuation to neurosyphilis despite seemingly appro-
priate single-dose therapy.
In the review of the recent increase of syphilis in
MSM, high rates of coinfection with HIV have been
documented. Although many factors are involved, the
mucosal damage created by the spirochetes probably
provides greater access for HIV infection. Patients
diagnosed with syphilis, especially MSM, also should
be tested for HIV.
GONORRHEA
Gonorrhea, a sexually transmitted disease that is pro-
duced by Neisseria gonorrhoeae, represents the most
common reportable bacterial infection in the United
States, with an estimated 700,000 to 800,000 persons
infected each year. The disease is epidemic, especially
in urban areas; worldwide, millions of people are
infected each year. The prevalence of gonorrhea has
been declining since a peak in 1975. In 2004, the last
year with complete data from the CDC, the rate of
infection was the lowest ever reported. Despite this, the
rate in the United States remains the highest of any `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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194 ORAL AND MAXILLOFACIAL PATHOLOGY
industrialized country, and certain segments of the
population, such as those with a low socioeconomic or
education level, injecting drug users, prostitutes, homo-
sexual men, and military personnel, remain at high
risk. In contrast to many other sexually transmitted
diseases, women are affected slightly more frequently
than men. Although the rate of infection continues to
decrease in all races, African Americans are infected
19 times more often than whites.
CLINICAL FEATURES
The infection is spread through sexual contact, and
most lesions occur in the genital areas. Indirect infec-
tion is rare because the organism is sensitive to drying
and cannot penetrate intact stratiﬁed squamous epi-
thelium. The incubation period is typically 2 to 5 days.
Affected areas often demonstrate signiﬁcant purulent
discharge, but approximately 10% of men and up
to 80% of women who contract gonorrhea are
asymptomatic.
In men the most frequent site of infection is the
urethra, resulting in purulent discharge and dysuria.
Less common primary sites include the anorectal and
pharyngeal areas. The cervix is the primary site of
involvement in women, and the chief complaints are
increased vaginal discharge, intermenstrual bleeding,
genital itching, and dysuria. The organism may ascend
to involve the uterus and ovarian tubes, leading to the
most important female complication of gonorrhea—
pelvic inﬂammatory disease (PID). The symptoms
of PID include cramps and abnormal bleeding, which
may be severe or mild. The long-term complications of
PID include ectopic pregnancies or infertility from
tubal obstruction.
Between 0.5% and 3.0% of untreated patients with
gonorrhea will have disseminated gonococcal infec-
tions from systemic bacteremia. The most common
signs of dissemination are myalgia, arthralgia, polyar-
thritis, and dermatitis. In 75% of patients with dissemi-
nated disease, a characteristic skin rash develops. The
dermatologic lesions consist of discrete papules and
pustules that often exhibit a hemorrhagic component
and occur primarily on the extremities. Less common
alterations secondary to gonococcal septicemia include
fever, endocarditis, pericarditis, meningitis, and oral
mucosal lesions of the soft palate and oropharynx,
which are similar to aphthous ulcerations.
The prevalence of oral sex appears to be increasing
and is thought by many to be the result of the miscon-
ception that it represents a low-risk sexual practice and
a safe alternative to high-risk activities such as anal or
vaginal sex. Most cases of oral gonorrhea appear to be
a result of fellatio, although oropharyngeal gonorrhea
may be the result of gonococcal septicemia, kissing, or
cunnilingus. Therefore, the majority of oropharyngeal
gonorrhea cases have been reported in women or
homosexual men. Another contributing problem is that
pharyngeal gonorrhea often is asymptomatic, making
delay in diagnosis and spread more likely. In a recent
review of 200 men with urethral gonorrhea, more than
50% admitted to having sex with men (i.e., MSM), and
58% of the MSM group identiﬁed oral sex as the sole
risk factor for their infection.
The most common site of oropharyngeal involve-
ment is the pharynx along with the tonsils and uvula.
Although pharyngeal gonorrhea usually is asymptom-
atic, a mild-to-moderate sore throat may occur and be
accompanied by nonspeciﬁc, diffuse oropharyngeal
erythema. Involved tonsils typically demonstrate
edema and erythema, often with scattered, small punc-
tate pustules. Although most cases of pharyngeal infec-
tion resolve spontaneously without adverse sequelae,
treatment is important to reduce the potential for
spreading the infection.
Rarely, lesions have been reported in the anterior
portion of the oral cavity, with areas of infection appear-
ing erythematous, pustular, erosive, or ulcerated. Occa-
sionally, the infection may simulate necrotizing
ulcerative gingivitis (NUG), but some clinicians have
reported that the typical fetor oris is absent, providing
an important clue to the actual cause (Fig. 5-18). Sub-
mandibular or cervical lymphadenopathy may be
present.
During birth, infection of an infant’s eyes can occur
from an infected mother who may be asymptomatic.
This infection is called gonococcal ophthalmia neo-
natorum and can rapidly cause perforation of the
globe of the eye and blindness. Common signs of infec-
tion include signiﬁcant conjunctivitis and a mucopuru-
lent discharge from the eye.
Fig. 5-18 Gonorrhea. Necrosis, purulence, and hemorrhage
of the anterior mandibular gingiva. (From Williams LN: The risks of
oral-genital contact: a case report, Gen Dent 50:282-284, 2002.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 195
DIAGNOSIS
In males with a urethral discharge, a Gram stain of the
purulent material can be used to demonstrate gram-
negative diplococci within the neutrophils; additional
testing usually is not indicated. Although Gram stains
may be beneﬁcial in women, conﬁrmation of the diag-
nosis is recommended by culture of endocervical swabs
if conditions are adequate to maintain viability of the
organisms. A number of other diagnostic studies have
been available for many years. Nucleic acid ampliﬁca-
tion tests (NAATs) amplify and detect N. gonorrhoeae–
speciﬁc DNA or RNA sequences and are recommended
for the diagnosis when conditions are not adequate
to maintain the viability of the organisms. In spite of
the availability of NAATs, culture remains the pre-
ferred diagnostic method for diagnosis of oropharyn-
geal infections.
TREATMENT AND PROGNOSIS
The primary therapy for gonorrhea has been ﬂuoro-
quinolones such as ciproﬂoxacin, levoﬂoxacin, or
oﬂoxacin; however, increasing resistance has been
documented in MSM and in infections acquired
in Asia, the Paciﬁc islands (including Hawaii), and
California. Although oral ciproﬂoxacin remains ﬁrst-
line therapy for most patients, those at risk for resistant
disease should receive intramuscular ceftriaxone. Oral
ceﬁxime also is effective but currently is not available
in the United States in an appropriate formulation.
Patients with gonorrhea are at risk for additional sexu-
ally transmitted diseases, most commonly Chlamydia
trachomatis for which a C. trachomatis–speciﬁc NAAT is
available. If chlamydia has not been ruled out, then
affected patients also should receive either azithromy-
cin or doxycycline. Rescreening is recommended 1 to
2 months after therapy. The most common cause for
treatment failure is reexposure to infected partners,
who often are asymptomatic; therefore, the treatment
of all recent sexual partners is recommended. Truly
resistant infections should be cultured with antimicro-
bial testing and selection of an appropriate alternate
antibiotic. Prophylactic ophthalmic erythromycin, tet-
racycline, or silver nitrate is applied to the newborn’s
eyes to prevent the occurrence of gonococcal ophthal-
mia neonatorum.
TUBERCULOSIS
Tuberculosis (TB) is a chronic infectious disease
caused by Mycobacterium tuberculosis. Worldwide, it
is estimated that 2 billion people (one third of the pop-
ulation) are infected; each year 9 million additional
individuals become infected. It is estimated that
approximately 2 million deaths annually can be attrib-
uted to TB. In the United States the disease has been
declining since the 1800s, especially since the intro-
duction of effective antimicrobials in the 1940s. The
decline ceased abruptly in the early 1980s and
appeared to be the result of a combination of several
factors. Wars and famine in the developing world, the
HIV epidemic, increased immigration from countries
with endemic TB, transmission of TB in crowded or
unsanitary environments, a decline of the health care
infrastructure, and an increased prevalence of multi-
drug-resistant TB have been implicated in the recent
resurgence.
In the 1990s an increased emphasis was placed on
TB control and prevention, with a resultant steady
decline in the frequency of this serious infection since
1993. In 2006 the directed interventions resulted in
the lowest number of recorded cases in the United
States since reporting began in 1953, but the average
annual decline has slowed since 2000. Immigration
and the increased prevalence of multidrug-resistant TB
are thought to be largely responsible for the slowing
rate of decline of the infection. In 2006 the infection
rate in foreign-born persons in the United States was
9.5 times that of persons born in the United States,
with more cases reported among Hispanics than any
other racial or ethnic population. At the same time, the
rate of infection in Hispanics, blacks, and Asians was
respectively 7.6, 8.4, and 21.2 higher than in whites.
Most infections are the result of direct person-to-person
spread through airborne droplets from a patient with
active disease.
Nontuberculous mycobacterial disease can occur
from a variety of organisms. Before the tuberculin
testing of dairy herds, many cases arose from the con-
sumption of milk infected with Mycobacterium bovis.
Except for HIV-infected individuals, most other cases
of nontuberculous mycobacterial disease appear as
localized chronic cervical lymphadenitis in otherwise
healthy children. In patients with AIDS (see page 274),
M. avium-intracellulare is a common cause of opportu-
nistic infections.
Infection must be distinguished from active disease.
Primary tuberculosis occurs in previously unexposed
people and almost always involves the lungs. Most
infections are the result of direct person-to-person
spread through airborne droplets from a patient with
active disease. The organism initially elicits a nonspe-
ciﬁc, chronic inﬂammatory reaction. In most individu-
als, the primary infection results only in a localized,
ﬁbrocalciﬁed nodule at the initial site of involvement.
However, viable organisms may be present in these
nodules and remain dormant for years to life.
Only about 5% to 10% of patients with TB progress
from infection to active disease, and an existing state of `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

196 ORAL AND MAXILLOFACIAL PATHOLOGY
immunosuppression often is responsible. In rare
instances, active TB may ensue directly from the
primary infection. However, active disease usually
develops later in life from a reactivation of organisms
in a previously infected person. This reactivation is
typically associated with compromised host defenses
and is called secondary tuberculosis. Diffuse dis-
semination through the vascular system may occur and
often produces multiple small foci of infection that
grossly and radiographically resemble millet seeds,
resulting in the nickname, miliary tuberculosis. Sec-
ondary tuberculosis often is associated with immuno-
suppressive medications, diabetes, old age, poverty,
and crowded living conditions. AIDS represents one of
the strongest known risk factors for progression from
infection to disease. The prevalence of active TB in
patients with AIDS is approximately 100 times that
documented in the general population.
CLINICAL AND RADIOGRAPHIC
FEATURES
Primary TB is usually asymptomatic. Occasionally,
fever and pleural effusion may occur.
Classically, the lesions of secondary TB are located
in the apex of the lungs but may spread to many differ-
ent sites by expectorated infected material or through
the lymphatic or vascular channels. Typically, patients
have a low-grade fever, malaise, anorexia, weight loss,
and night sweats. With pulmonary progression, a pro-
ductive cough develops, often with hemoptysis or chest
pain. Progressive TB may lead to a wasting syndrome
that, in the past, was termed consumption, because it
appeared that the patient’s body was being consumed
or destroyed.
Extrapulmonary TB is seen and represents an
increasing proportion of the currently diagnosed cases.
In patients with AIDS, more than 50% will have extra-
pulmonary lesions. Any organ system may be involved,
including the lymphatic system, skin, skeletal system,
CNS, kidneys, and gastrointestinal tract. Involvement
of the skin may develop and has been called lupus
vulgaris.
Head and neck involvement may occur. The most
common extrapulmonary sites in the head and neck
are the cervical lymph nodes followed by the larynx
and middle ear. Much less common sites include the
nasal cavity, nasopharynx, oral cavity, parotid gland,
esophagus, and spine.
Oral lesions of TB are uncommon, with most cases
appearing as a chronic painless ulcer. Less frequent
presentations include nodular, granular, or (rarely)
ﬁrm leukoplakic areas. The majority of the lesions rep-
resent secondary infection from the initial pulmonary
foci, occurring most frequently in middle-aged adults.
It is unclear whether these lesions develop from hema-
togenous spread or from exposure to infected sputum.
The reported prevalence of clinically evident oral
lesions varies from 0.5% to 5.0%. However, one autopsy
study revealed a prevalence of close to 20% when the
tongues of those infected were examined microscopi-
cally. The discovery of pulmonary TB as a result of the
investigation of oral lesions occurs but is unusual.
Primary oral TB without pulmonary involvement
is rare and is more common in children and
adolescents.
When present, primary oral TB usually involves the
gingiva, mucobuccal fold, and areas of inﬂammation
adjacent to teeth or in extraction sites; secondary oral
lesions are mostly present on the tongue, palate, and
lip (Figs. 5-19 and 5-20). Primary oral lesions are
usually associated with enlarged regional lymph nodes.
Tuberculous osteomyelitis has been reported in the
jaws and appears as ill-deﬁned areas of radiolucency.
Fig. 5-19 Tuberculosis. Chronic mucosal ulceration of the
ventral surface of the tongue on the right side. (Reprinted with
permission from the American Dental Association.)
Fig. 5-20 Tuberculosis. Area of granularity and ulceration
of the lower alveolar ridge and ﬂoor of mouth. (Courtesy of Dr.
Brian Blocher.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 197
Nontuberculous mycobacterial infections from con-
taminated milk are currently rare in the industrialized
world because of pasteurization of milk, as well as
rapid identiﬁcation and elimination of infected cows.
Drinking contaminated milk can result in a form of
mycobacterial infection known as scrofula. Scrofula is
characterized by enlargement of the oropharyngeal
lymphoid tissues and cervical lymph nodes (Fig. 5-21).
On occasion, the involved nodes may develop signiﬁ-
cant caseous necrosis and form numerous sinus tracts
through the overlying skin (Fig. 5-22). In addition,
areas of nodal involvement may radiographically
appear as calciﬁed lymph nodes that may be confused
with sialoliths (Fig. 5-23). Pulmonary involvement is
unusual in patients with scrofula.
HISTOPATHOLOGIC FEATURES
The cell-mediated hypersensitivity reaction is respon-
sible for the classic histopathologic presentation of TB.
Areas of infection demonstrate the formation of granu-
lomas, which are circumscribed collections of epithe-
lioid histiocytes, lymphocytes, and multinucleated
giant cells, often with central caseous necrosis (Fig.
5-24). In a person with TB, one of these granulomas
is called a tubercle. Special stains, such as the
Fig. 5-21 Tuberculosis. Enlargement of numerous cervical
lymph nodes. (Courtesy of Dr. George Blozis.)
Fig. 5-22 Tuberculosis. Submandibular ﬁstula secondary to
involvement of underlying cervical lymph nodes.
Fig. 5-23 Tuberculosis. Multiple calciﬁed cervical lymph
nodes.
Fig. 5-24 Tuberculosis. Histopathologic presentation of the
same lesion depicted in Fig. 5-20. Sheets of histiocytes are
intermixed with multinucleated giant cells and areas of
necrosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

198 ORAL AND MAXILLOFACIAL PATHOLOGY
Ziehl-Neelsen or other acid-fast stains, are required to
demonstrate the mycobacteria (Fig. 5-25). Because of
the relative scarcity of the organisms within tissue, the
special stains successfully demonstrate the organism in
only 27% to 60% of cases. Therefore, a negative result
does not completely rule out the possibility of TB.
DIAGNOSIS
Approximately 2 to 4 weeks after initial exposure, a
cell-mediated hypersensitivity reaction to tubercular
antigens develops. This reaction is the basis for the
puriﬁed protein derivative (PPD) skin test (i.e., tuber-
culin skin test), which uses a ﬁltered precipitate of
heat-sterilized broth cultures of M. tuberculosis. Positiv-
ity runs as high as 80% in developing nations; only 5%
to 10% of the population in the United States is positive.
A positive tuberculin skin test result indicates exposure
to the organism and does not distinguish infection from
active disease. A negative tuberculin skin test result
does not totally rule out the possibility of TB. False-
negative reactions have been documented in older
adults; the immuno compromised; patients with sar-
coidosis, measles, or Hodgkin’s lymphoma; and when
the antigen was placed intradermally. The false-nega-
tive rate may be as high as 66% in patients with AIDS.
Special mycobacterial stains and culture of infected
sputum or tissue must be used to conﬁrm the diagnosis
of active disease. Even if detected with special stains,
identiﬁcation of the organism by culture is appropriate.
This identiﬁcation is important because some forms
of nontuberculous mycobacteria have a high level of
resistance to traditional antituberculous therapy and
frequently require surgical excision. Because 4 to 6
weeks may be required to identify the organism in
culture, antituberculous therapy often is initiated
before deﬁnitive classiﬁcation. Polymerase chain reac-
tion (PCR) is also used to identify M. tuberculosis DNA
and speeds the diagnosis without the need to await
culture results.
TREATMENT AND PROGNOSIS
M. tuberculosis can mutate and develop resistance to
single-agent medications. To combat this ability, mul-
tiagent therapy is the treatment of choice for an active
infection, and treatment usually involves two or more
active drugs for several months to years. A frequently
used protocol consists of an 8-week course of isoniazid,
rifampin, and pyrazinamide, followed by a 16-week
course of isoniazid and rifampin. Other ﬁrst-line medi-
cations include ethambutol and streptomycin. Relapse
rates of approximately 1.5% are seen. With an altera-
tion of doses and the administration schedule, the
response to therapy in patients with AIDS has been
good, but relapses and progression of infection have
been seen.
A different protocol termed chemoprophylaxis is used
for patients who have a positive PPD skin test but no
signs or symptoms of active disease. Although this situ-
ation does not mandate therapy, several investigators
have demonstrated the value of therapy, especially in
young individuals. Bacillus Calmette-Guérin (BCG)
vaccine for TB is available to approximately 85% of
the global population, but its use is restricted in the
United States because of a controversy related to its
effectiveness.
LEPROSY (HANSEN DISEASE)
Leprosy is a chronic infectious disease produced by
Mycobacterium leprae. Because of worldwide efforts
coordinated by the World Health Organization (WHO),
a dramatic decrease in the prevalence of leprosy has
been seen over the past 15 years. Since the mid-1980s,
the number of estimated cases of active leprosy has
dropped from between 10 and 12 million to 1.15
million, with the number of ofﬁcially registered cases
falling 85%. However, leprosy remains a public health
problem in many areas of the world. Approximately
82% of all currently reported cases are noted in ﬁve
countries: Brazil, India, Indonesia, Myanmar, and
Nigeria.
The organism has a low infectivity, and exposure
rarely results in clinical disease. Small endemic areas
of infection are present in Louisiana and Texas, but
most patients in the United States have been infected
abroad. Many believe that the organism requires a cool
host body temperature for survival. Although the exact
route of transmission is not known, the high number
Fig. 5-25 Tuberculosis. Acid-fast stain of specimen
depicted in Fig. 5-24 exhibiting scattered mycobacterial
organisms presenting as small red rods. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 199
of organisms in nasal secretions suggests that in some
cases the initial site of infection may be the nasal or
oropharyngeal mucosa. Although humans are consid-
ered the major host, other animals (e.g., armadillo,
chimpanzee, mangabey monkey) may be additional
possible reservoirs of infection. The nine-banded arma-
dillo is relatively unique because of its low body core
temperature, and it is naturally susceptible to the infec-
tion. Infected armadillos have been discovered in
Louisiana.
For decades, leprologists have believed the bacillus
is highly temperature dependent and produces lesions
primarily in cooler parts of the body, such as the skin,
nasal cavity, and palate. This concept has been ques-
tioned because the organism may be seen in signiﬁcant
numbers at sites of core body temperature, such as the
liver and spleen. Recently, one investigator mapped
common sites of oral involvement and compared this
pattern to a map of the local temperature. This com-
parison demonstrated that the oral lesions tend
to occur more frequently in the areas of the mouth
with a lower surface temperature. The temperature-
dependent theory of leprosy infection remains an area
of interest and controversy.
Historically, two main clinical presentations are
noted, and these are related to the immune reaction to
the organism. The ﬁrst, called tuberculoid leprosy,
develops in patients with a high immune reaction.
Typically, the organisms are not found in skin biopsy
specimens, skin test results to heat-killed organisms
(lepromin) are positive, and the disease is usually local-
ized. The second form, lepromatous leprosy, is seen
in patients who demonstrate a reduced cell-mediated
immune response. These patients exhibit numerous
organisms in the tissue, do not respond to lepromin
skin tests, and exhibit diffuse disease. Borderline and
less common variations exist. Active disease progresses
through stages of invasion, proliferation, ulceration,
and resolution with ﬁbrosis. The incubation period is
prolonged, with an average of 2 to 5 years for the tuber-
culoid type and 8 to 12 years for the lepromatous
variant.
CLINICAL FEATURES
Currently, leprosy is classiﬁed into two separate cate-
gories, paucibacillary and multibacillary, with the
distinction inﬂuencing the recommended form of
therapy. Because laboratory services such as skin
smears often are not available, patients are increasingly
being classiﬁed on clinical grounds using the number
of lesions (primarily skin) and the number of body
areas affected.
Paucibacillary leprosy corresponds closely to the
tuberculoid pattern of leprosy and exhibits a small
number of well-circumscribed, hypopigmented skin
lesions. Nerve involvement usually results in anesthe-
sia of the affected skin, often accompanied by a loss of
sweating. Oral lesions are rare in this variant.
Multibacillary leprosy corresponds well to the
lepromatous pattern of leprosy and begins slowly with
numerous, ill-deﬁned, hypopigmented macules or
papules on the skin that, with time, become thickened
(Fig. 5-26). The face is a common site of involvement,
and the skin enlargements can lead to a distorted facial
appearance (leonine facies). Hair, including the eye-
brows and lashes, often is lost (Fig. 5-27). Nerve involve-
ment leads to a loss of sweating and decreased light
touch, pain, and temperature sensors. This sensory loss
begins in the extremities and spreads to most of the
body. Nasal involvement results in nosebleeds, stufﬁ-
ness, and a loss of the sense of smell. The hard tissue
of the ﬂoor, septum, and bridge of the nose may be
affected. Collapse of the bridge of the nose is consid-
ered pathognomonic.
Fig. 5-26 Multibacillary (lepromatous) leprosy. Numerous
thickened facial nodules.
Fig. 5-27 Multibacillary (lepromatous) leprosy. Loss of
eyebrows and eyelashes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

200 ORAL AND MAXILLOFACIAL PATHOLOGY
Oral lesions are not rare in multibacillary leprosy,
and reports on their prevalence vary from 19% to 60%.
In an excellent review by Prabhu and Daftary of 700
patients with leprosy, the prevalence of facial skin
involvement was 28%, and oral lesions were noted in
11.5%. The lesions tended to be more frequent during
the ﬁrst 5 years of the disease.
The sites that are cooled by the passage of air appear
to be affected most frequently. The locations affected
in order of frequency are the hard palate, soft palate,
labial maxillary gingiva, tongue, lips, buccal maxillary
gingiva, labial mandibular gingiva, and buccal mucosa.
Affected soft tissue initially appears as yellowish to red,
sessile, ﬁrm, enlarging papules that develop ulceration
and necrosis, followed by attempted healing by second-
ary intention. Continuous infection of an area can lead
to signiﬁcant scarring and loss of tissue. Complete loss
of the uvula and ﬁxation of the soft palate may occur.
The lingual lesions appear primarily in the anterior
third and often begin as areas of erosion, which may
develop into large nodules. Infection of the lip can
result in signiﬁcant macrocheilia, which can be con-
fused clinically and microscopically with cheilitis gran-
ulomatosa (see page 342).
Direct inﬁltration of the inﬂammatory process asso-
ciated with lepromatous leprosy can destroy the bone
underlying the areas of soft tissue involvement. Often
the infection creates a unique pattern of facial destruc-
tion that has been termed facies leprosa and demon-
strates a triad of lesions consisting of atrophy of the
anterior nasal spine, atrophy of the anterior maxillary
alveolar ridge, and endonasal inﬂammatory changes.
Involvement of the anterior maxilla can result in sig-
niﬁcant bone erosion, with loss of the teeth in this area.
Maxillary involvement in children can affect the devel-
oping teeth and produce enamel hypoplasia and short
tapering roots. Dental pulp infection can lead to inter-
nal resorption or pulpal necrosis. Teeth with pulpal
involvement may demonstrate a clinically obvious red
discoloration of the crown. The cause of the discolor-
ation is unknown but appears to be related to intrapulpal
vascular damage secondary to the infection. Granulo-
matous involvement of the nasal cavity can erode
through the palatal tissues and result in perforation.
The facial and trigeminal nerves can be involved
with the infectious process. Facial paralysis may be
unilateral or bilateral. Sensory deﬁcits may affect any
branch of the trigeminal nerve, but the maxillary divi-
sion is the most commonly affected.
HISTOPATHOLOGIC FEATURES
Biopsy specimens of paucibacillary leprosy typically
reveal the tuberculoid pattern that demonstrates gran-
ulomatous inﬂammation with well-formed clusters of
epithelioid histiocytes, lymphocytes, and multinucle-
ated giant cells (Fig. 5-28). A paucity of organisms
exists; when present, they can be demonstrated only
when stained with acid-fast stains, such as the Fite
method. Multibacillary leprosy is associated with a
lepromatous pattern that demonstrates no well-formed
granulomas; the typical ﬁnding is sheets of lympho-
cytes intermixed with vacuolated histiocytes known as
lepra cells (Fig. 5-29). Unlike tuberculoid leprosy, an
abundance of organisms can be demonstrated with
acid-fast stains in the lepromatous variant (Fig. 5-30).
Fig. 5-28 Paucibacillary (tuberculoid) leprosy. Well-
formed granulomatous inﬂammation demonstrating clusters
of lymphocytes and histiocytes.
Fig. 5-29 Multibacillary (lepromatous) leprosy. Sheets of
lymphocytes and histiocytes exhibiting scattered vacuolated
lepra cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 201
It has been reported that the organism can be found
with special stains in 100% of lepromatous leprosy
cases, 75% of borderline cases, and only 5% of tubercu-
loid cases.
DIAGNOSIS
The deﬁnitive diagnosis is based on the clinical presen-
tation and supported by the demonstration of acid-fast
organisms on a smear or in the tissue. The organism
cannot be cultivated on artiﬁcial media, but M. leprae
can be identiﬁed by using molecular biologic tech-
niques. No reliable test is available to determine
whether a person has been exposed to M. leprae without
developing the disease; this creates difﬁculties in estab-
lishing the diagnosis and determining the prevalence
of the infection.
TREATMENT AND PROGNOSIS
One of the major reasons for the decreasing prevalence
of leprosy is the provision of an uninterrupted supply
of free, high-quality medications in calendar blister
packs to all patients regardless of the living conditions
or remoteness of the location. Paucibacillary leprosy is
treated with a 6-month regimen of rifampin and
dapsone, whereas patients with multibacillary leprosy
receive 24 months of rifampin, dapsone, and clofazi-
mine. Long-term follow up is recommended because
of occasional relapses. Patients allergic to rifampin are
treated with a 24-month course of clofazimine, oﬂoxa-
cin, and minocycline.
After resolution of the infection, the therapy must
be directed toward reconstruction of the damage, in
addition to physiotherapy and education of the patients
who must live not only with their physical damage but
also with the psychologic stigmata. As medical therapy
becomes more successful, the number of long-term
survivors of the infection increases. Worldwide, it is
estimated that currently about 3 million individuals
have leprosy-related impairments and disability.
NOMA (CANCRUM ORIS; OROFACIAL
GANGRENE; GANGRENOUS
STOMATITIS; NECROTIZING
STOMATITIS)
The term noma is derived from the Greek word nomein,
meaning to devour. Noma is a rapidly progressive, poly-
microbial, opportunistic infection caused by compo-
nents of the normal oral ﬂora that become pathogenic
during periods of compromised immune status. Fuso-
bacterium necrophorum and Prevotella intermedia are
thought to be key players in the process and interact
with one or more other bacterial organisms, of which
the most commonly implicated are Borrelia vincentii,
Porphyromonas gingivalis, Tannerella forsynthesis, Trepo-
nema denticola, Staphylococcus aureus, and nonhemolytic
Streptococcus spp. The reported predisposing factors
include the following:
● Poverty
●Malnutrition or dehydration
●Poor oral hygiene
● Poor sanitation
●Unsafe drinking water
●Proximity to unkempt livestock
● Recent illness
● Malignancy
● An immunodeﬁciency disorder, including AIDS
In many cases a recent debilitating illness appears
to set the stage for the development of noma. Measles
most frequently precedes development of noma; other
common but less frequent predisposing illnesses
include herpes simplex, varicella, scarlet fever, malaria,
tuberculosis, gastroenteritis, and bronchopneumonia.
Cases associated with malignancies (e.g., leukemia)
are not rare. In many instances the infection begins as
necrotizing ulcerative gingivitis (NUG) (see page 157),
and several investigators believe that noma is merely
an extension of the same process. Because the disease
usually is well advanced at the time of initial presenta-
tion, descriptions of the initial stages of the disease are
sketchy.
In the developed world, noma has virtually disap-
peared except for an occasional case related to immu-
nosuppressive conditions such as HIV infection, severe
combined immunodeﬁciency syndrome, or intense
immunosuppressive therapy. The World Health Orga-
nization (WHO) estimates the global yearly incidence
to be approximately 140,000, with 100,000 of these
patients being between the ages of 1 and 7 years and
living in sub-Saharan Africa. In these areas the chil-
Fig. 5-30 Multibacillary (lepromatous) leprosy. Acid-fast
stain exhibiting numerous small mycobacterial organisms
seen individually and in clusters. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

202 ORAL AND MAXILLOFACIAL PATHOLOGY
dren are at increased risk after discontinuation of
breast feeding, which is replaced by a carbohydrate-
rich diet with unsafe water.
CLINICAL FEATURES
Noma usually arises in children from 1 to 10 years of
age, although it also can occur in adults with a major
debilitating disease (e.g., diabetes mellitus, leukemia,
lymphoma, HIV infection). The infection often begins
on the gingiva as NUG, which may extend either facially
or lingually to involve the adjacent soft tissue and form
areas called necrotizing ulcerative mucositis. Zones
of necrosis also may develop in soft tissue not continu-
ous with the gingiva, particularly in areas of trauma
(Fig. 5-31). The necrosis can extend into deeper tissues;
over the next few days, zones of blue-black discolor-
ation of the overlying skin surface may develop (Fig.
5-32). Often the necrotic zone is cone shaped, with a
small point of cutaneous necrosis overlying a larger
zone of oral mucosal destruction. Unlike other infec-
tions, the process does not follow tissue planes and
tends to spread through anatomic barriers such as
muscle. These discolored zones break down into areas
of yellowish necrosis that also frequently spreads
into adjacent bone, with large areas of osteomyelitis
possible. In most instances the necrotic area is well
deﬁned and unilateral. Fetid odor, signiﬁcant pain,
fever, malaise, tachycardia, increased respiratory rate,
anemia, leukocytosis, and regional lymphadenopathy
are typical. Additional lesions also may occur in distant
sites, such as the scalp, neck, ear, shoulders, chest,
perineum, and vulva.
The majority of affected children also demonstrate
signiﬁcant stunting of growth. Although many families
will have numerous children living in the same envi-
ronment, those affected with noma typically are iso-
lated, which suggests additional factors at work. Some
have suggested that victims of intrauterine growth
retardation and premature birth may be predisposed
to future development of noma. Others have suggested
that infection with certain herpesviruses, such as cyto-
megalovirus, may lower local immunity and promote
development of noma.
TREATMENT AND PROGNOSIS
In addition to using appropriate antibiotics to treat
noma, the clinician must direct therapeutic attention
not only to local wound care but also toward correcting
the inadequate nutrition, hydration, and electrolyte
imbalances. Penicillin and metronidazole are the ﬁrst-
A B
Fig. 5-31 Necrotizing ulcerative mucositis. A, Large area of soft tissue necrosis of the
posterior soft palate on the left side. B, Healing site of necrotizing mucositis 6 days after
initiation of tetracycline therapy.
Fig. 5-32 Noma. Extensive blackish orofacial necrosis of
the right cheek in an immunocompromised patient. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 203
line therapeutic antibiotics for necrotizing stomatitis.
The therapy of noma neonatorum is directed against
the Pseudomonas organisms and often consists of piper-
acillin, gentamicin, or clindamycin. Conservative
débridement of gross necrotic areas is recommended,
but aggressive removal is contraindicated because it
does not stop the extension of the process and com-
pounds the reconstruction problems. Necrotic bone is
left in place to help hold the facial form but is removed
as it sequestrates. Reconstruction should be delayed for
1 year to ensure complete recovery.
Before the development of antibiotics, the mortality
rate approached 95% and still remains high in many
portions of the world. In the United States, fewer than
10% of appropriately treated patients die. Common
causes of death include infectious complications, such
as pneumonia, diarrhea, and septicemia. Noma infec-
tion can cause signiﬁcant morbidity when it is not fatal.
Facial disﬁgurement that affects the patient’s future
growth and development is not rare. Reconstruction
often is extremely challenging and should be delayed
until healing is complete. Trismus from signiﬁcant
scarring associated with mandibular involvement can
occur, but it can be countered with early postoperative
and long-term physiotherapy. Noma neonatorum is
much more dangerous because the septicemia that is
related to Pseudomonas spp. infection is usually fatal.
ACTINOMYCOSIS
Although the term actinomycosis seems to imply a
fungal infection, it is an infection of ﬁlamentous,
branching, gram-positive anaerobic bacteria. Actino-
mycetes are normal saprophytic components of the
oral ﬂora. Documented sites of colonization in healthy
patients include the tonsillar crypts, dental plaque and
calculus, carious dentin, gingival sulci, and periodontal
pockets. The colonies within the tonsillar crypts may
form concretions and become large enough for the
patient to feel the ﬁrm plugs within the crypts (see page
185). In surveys of documented actinomycosis, Actino-
myces israelii is the causative organism in the majority,
with A. viscosus being a close second. Much less fre-
quent causes of the infection are A. naeslundii, A. odonto-
lyticus, A. meyeri, A. pyogenes, A. viscosus, and A. bovis,
along with Arachnia propionica and Biﬁdobacterium
dentium. In most such cases the primary organism is
combined synergistically with streptococci and
staphylococci.
CLINICAL FEATURES
Actinomycosis may be either an acute, rapidly pro-
gressing infection or a chronic, slowly spreading lesion
that is associated with ﬁbrosis. Approximately 55% of
cases of actinomycosis are diagnosed in the cervicofa-
cial region, with 25% occurring in the abdominal and
pelvic region and 15% in the pulmonary system. The
remaining 5% exhibits a variety of patterns, such as
superﬁcial skin infections, or infections of the genito-
urinary region (often linked to use of intrauterine con-
traceptive devices).
The suppurative reaction of the infection may dis-
charge large yellowish ﬂecks that represent colonies of
the bacteria called sulfur granules. Although common,
sulfur granules are not present invariably. In addition,
another infection that also can produce sulfur granules
and mimic actinomycosis is botryomycosis, an unre-
lated process that represents an unusual host reaction
to Staphylococcus aureus and other bacteria.
In the cervicofacial region, the organism typically
enters tissue through an area of prior trauma, such as
a soft tissue injury, periodontal pocket, nonvital tooth,
extraction socket, or infected tonsil. The infection does
not spread along the typical fascial planes and usually
disregards the normal lymphatic and vascular routes.
Direct extension through soft tissue is seen, and lymph
nodes become involved only if they are in the path of
the process. The classic description is of a “wooden”
indurated area of ﬁbrosis, which ultimately forms a
central, softer area of abscess. The infection may extend
to the surface, forming a sinus tract (Fig. 5-33). Pain
often is minimal. The soft tissues of the submandibular,
submental, and cheek areas are common areas of
involvement, with the area overlying the angle of the
mandible being the most frequently affected site.
Localized abscesses without the associated chronic
ﬁbrosing reaction have been reported in soft tissue that
has received minor trauma. The tongue is the most
frequently mentioned site, but any oral mucosal loca-
tion is possible. Involvement of the tonsillar crypts may
produce infectious symptoms; in most cases, however,
Fig. 5-33 Actinomycosis. Draining ﬁstula of the right
submandibular area. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

204 ORAL AND MAXILLOFACIAL PATHOLOGY
the primary change is one of variable hyperplasia. Ton-
sillar hyperplasia thought to be secondary to actinomy-
cotic infestation of the crypts does not appear responsive
to antibiotics, probably because of the superﬁcial loca-
tion of the bacterial colonies. Tonsillectomy is gener-
ally the most effective treatment for this situation.
Salivary gland involvement also is not unusual.
Intraductal colonization by the organism may lead to
infections in both the submandibular and parotid
glands, resulting in abscess formation in the subman-
dibular and masseter spaces, respectively. In addition,
more localized infections occur in minor salivary gland
ducts, which also may demonstrate mucous plugs or
sialoliths.
Actinomycotic osteomyelitis of the mandible and
maxilla has been reported. Trauma, periodontal infec-
tions, nonvital teeth, and extraction sites have all pro-
vided access. Ill-deﬁned areas of radiolucency, often
surrounded by radiopacity, may be found with or
without involvement of the overlying soft tissue.
Intrabony colonization of dentigerous cysts without
other signiﬁcant clinical or radiographic spread has
been reported. Periapical inﬂammatory lesions
involved by the bacteria can result in lesions that are
difﬁcult to resolve with standard endodontic treatment,
but such lesions typically remain localized and do not
evolve into invasive cervicofacial actinomycosis.
HISTOPATHOLOGIC FEATURES
The tissue removed from areas of active infection dem-
onstrates a peripheral band of ﬁbrosis encasing a zone
of chronically inﬂamed granulation tissue surrounding
large collections of polymorphonuclear leukocytes
and, with luck, colonies of organisms (Fig. 5-34). The
colonies consist of club-shaped ﬁlaments that form a
radiating rosette pattern (Fig. 5-35). With hematoxylin
and eosin (H&E) stains, the central core stains baso-
philic and the peripheral portion is eosinophilic.
Methenamine silver stains demonstrate the organisms
well. If the colonies of actinomycetes become dis-
placed from the exudate, then a rim of neutrophils
typically clings to the periphery of the organisms.
DIAGNOSIS
The diagnosis of actinomycosis is achieved ideally by
culture, but less than 50% of cases are positive because
of the overgrowth of associated bacteria, prior antibi-
otic therapy, or improper anaerobic media conditions.
Lacking positive culture results, a strong presumptive
diagnosis can be obtained through a demonstration of
the typical colonies in lesional biopsy material. The
material for culture and histopathologic examination is
typically obtained during surgical exploration, with
ﬁne-needle aspiration being a satisfactory substitute in
many cases. Sulfur granules in infections other than
actinomycosis are so rare that their demonstration
strongly supports the diagnosis. If desired, then ﬂuores-
cein-conjugated antiserum can be used on the granules
to speciﬁcally identify the Actinomyces species.
TREATMENT AND PROGNOSIS
The treatment of choice for actinomycosis in chronic
ﬁbrosing cases is prolonged high doses of antibiotics in
association with abscess drainage and excision of the
sinus tracts. A high antibiotic concentration is required
to penetrate larger areas of suppuration and ﬁbrosis.
Although penicillin remains the standard of care with
no documented in vivo resistance, some clinicians
believe amoxicillin represents a better ﬁrst-choice
Fig. 5-34 Actinomycosis. Colony of actinomycotic
organisms surrounded by polymorphonuclear leukocytes.
Fig. 5-35 Actinomycosis. Actinomycotic colony exhibiting
club-shaped ﬁlaments arranged in a radiating rosette pattern. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 205
antibiotic. Other investigators have demonstrated
in vitro resistance to penicillin and recommend tetra-
cycline, which is as effective as penicillin and is the
drug of choice for patients with a known allergy to
penicillin. Early cervicofacial actinomycosis typically
responds to a 5- to 6-week course of penicillin; patients
with deep-seated infections may require up to 12
months.
In cases of osteomyelitis caused by actinomycetes,
antibiotic therapy alone often is associated with persis-
tent disease. Adequate débridement appears to be the
cornerstone of therapy and ultimately determines the
success of the subsequent antibiotic treatment. When
combined with appropriate surgery, a 3-month course
of penicillin usually is curative. In resistant cases,
repeated débridement should be combined with cul-
tures to direct future antibiotic therapy. Care should be
taken to ensure that colonization of bony sequestra by
actinomycotic colonies is not mistaken for invasive
actinomycotic osteomyelitis.
Several authors have indicated that localized acute
actinomycotic infections may be treated more conser-
vatively than the deep, chronic cases of actinomycosis.
Localized periapical and pericoronal actinomycosis,
tongue abscesses, and focal subacute sialadenitis with
intraductal involvement frequently respond well to
surgical removal of infected tissue. In these cases it
appears best to reserve antibiotics for patients in whom
local surgical excision fails.
CAT-SCRATCH DISEASE
Cat-scratch disease is an infectious disorder that
begins in the skin but classically spreads to the adjacent
lymph nodes. This infection is the most common cause
of chronic regional lymphadenopathy in children, with
an estimated 22,000 cases occurring annually in the
United States. This disease has been recognized since
1931, but the deﬁnitive cause was not determined
until the 1980s. Isolation and culture of the organism
were ﬁnally achieved in 1988. The causative organism
was initially named Rochalimaea henselae but was reclas-
siﬁed as Bartonella henselae. On very rare occasions, cat-
scratch disease is caused by related species, Bartonella
quintana or Bartonella clarridgeiae.
Almost all cases arise after contact with a cat, usually
a kitten. Cat ﬂeas appear to be involved in the transmis-
sion of the causative organism among cats, but the role
of ﬂeas in the transmission from cats to humans is
unclear. Most human infections appear to follow
scratches, licks, or bites from domestic cats. Infection
from other sources is highly unlikely, but the disease
rarely has been described via dogs, monkeys, porcu-
pine quills, and thorns. Person-to-person transmission
has not been documented.
CLINICAL FEATURES
Eighty percent of the cases occur in patients younger
than 21 years of age. Cat-scratch disease begins as a
papule or pustule that develops in 3 to 14 days along
the initial scratch line (Fig. 5-36). The lymph node
changes develop in approximately 3 weeks and often
may be accompanied by fever or malaise (Fig. 5-37).
Scratches on the face typically lead to submandibular
lymphadenopathy, and the patient may be referred to
dental practitioners to rule out an odontogenic infec-
tion. Often the primary site of trauma may have
resolved by the time that the symptomatic lymphade-
nopathy is diagnosed. Therefore, cat-scratch disease
must be considered strongly in the differential diagno-
sis of patients with unexplained symptomatic lymph-
adenopathy. In about half of the cases, a single node is
involved. Multiple regional nodes are affected in about
20%, and nodal enlargement is discovered in multiple
sites in about 33%. Suppuration is noted in approxi-
mately 10% of affected patients.
A few patients with cat-scratch disease demonstrate
unusual presentations. The infection can appear as an
intraoral mass in the buccal mucosa when lymphoid
aggregates become involved from an adjacent cutane-
ous primary site. Scratches in the preauricular area
may localize in parotid lymphoid tissue and can
cause signiﬁcant parotid pain or even temporary facial
paralysis. Other less common problems include granu-
lomatous osteomyelitis, arthralgias, encephalopathy,
erythematous and maculopapular rashes, splenomeg-
aly, hepatic lesions, thrombocytopenia, pneumonia,
anemia, pleural effusions, and recurrent bacterial
infections.
Primary lesions adjacent to the eye can result in a
conjunctival granuloma that is associated with preau-
ricular lymphadenopathy (oculoglandular syndrome
Fig. 5-36 Cat-scratch disease. Papule that developed at
initial site of injury. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

206 ORAL AND MAXILLOFACIAL PATHOLOGY
of Parinaud); this pattern is thought to occur when an
individual touches fur moistened with the cat’s saliva
during grooming. When the individual rubs their eye,
the organism is transmitted to the conjunctiva.
During the past 2 decades, an unusual subcutane-
ous vascular proliferation, histopathologically similar
to histiocytoid hemangioma, has been recognized in
patients with AIDS. This proliferation has been termed
bacillary angiomatosis, with most cases being deﬁni-
tively associated with Bartonella henselae. In a minority
of the cases, bacillary angiomatosis is caused by a
related organism, B. quintana. The affected areas often
resemble Kaposi’s sarcoma (see page 270) and appear
as variable numbers of red-to-purple skin lesions. These
may be macular, papular, or pedunculated and exhibit
a widespread distribution on the skin. Pain and tender-
ness are common. The larger lesions are friable and
bleed easily.
Oral lesions have been seen in bacillary angiomato-
sis and also may resemble Kaposi’s sarcoma. The
affected areas may exhibit zones of alveolar bone loss
or may be within the soft tissue and appear as a prolif-
erative vascular lesion.
HISTOPATHOLOGIC FEATURES
The involved lymph nodes are enlarged as a result of
signiﬁcant cortical hyperplasia, which classically con-
tains areas of stellate suppurative necrosis surrounded
by a band of histiocytes and neutrophils (Fig. 5-38). In
some cases, signiﬁcant necrosis is absent, but areas of
karyorrhexis are present around proliferations of plump
vascular channels that often exhibit thickened eosino-
philic walls. On staining with the Warthin-Starry
method, cat-scratch bacilli are usually found in areas
without signiﬁcant necrosis. As the disease progresses
and necrosis increases, the organisms become more
difﬁcult to identify. In addition, the Brown-Hopps
method of gram staining may be used to highlight the
bacilli. Recently, a commercially available monoclonal
antibody against B. henselae has been used to demon-
strate the organisms via immunoperoxidase techniques
on parafﬁn-embedded material. Upon immunostain-
ing, the organisms are highlighted dramatically, an
important advance over the previous special stains. One
downside is the failure of this speciﬁc antibody to react
with the organisms in the exceptional cases of cat-
scratch disease caused by B. quintana or B. clarridgeiae.
Bacillary angiomatosis reveals lobular proliferations
of small blood vessels in an edematous to ﬁbrotic
stroma. The supporting connective tissue typically
demonstrates a signiﬁcant number of neutrophils and
leukocytoclasis, important clues to the diagnosis. Also
present are variably sized amphophilic and granular
aggregates that upon Warthin-Starry staining prove to
be masses of the causative bacteria.
DIAGNOSIS
Today the diagnosis of cat-scratch disease usually is
established via serologic tests that demonstrate a high
degree of sensitivity and speciﬁcity. The most widely
Fig. 5-37 Cat-scratch disease. Submandibular
lymphadenopathy has developed after initial trivial injury to
skin. (Courtesy of Dr. George Blozis.)
Fig. 5-38 Cat-scratch disease. Intranodal area of necrosis
surrounded by a band of epithelioid histiocytes and
lymphocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 207
used is an indirect ﬂuorescent antibody assay for
detecting antibodies to B. henselae. Another commer-
cially available method is an enzyme-linked immuno-
sorbent assay (ELISA) for IgM antibodies to the
organism. Polymerase chain reaction (PCR) techniques
also are available but are not widely used.
TREATMENT AND PROGNOSIS
Cat-scratch disease is a self-limiting condition and nor-
mally resolves within 4 months. The use of local heat,
analgesics, and aspiration of the node on suppuration
is the typical pattern of therapy. If persistent discom-
fort makes nodal aspiration necessary, then drainage
should be achieved with a needle that is tunneled into
the node laterally through normal skin 1 to 2 cm away
from the lesion. Incision directly into the node could
result in a chronic draining sinus.
Although the organism has demonstrated sensitivity
to a number of antibiotics in culture, the results in
immunocompetent patients have been inconsistent
and difﬁcult to evaluate because the disease is self-
limited in most cases. Antibiotics typically are reserved
for those cases that demonstrate a prolonged course or
severe involvement. Use of antibiotic drugs in patients
with AIDS and bacillary angiomatosis has produced
dramatic resolution within 2 days. Although a number
of medications have been used successfully, the primary
antibiotics used for cat-scratch disease or bacillary
angiomatosis are azithromycin, erythromycin, doxycy-
cline, rifampin, ciproﬂoxacin, and gentamicin.
SINUSITIS
Sinusitis is one of the most common health complaints
in the United States. To understand the problem, the
clinician must ﬁrst have some knowledge of sinus
anatomy. Adults have bilateral maxillary, frontal, sphe-
noid, ethmoid, and mastoid sinuses. Except for the
mastoid sinuses, these cavities drain into the nose
through openings called ostia. The frontal, sphenoid,
and maxillary sinuses must drain through the middle
meatus. In addition, the ethmoids are located bilater-
ally in this area of the nose and present as a labyrinth
of 3 to 15 small sinuses, which drain through smaller
ostia. The ostiomeatal complex, with its numerous
narrow openings (Fig. 5-39), is the key to sinus disease
because it is the primary nasal site for the deposition
of foreign matter from inspired air.
Normal sinuses are lined by pseudostratiﬁed colum-
nar epithelium with cilia. The cilia are necessary to
move the sinus secretions toward the ostia. Gravity also
is beneﬁcial in removing the secretions, except in the
maxillary sinus where there is a superior location of the
ostial opening and, therefore, the ciliary apparatus
becomes even more important. Normal function of the
paranasal sinuses depends on the following:
●Patency of the ostial openings
●Proper function of the ciliary apparatus
●Quality of the nasal secretions
Disruption of this balance leads to sinusitis. For a
long time, researchers believed that primary inﬂam-
mation of the lining of the maxillary antrum was
the major cause of sinusitis; however, advances have
demonstrated that most sinus disease begins from a
blockage of the ostiomeatal complex that disrupts
normal drainage, decreases ventilation, and precipi-
tates disease. Less common localized sinus infections
can occur from focal areas of inﬂammation within a
single sinus, such as a dental infection affecting the
maxillary sinus.
Approximately 10% of maxillary sinusitis cases arise
from an odontogenic source such as infection from the
maxillary teeth, dental trauma, noninﬂammatory odon-
togenic pathoses, or iatrogenic causes such as dental
extractions, maxillary osteotomies, or placement of
dental implants. In such cases, therapy requires resolu-
tion of the odontogenic pathosis in addition to manage-
ment of the sinus infection.
All of the sinuses contain bacteria. In a person with
sinusitis, infection is present initially or as the disease
F F
M M
E
MM
Fig. 5-39 The paranasal sinuses. Illustration
demonstrating the ostiomeatal complex and its importance
to appropriate sinus drainage. The left side demonstrates the
typical narrow middle meatus through which all sinus
drainage must pass. The right side reveals enlargement of the
middle meatus, such as that achieved through corrective
endoscopic surgery. M, Maxillary sinus; F, frontal sinus;
E, ethmoid sinuses; MM, middle meatus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

208 ORAL AND MAXILLOFACIAL PATHOLOGY
evolves. With bacteria already present in the sinuses,
changes as minor as a slight mucosal thickening in the
ostiomeatal complex can lead to improper sinus drain-
age and infection. The most common predisposing
factors are a recent upper respiratory viral infection or
allergic rhinitis. Other less common causes include
cystic ﬁbrosis, immotile cilia syndrome, bronchiectasis,
developmental abnormalities, and immunodeﬁciency
(including AIDS).
In otherwise healthy patients, the most common
organisms responsible for acute sinusitis are Streptococ-
cus pneumoniae, Haemophilus inﬂuenzae, and Moraxella
catarrhalis. If not corrected, some cases of acute sinus-
itis may become chronic. Chronic sinusitis is deﬁned as
recurring episodes of acute sinusitis or symptomatic
sinus disease lasting longer than 3 months. In these
cases the bacteria tend to be anaerobes and are most
frequently Streptococcus, Bacteroides, or Veillonella spp.
When sinusitis arises secondary to an odontogenic
infection, the causative organisms are usually those
that predominate in periodontal or endodontic infec-
tions and include bacteria such as Peptostreptococcus
spp., Fusobacterium spp., Prevotella spp., Bacteroides spp.,
and Porphyromonas spp.
Infrequently, in an environment of chronic sinusitis,
an area of dystrophic calciﬁcation (antrolith) may
develop and be detected radiographically. The nidus
for this calciﬁcation may be endogenous from materi-
als such as inﬂamed mucus, pus, or clots. In other cases
the source may be exogenous from tooth roots or
foreign bodies, such as dental materials, vegetable
matter, paper, glass, and stone. Focal antral calciﬁca-
tion also has been seen in sinuses ﬁlled with a fungal
ball of Aspergillus fumigatus (noninvasive mycetoma)
(see page 234). A sinus that is unresponsive to therapy
and exhibits focal antrolith formation within a diffuse
soft tissue opaciﬁcation is highly suggestive of noninva-
sive aspergillosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
Presenting symptoms of acute sinusitis in adults include
headache, fever, and facial pain over the affected sinus.
Anorexia, photophobia, and malaise also may be seen.
Anterior nasal or posterior pharyngeal discharge is
present; it may be thick or thin in consistency and
appear clear, mucoid, or purulent. Children, with their
less complex sinuses, typically have only persistent
cough, fever, and purulent rhinorrhea. Localized
involvement of the maxillary sinus can occur as pain
over the cheekbone, toothache, periorbital pain, or
temporal headache. Maxillary sinusitis is associated
with increased pain when the head is held upright and
less discomfort when the patient is supine.
Chronic sinusitis is less diagnostic, and radiographic
imaging becomes more important. Frequent com-
plaints include facial pressure, pain, or a sensation of
obstruction. In some cases, nonspeciﬁc symptoms,
such as headache, sore throat, lightheadedness, or gen-
eralized fatigue, also may be present or even dominate.
Radiographically, the involved sinus has a cloudy,
increased density (Fig. 5-40).
At times, sinusitis can be confused with an odonto-
genic infection. In such cases, close examination of
periapical radiographs, a thorough periodontal exami-
nation, and assessment of tooth vitality often will rule
out or point to an odontogenic infection. A sinus infec-
tion should be strongly considered when patients
complain of pain from several teeth, demonstrate ten-
derness over one or both of the maxillary sinuses,
exhibit nasal congestion, or have a nasal discharge
accompanied by a foul odor, fever, and headache.
In addition to the patient’s symptoms, the diagnosis
in the past often was made by procedures such as
transillumination and by plain radiographs, such as
the Waters, Caldwell-Luc, lateral, and submental vertex
views. Today, when the diagnosis is in question, many
clinicians use nasal endoscopy and computed tomog-
raphy (CT). Areas of infection and sites of improper
drainage will be found. These techniques not only
conﬁrm the diagnosis but also pinpoint the primary
pathologic alteration that led to the obstructive
sinusitis.
An antrolith appears radiographically as a radio-
dense focus within the sinus. The calciﬁcation often is
seen in association with a thickening of the antral lining
or diffuse clouding of the affected sinus.
TREATMENT AND PROGNOSIS
Although acute sinusitis is usually a self-limiting
disease, antibiotics are frequently prescribed. Few
placebo-controlled, double-blind, randomized clinical
trials have been published, and the results are inconsis-
tent. Although the supporting evidence is weak, the few
well-performed trials suggest that patients with more
severe signs and symptoms may beneﬁt from an antibi-
otic, whereas those with less severe manifestations do
not require antibiotic therapy.
If antibiotics are used, the ﬁrst-line therapy for acute
sinusitis in otherwise healthy patients is amoxicillin.
Because of drug resistance, additional medications
are used if the patient does not respond to the initial
antibiotic. Amoxicillin-clavulanate, trimethoprim-
sulfamethoxazole, or cefaclor are good antibiotic drugs
for resistant cases. Although topical decongestants
shrink nasal membranes and improve ostial drainage,
they are not recommended because of the resultant
decreased ciliary function and decreased mucosal `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 209
blood ﬂow, which leads to impaired antibiotic delivery.
The effect of systemic antihistamine and decongestant
medications on sinusitis has not been studied
adequately.
In otherwise healthy adult patients, chronic sinusitis
that is not responsive to typical medical management
often is corrected surgically. In the past, radical strip-
ping of the diseased sinus mucosa was the therapy of
choice. Today, nasal endoscopy has shown that sinus-
itis is a disease of obstruction and that mucosal inﬂam-
mation is usually a secondary development. Functional
endoscopic sinus surgery enlarges the ostial openings
and corrects blockages in the ostiomeatal complex,
often with a rapid resolution of the signs and symptoms
(see Fig. 5-35). The surgery is delicate because it
extends close to the orbit and the central nervous
system. Each patient’s unique anatomy should be eval-
uated carefully by CT and nasal endoscopy before
surgery.
Although endoscopic surgery is considered by many
to be the current standard of care for chronic sinusitis,
a few investigators still use the more invasive Caldwell-
Luc procedure in selected patients. Although the
Caldwell-Luc procedure is associated with a higher
prevalence of signiﬁcant complications, it also is associ-
ated with a lower number of reoperations when com-
pared with the less invasive endoscopic procedure.
Therefore, some clinicians continue to use the old tech-
nique in patients who demonstrate recurrent disease
limited to the maxillary sinus and prefer a single
major operation rather than multiple, less invasive
procedures.
When the infection is isolated to a single maxillary
sinus and associated with a odontogenic cause, the
dental pathosis must be resolved in addition to treating
the diseased sinus. Although the Caldwell-Luc proce-
dure continues to be used, endoscopic shaver-assisted
techniques are becoming more popular to perform an
antrostomy and accomplish removal of pathoses, such
as irreversibly diseased antral lining, polyps, tooth frag-
ments, and foreign material. When the sinus disease is
caused by an oroantral communication, defects less
than 5 mm typically close spontaneously. With small
openings, the defect can be covered and protected
during the early stages of healing with a resorbable
barrier such as an absorbable gelatin sponge. Oroantral
ﬁstulae larger that 5 mm should be closed primarily,
but this should be done only after resolution of any
associated acute infection within the associated sinus.
In children, continued medical management is the
therapy of choice for uncomplicated acute or recurrent
acute sinusitis. The anatomy in the child, with the
decreased distance between the orbit and brain,
increases the difﬁculty of any surgical procedure. Sur-
gical management is indicated in only a small number
of childhood sinusitis cases. Suppurative sinusitis
extending into surrounding tissues or true chronic
sinusitis caused by serious underlying systemic disease
are examples of indications for the surgical manage-
ment of sinus disease in a child.
Fig. 5-40 Sinusitis. Cloudy right maxillary antrum. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

210 ORAL AND MAXILLOFACIAL PATHOLOGY
BIBLIOGRAPHY
General References
Gorbach SL, Bartlett JG, Blacklow NR: Infectious diseases, ed 2,
Philadelphia, 1998, WB Saunders.
Holmes KK: Sexually transmitted diseases, ed 3, New York, 1999,
McGraw-Hill.
Katz SL, Gershon AA, Hotez PJ et al: Krugman’s infectious diseases
of children, ed 10, St Louis, 1999, Mosby.
Streptococcal Infections (Impetigo; Erysipelas; Streptococcal
Pharyngitis and Tonsillitis; Scarlet Fever)
Bialecki C, Feder HM, Grant-Kels JM: The six classic childhood
exanthems: a review and update, J Am Acad Dermatol 21:891-
903, 1989.
Bisno AL, Gerber MA, Gwaltney Jr JM et al: Practice guidelines
for the diagnosis and management of group A streptococcal
pharyngitis, Clin Infect Dis 35:113-125, 2002.
Bonnetblanc J-M, Bédane C: Erysipelas. Recognition and man-
agement, Am J Clin Dermatol 4:157-163, 2003.
Bratton RL, Neese RE: St. Anthony’s ﬁre: diagnosis and manage-
ment of erysipelas, Am Fam Physician 51:401-404, 1995.
Gerber MA: Diagnosis and treatment of pharyngitis in children,
Pediatr Clin North Am 52:729-747, 2005.
Giunta JL: Comparison of erysipelas and odontogenic cellulitis,
J Endod 13:291-294, 1987.
Hirschmann JV: Impetigo: etiology and therapy, Curr Clin Top
Infect Dis 22:42-51, 2002.
Jaggi P, Shulman ST: Group A streptococcal infections, Pediatr
Rev 27:99-105, 2006.
Katzenell U, Shemer J, Bar-Dayan Y: Streptococcal contamina-
tion of food: an unusual cause of epidemic pharyngitis, Epide-
miol Infect 127:179-184, 2001.
Kolokotronis A, Doumas S, Lambroudi M et al: Facial and peri-
oral primary impetigo: a clinical study, J Clin Pediatr Dent
29:341-346, 2005.
Koning S, Verhagen AP, van Suijlekom-Smit LW et al: Interven-
tions for impetigo, Cochrane Database Syst Rev 2:CD003261,
2004.
Ochs MW, Dolwick MF: Facial erysipelas: report of a case and
review of the literature, J Oral Maxillofac Surg 49:1116-1120,
1991.
Österlund A, Kahlmeter G, Hæggman S et al: Staphylococcus
aureus resistance to fusidic acid among Swedish children: a
follow-up study, Scand J Infect Dis 38:332-334, 2006.
Pavlotsky F, Amrani S, Trau H: Recurrent erysipelas: risk factors,
J Dtsch Dermatol Ges 2:89-95, 2004.
Pichichero M, Casy J: Comparison of European and U.S. results
for cephalosporin versus penicillin treatment of group A
streptococcal tonsillopharyngitis, Eur J Clin Microbiol Infect Dis
25:354-364, 2006.
Török L: Uncommon manifestations of erysipelas, Clin Dermatol
23:515-518, 2005.
Watkins P: Impetigo: aetiology, complications and treatment
options, Nurs Stand 19:50-54, 2005.
Tonsillar Concretions and Tonsillolithiasis
Cooper MM, Steinberg JJ, Lastra M et al: Tonsillar calculi: report
of a case and review of the literature, Oral Surg Oral Med Oral
Pathol 55:239-243, 1983.
Finkelstein Y, Talmi YP, Ophir D et al: Laser cryptolysis for the
treatment of halitosis, Otolaryngol Head Neck Surg 131:372-
377, 2004.
Özcan E, Ural A, Öktemer TK et al: Bilateral tonsillolithiasis: a
case report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
102:e17-18, 2006.
Myers NE, Compliment JM, Post JC et al: Tonsilloliths a common
ﬁnding in pediatric patients, Nurse Pract 31:53-54, 2006.
Ram S, Siar CH, Ismail SM et al: Pseudo bilateral tonsilloliths: a
case report and review of the literature, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 98:110-114, 2004.
Sezer B, Tugsel Z, Bilgen C: An unusual tonsillolith, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 95:471-473, 2003.
Verghese A, Fernando C, Roberson D et al: The foul-smelling,
removable tonsillar concretion: a poorly appreciated mani-
festation of colonization with Actinomyces, J Tenn Med Assoc
83:71-73, 1990.
Diphtheria
Centers for Disease Control and Prevention: Fatal respiratory
diphtheria in a U.S. traveler to Haiti—Pennsylvania, 2003,
MMWR Morb Mortal Wkly Rep 52:1285-1286, 2004.
deBenoist A-C, White JM, Efstratiou et al: Imported cutaneous
diphtheria, United Kingdom, Emerg Infect Dis 10:511-513,
2004.
Galazka A: Implications of the diphtheria epidemic in the former
Soviet Union for immunization programs, J Infect Dis
181(suppl 1):S244-248, 2000.
Galazka A: The changing epidemiology of diphtheria in the
vaccine era, J Infect Dis 181(suppl 1):S2-9, 2000.
Hadﬁeld TL, McEvoy P, Polotsky Y et al: The pathology of diph-
theria, J Infect Dis 181(suppl 1):S116-120, 2000.
Jayashree M, Shruthi N, Singhi S: Predictors of outcome in
patients with diphtheria receiving intensive care, Indian
Pediatr 43:155-160, 2006.
Nikolaeva IN, Astafeva NV, Barer GM et al: Diphtheria of the oral
mucosa, Stomatologiia (Mosk) 74:26-28, 1995.
Syphilis
Barrett AW, Dorrego MV, Hodgson TA et al: The histopathology
of syphilis of the oral mucosa, J Oral Pathol Med 33:286-291,
2004.
Centers for Disease Control and Prevention: Congenital syphi-
lis—United States, 2002, MMWR Morb Mortal Wkly Rep
53:716-719, 2004.
Centers for Disease Control and Prevention: Primary and sec-
ondary syphilis—United States, 2003-2004, MMWR Morb
Mortal Wkly Rep 55:2659-2673, 2006.
Centers for Disease Control and Prevention: Transmission of
primary and secondary syphilis by oral sex—Chicago, Illinois,
1998-2002, MMWR Morb Mortal Wkly Rep 53:966-968,
2004.
Fiumara NJ, Lessel S: Manifestations of late congenital syphilis:
an analysis of 271 patients, Arch Dermatol 102:78-83, 1970.
Leão JC, Gueiros LA, Porter SR: Oral manifestations of syphilis,
Clinics 61:161-166, 2006.
Little JW: Syphilis: an update, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 100:3-9, 2005.
Meyer I, Abbey LM: The relationship of syphilis to primary car-
cinoma of the tongue, Oral Surg Oral Med Oral Pathol 30:678-
681, 1970.
Meyer I, Shklar G: The oral manifestations of acquired syphilis:
a study of eighty-one cases, Oral Surg Oral Med Oral Pathol
23:45-61, 1967.
Gonorrhea
Centers for Disease Control and Prevention: Increases in ﬂuoro-
quinolone-resistant Neisseria gonorrhoeae among men who
have sex with men—United States, 2003, and revised recom-
mendations for gonorrhea treatment, 2004, MMWR Morb
Mortal Wkly Rep 53:335-338, 2004.
Centers for Disease Control and Prevention: Screening tests
to detect Chlamydia trachomatis and Neisseria gonorrhoeae `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 5 BACTERIAL INFECTIONS 211
infection—2002, MMWR Morb Mortal Wkly Rep 51(RR-15):1-
38, 2002.
Giunta JL, Fiumara NJ: Facts about gonorrhea and dentistry, Oral
Surg Oral Med Oral Pathol 62:529-531, 1986.
Janier M, Lassau F, Casin I et al: Pharyngeal gonorrhoea: the
forgotten reservoir, Sex Transm Infect 79:345, 2003.
Little JW: Gonorrhea: update, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 101:137-143, 2006.
Miller KE: Diagnosis and treatment of Neisseria gonorrhoeae infec-
tions, Am Fam Physician 73:1779-1184, 2006.
Siegel MA: Syphilis and gonorrhea, Dent Clin North Am 40:369-
383, 1996.
Williams LN: The risks of oral-genital contact: a case report, Gen
Dent 50:282-284, 2002.
Tuberculosis
Centers for Disease Control and Prevention: Emergence of Myco-
bacterium tuberculosis with extensive resistance to second-line
drugs—worldwide, 2000-2004, MMWR Morb Mortal Wkly Rep
55:301-305, 2006.
Centers for Disease Control and Prevention: Trends in tubercu-
losis incidence—United States, 2006, MMWR Morb Mortal
Wkly Rep 56:245-250, 2007.
Darlington CC, Salman I: Oral tuberculous lesions, Am Rev
Tuberc 35:147-179, 1937.
Eng H-L, Lu S-Y, Yang C-H et al: Oral tuberculosis, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 81:415-420, 1996.
Kolokotronis A, Avramidou E, Zaraboukas T et al: Oral tubercu-
losis associated with a treatment with anti-rheumatic drugs,
J Oral Pathol Med 35:123-125, 2006.
Mandel L: Tuberculous cervical node calciﬁcations mimicking
sialolithiasis: a case report, J Oral Maxollofac Surg 64:1439-
1442, 2006.
Phelan JA, Jimenez V, Tompkins DC: Tuberculosis, Dent Clin
North Am 40:327-341, 1996.
Rinaggio J: Tuberculosis, Dent Clin North Am 47:449-465,
2003.
Samaranayake LP: Re-emergence of tuberculosis and its variants:
implications for dentistry, Int Dent J 52:330-336, 2002.
Yepes JF, Sullivan J, Pinto A: Tuberculosis: medical management
update, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
98:267-273, 2004.
Leprosy
Brand PW: Temperature variations and leprosy deformity, Int J
Lepr 27:1-7, 1959.
Girdhar BK, Desikan KV: A clinical study of the mouth in
untreated lepromatous patients, Lepr Rev 50:25-35, 1979.
Handa S, Saraswat A, Radotra BD et al: Chronic macrocheilia: a
clinico-pathologic study of 28 patients, Clin Exp Dermatol
28:245-250, 2003.
Prabhu SR, Daftary DK: Clinical evaluation of oro-facial lesions
of leprosy, Odontostomatol Trop 4:83-95, 1981.
Reichart P: Facial and oral manifestations in leprosy: an evalua-
tion of seventy cases, Oral Surg Oral Med Oral Pathol 41:385-
399, 1976.
Rendall JR, McDougall AC: Reddening of the upper central inci-
sors associated with periapical granuloma in lepromatous
leprosy, Br J Oral Surg 13:271-277, 1976.
Ramos-e-Silva M: Facial and oral aspects of some venereal and
tropical diseases, Acta Dermatovenerol Croat 12:173-180,
2004.
Scheepers A: Correlation of oral surface temperature and the
lesions of leprosy, Int J Lepr 66:214-217, 1998.
Scheepers A, Lemmer J, Lownie JF: Oral manifestations of
leprosy, Lepr Rev 64:37-43, 1993.
Scollard DM, Skinsnes OK: Oropharyngeal leprosy in art, history,
and medicine, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 87:463-470, 1999.
World Health Organization: WHO expert committee on leprosy,
World Health Organ Tech Rep Ser 874:1-43, 1998.
Noma
Adekeye EO, Ord RA: Cancrum oris: principles of management
and reconstructive surgery, J Maxillofac Surg 11:160-170,
1983.
Baratti-Mayer D, Pittet B, Montandon D et al: Noma: an “infec-
tious” disease of unknown aetiology, Lancet Infect Dis 3:419-
431, 2003.
Berthold P: Noma: a forgotten disease, Dent Clin North Am
47:559-574, 2003.
Bourgeois DM, Leclercq MH: The World Health Organization
initiative on noma, Oral Dis 5:172-174, 1999.
Enwonwu CO: Noma—the ulcer of extreme poverty, N Engl J Med
354:221-224, 2006.
Enwonwu CO, Falkler WA Jr, Phillips RS: Noma (cancrum oris),
Lancet 368:147-156, 2006.
Uohara GI, Knapp MJ: Oral fusospirochetosis and associated
lesions, Oral Surg Oral Med Oral Pathol 24:113-123, 1967.
Actinomycosis
Bhargava D, Bhusnurmath B, Sundaram KR et al: Tonsillar acti-
nomycosis: a clinicopathologic study, Acta Tropica 80:163-
168, 2001.
Bennhoff DF: Actinomycosis: diagnostic and therapeutic consid-
erations and a review of 32 cases, Laryngoscope 94:1198-
1217, 1984.
Miller M, Haddad AJ: Cervicofacial actinomycosis, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 85:496-508, 1998.
Nagler R, Peled M, Laufer D: Cervicofacial actinomycosis. A
diagnostic challenge, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 83:652-656, 1997.
Robinson JL, Vaudry WL, Dobrovolsky W: Actinomycosis pre-
senting as osteomyelitis in the pediatric population, Pediatr
Infect Dis J 24:365-369, 2005.
Rush JR, Sulte HR, Cohen DM et al: Course of infection and case
outcome in individuals diagnosed with microbial colonies
morphologically consistent with Actinomyces species, J Endod
28:613-618, 2002.
Sakellariou PL: Periapical actinomycosis: report of a case and
review of the literature, Endod Dent Traumatol 12:151-154,
1996.
Sprague WG, Shafer WG: Presence of actinomyces in
dentigerous cyst: report of two cases, J Oral Surg 21:243-245,
1963.
Cat-Scratch Disease
Centers for Disease Control: Cat-scratch disease in children—
Texas, September 2000—August 2001, MMWR Morb Mortal
Wkly Rep 51:212-214, 2002.
Cheuk W, Chan AK, Wong MC et al: Conﬁrmation of diagnosis
of cat scratch disease by immunohistochemistry, Am J Surg
Pathol 30:274-275, 2006.
English CK, Wear DJ, Margileth AM et al: Cat-scratch disease:
isolation and culture of the bacterial agent, JAMA 259:1347-
1352, 1988.
English R: Cat-scratch disease, Pediatr Rev 27:123-128, 2006.
Lamps LW, Scott MA: Cat-scratch disease. Historic, clinical, and
pathologic perspectives, Am J Clin Pathol 121(suppl 1):S71-
80, 2004.
Margileth AM, Wear DJ, English CK: Systemic cat scratch
disease: report of 23 patients with prolonged or recurrent
severe bacterial infection, J Infect Dis 155:390-402, 1987. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

212 ORAL AND MAXILLOFACIAL PATHOLOGY
Wear DJ, Margileth AM, Hadﬁeld TL et al: Cat scratch disease:
a bacterial infection, Science 221:1403-1405, 1983.
Windsor JJ: Cat-scratch disease: epidemiology, aetiology and
treatment, Br J Biomed Sci 58:101-110, 2001.
Sinusitis
Boork I: Sinusitis of odontogenic origin, Otolaryngol Head Neck
Surg 135:349-355, 2006.
Jacobsen PL, Casagrande AM: Sinusitis as a source of dental pain,
Dent Today 22:110-113, 2003.
Kennedy DW: First-line management of sinusitis: a national
problem? Overview, Otolaryngol Head Neck Surg
103(suppl):847-854, 1990.
Kennedy DW: First-line management of sinusitis: a national
problem? Surgical update, Otolaryngol Head Neck Surg
103(suppl):884-886, 1990.
Lopatin AS, Sysolyatin SP, Sysolyatin PG et al: Chronic maxillary
sinusitis of dental origin: is external surgical approach man-
datory? Laryngoscope 112:1056-1059, 2002.
Mehra P, Murad H: Maxillary sinus disease of odontogenic
origin, Otolaryngol Clin North Am 37:347-364, 2004.
Närkiö-Mäkelä M, Qvarnberg Y: Endoscopic sinus surgery or
Caldwell-Luc operation in the treatment of chronic and
recurrent maxillary sinusitis, Acta Otolaryngol Suppl 529:177-
180, 1997.
Ogata Y, Okinaka Y, Takahashi M: Antrolith associated with
aspergillosis of the maxillary sinus: report of a case, J Oral
Maxillofac Surg 55:1339-1341, 1997.
Richtsmeier WJ: Medical and surgical management of sinusitis
in adults, Ann Otol Rhinol Laryngol 101(suppl 155):46-50,
1992. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

213
6
Fungal and Protozoal Diseases
CHAPTER OUTLINE
Candidiasis
Pseudomembranous Candidiasis
Erythematous Candidiasis
Chronic Hyperplastic Candidiasis
Mucocutaneous Candidiasis
Histoplasmosis
Blastomycosis
In the past, candidiasis was considered to be only an
opportunistic infection, affecting individuals who were
debilitated by another disease. Certainly, such patients
make up a large percentage of those with candidal
infections today. However, now clinicians recognize
that oral candidiasis may develop in people who are
otherwise healthy. As a result of this complex host and
organism interaction, candidal infection may range
from mild, superﬁcial mucosal involvement seen in
most patients to fatal, disseminated disease in severely
immunocompromised patients. This chapter focuses
on those clinical presentations of candidiasis that affect
the oral mucosa.
CLINICAL FEATURES
Candidiasis of the oral mucosa may exhibit a variety of
clinical patterns, which are summarized in Table 6-1.
Many patients will display a single pattern, although
some individuals will exhibit more than one clinical
form of oral candidiasis.
PSEUDOMEMBRANOUS CANDIDIASIS
The best recognized form of candidal infection is pseu-
domembranous candidiasis. Also known as thrush,
pseudomembranous candidiasis is characterized by
the presence of adherent white plaques that resemble
cottage cheese or curdled milk on the oral mucosa
(Figs. 6-1 and 6-2). The white plaques are composed of
tangled masses of hyphae, yeasts, desquamated epithe-
CANDIDIASIS
Infection with the yeastlike fungal organism Candida
albicans is termed candidiasis or, as the British prefer,
candidosis. An older name for this disease is moniliasis;
the use of this term should be discouraged because it
is derived from the archaic designation Monilia albicans.
Other members of the Candida genus, such as C. tropica-
lis, C. krusei, C. parapsilosis, and C. guilliermondii, may also
be found intraorally, but they rarely cause disease.
Like many other pathogenic fungi, C. albicans may
exist in two forms—a trait known as dimorphism. The
yeast form of the organism is believed to be relatively
innocuous, but the hyphal form is usually associated
with invasion of host tissue.
Candidiasis is by far the most common oral fungal
infection in humans and has a variety of clinical mani-
festations, making the diagnosis difﬁcult at times. In
fact, C. albicans may be a component of the normal oral
microﬂora, with as many as 30% to 50% of people
simply carrying the organism in their mouths without
clinical evidence of infection. This rate of carriage has
been shown to increase with age, and C. albicans can be
recovered from the mouths of nearly 60% of dentate
patients older than 60 years who have no sign of oral
mucosal lesions. At least three general factors may deter-
mine whether clinical evidence of infection exists:
1.The immune status of the host
2.The oral mucosal environment
3.The strain of C. albicans
Paracoccidioidomycosis
Coccidioidomycosis
Cryptococcosis
Zygomycosis
Aspergillosis
Toxoplasmosis `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

214 ORAL AND MAXILLOFACIAL PATHOLOGY
Table 6-1 Clinical Forms of Oral Candidiasis
Clinical Type
Appearance and
Symptoms Common Sites
Associated Factors and
Comments
Pseudomembranous (thrush) Creamy-white plaques,
removable; burning
sensation, foul taste
Buccal mucosa, tongue,
palate
Antibiotic therapy,
immunosuppression
Erythematous Red macules, burning
sensation
Posterior hard palate, buccal
mucosa, dorsal tongue
Antibiotic therapy, xerostomia,
immunosuppression,
idiopathic
Central papillary atrophy
(median rhomboid
glossitis)
Red, atrophic mucosal
areas; asymptomatic
Midline posterior dorsal
tongue
Idiopathic, immunosuppression
Chronic multifocal Red areas, often with
removable white
plaques; burning
sensation,
asymptomatic
Posterior palate, posterior
dorsal tongue, angles of
mouth
Immunosuppression, idiopathic
Angular cheilitis Red, ﬁssured lesions;
irritated, raw feeling
Angles of mouth Idiopathic, immunosuppression,
loss of vertical dimension
Denture stomatitis (chronic
atrophic candidiasis,
denture sore mouth)
Red, asymptomatic Conﬁned to palatal denture-
bearing mucosa
Probably not true infection;
denture often is positive on
culture but mucosa is not
Hyperplastic (candidal
leukoplakia)
White plaques that are
not removable;
asymptomatic
Anterior buccal mucosa Idiopathic, immunosuppression;
care must be taken not to
confuse this with other
keratotic lesions with
superimposed candidiasis
Mucocutaneous White plaques, some
of which may be
removable; red areas
Tongue, buccal mucosa,
palate
Rare; inherited or sporadic
idiopathic immune
dysfunction
Endocrine-candidiasis
syndromes
White plaques, most
of which are not
removable
Tongue, buccal mucosa,
palate
Rare; endocrine disorder
develops after candidiasis
Fig. 6-1 Pseudomembranous candidiasis. Multiple white
plaques on the soft palate.
lial cells, and debris. Scraping them with a tongue
blade or rubbing them with a dry gauze sponge can
remove these plaques. The underlying mucosa may
appear normal or erythematous. If bleeding occurs,
then the mucosa has probably also been affected by
another process, such as lichen planus or cancer
chemotherapy.
Pseudomembranous candidiasis may be initiated by
exposure of the patient to broad-spectrum antibiotics
(thus eliminating competing bacteria) or by impair-
ment of the patient’s immune system. The immune
dysfunctions seen in leukemic patients (see page 587)
or those infected with human immunodeﬁciency virus
(HIV) (see page 264) are often associated with pseudo-
membranous candidiasis. Infants may also be affected,
ostensibly because of their underdeveloped immune
systems. Antibiotic exposure is typically responsible
for an acute (rapid) expression of the condition; immu-
nologic problems usually produce a chronic (slow- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 215
onset, long-standing) form of pseudomembranous
candidiasis.
Symptoms, if present at all, are usually relatively
mild, consisting of a burning sensation of the oral
mucosa or an unpleasant taste in the mouth, variably
described as salty or bitter. Sometimes patients com-
plain of “blisters,” when in fact they feel the elevated
plaques rather than true vesicles. The plaques are char-
acteristically distributed on the buccal mucosa, palate,
and dorsal tongue.
ERYTHEMATOUS CANDIDIASIS
In contrast to the pseudomembranous form, patients
with erythematous candidiasis either do not show
white ﬂecks, or a white component is not a prominent
feature. Erythematous candidiasis is undoubtedly
more common than pseudomembranous candidiasis,
although it is often overlooked clinically. Several clini-
cal presentations may be seen. Acute atrophic candi-
diasis or “antibiotic sore mouth,” typically follows a
course of broad-spectrum antibiotic therapy. Patients
often complain that the mouth feels as if a hot beverage
had scalded it. This burning sensation is usually accom-
panied by a diffuse loss of the ﬁliform papillae of the
dorsal tongue, resulting in a reddened, “bald” appear-
ance of the tongue (Fig. 6-3). Burning mouth syndrome
(see page 873) frequently manifests with a scalded sen-
sation of the tongue; however, the tongue appears
normal in that condition. Patients who suffer from
xerostomia for any reason (e.g., pharmacologic, postra-
diation therapy, Sjögren syndrome) have an increased
prevalence of erythematous candidiasis that is com-
monly symptomatic as well.
A B
Fig. 6-2 Pseudomembranous candidiasis. A, Classic “curdled milk” appearance of the oral lesions
of pseudomembranous candidiasis. This patient had no apparent risk factors for candidiasis
development. B, Removal of one of the pseudomembranous plaques (arrow) reveals a mildly
erythematous mucosal surface. (From Allen CM, Blozis GG: Oral mucosal lesions. In Cummings CW, Fredrickson JM,
Harker LA et al, editors: Otolaryngology: head and neck surgery, ed 3, St Louis, 1998, Mosby.)
Fig. 6-3 Erythematous candidiasis. The patchy, denuded
areas (not the white areas) of the dorsal tongue represent
erythematous candidiasis. The patient had received a broad-
spectrum antibiotic. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

216 ORAL AND MAXILLOFACIAL PATHOLOGY
Other forms of erythematous candidiasis are usually
asymptomatic and chronic. Included in this category is
the condition known as central papillary atrophy of
the tongue, or median rhomboid glossitis. In the
past, this was thought to be a developmental defect of
the tongue, occurring in 0.01% to 1.00% of adults. The
lesion was supposed to have resulted from a failure of
the embryologic tuberculum impar to be covered by
the lateral processes of the tongue. Theoretically, the
prevalence of central papillary atrophy in children
should be identical to that seen in adults; however, in
one study in which 10,000 children were examined,
not a single lesion was detected. Other investigators
have noted a consistent relationship between the lesion
and C. albicans, and similar lesions have been induced
experimentally on the dorsal tongues of rats.
Clinically, central papillary atrophy appears as a
well-demarcated erythematous zone that affects the
midline, posterior dorsal tongue and often is asymp-
tomatic (Fig. 6-4). The erythema is due in part to the
loss of the ﬁliform papillae in this area. The lesion is
usually symmetrical, and its surface may range from
smooth to lobulated. Often the mucosal alteration
resolves with antifungal therapy, although occasionally
only partial resolution can be achieved.
Some patients with central papillary atrophy may
also exhibit signs of oral mucosal candidal infection at
other sites. This presentation of erythematous candidi-
asis has been termed chronic multifocal candidiasis.
In addition to the dorsal tongue, the sites that show
involvement include the junction of the hard and soft
palate and the angles of the mouth. The palatal lesion
appears as an erythematous area that, when the tongue
is at rest, contacts the dorsal tongue lesion, resulting in
what is called a “kissing lesion” because of the intimate
proximity of the involved areas (Fig. 6-5).
The involvement of the angles of the mouth (angular
cheilitis, perlèche) is characterized by erythema, ﬁs-
suring, and scaling (Fig. 6-6). Sometimes this condition
is seen as a component of chronic multifocal candidia-
sis, but it often occurs alone, typically in an older person
with reduced vertical dimension of occlusion and
accentuated folds at the corners of the mouth. Saliva
tends to pool in these areas, keeping them moist and
thus favoring a yeast infection. Patients often indicate
that the severity of the lesions waxes and wanes. Micro-
biologic studies have indicated that 20% of these cases
are caused by C. albicans alone, 60% are due to a com-
bined infection with C. albicans and Staphylococcus
aureus, and 20% are associated with S. aureus alone.
Infrequently, the candidal infection more extensively
involves the perioral skin, usually secondary to actions
that keep the skin moist (e.g., chronic lip licking, thumb
sucking), creating a clinical pattern known as cheilo-
candidiasis (Fig. 6-7). Other causes of exfoliative chei-
litis often must be considered in the differential
diagnosis (see page 304).
Denture stomatitis should be mentioned because
it is often classiﬁed as a form of erythematous candidia-
sis, and some authors may use the term chronic atrophic
candidiasis synonymously. This condition is character-
ized by varying degrees of erythema, sometimes accom-
panied by petechial hemorrhage, localized to the
denture-bearing areas of a maxillary removable dental
prosthesis (Figs. 6-8 and 6-9). Although the clinical
appearance can be striking, the process is rarely symp-
tomatic. Usually the patient admits to wearing the
denture continuously, removing it only periodically to
A B
Fig. 6-4 Erythematous candidiasis. A, Severe presentation of central papillary atrophy. In this
patient the lesion was asymptomatic. B, Marked regeneration of the dorsal tongue papillae occurred
2 weeks after antifungal therapy with ﬂuconazole. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 217
clean it. Whether this represents actual infection by
C. albicans or is simply a tissue response by the host to
the various microorganisms living beneath the denture
remains controversial. The clinician should also rule
out the possibility that this reaction could be caused by
improper design of the denture (which could cause
unusual pressure on the mucosa), allergy to the denture
base, or inadequate curing of the denture acrylic.
Although C. albicans is often associated with this con-
dition, biopsy specimens of denture stomatitis seldom
show candidal hyphae actually penetrating the keratin
layer of the host epithelium. Therefore, this lesion does
not meet one of the main deﬁning criteria for the diag-
nosis of infection—host tissue invasion by the organism.
Furthermore, if the palatal mucosa and tissue-contact-
ing surface of the denture are swabbed and separately
streaked onto a Sabouraud’s agar slant, then the denture
typically shows much heavier colonization by yeast
(Fig. 6-10).
CHRONIC HYPERPLASTIC CANDIDIASIS
(CANDIDAL LEUKOPLAKIA)
In some patients with oral candidiasis, there may be a
white patch that cannot be removed by scraping; in this
case the term chronic hyperplastic candidiasis is appropri-
ate. This form of candidiasis is the least common and
is also somewhat controversial. Some investigators
believe that this condition simply represents candidia-
sis that is superimposed on a preexisting leukoplakic
lesion, a situation that may certainly exist at times. In
some instances, however, the candidal organism alone
may be capable of inducing a hyperkeratotic lesion.
A B
Fig. 6-5 Candidiasis. A, Multifocal oral candidiasis characterized by central papillary atrophy of the
tongue and other areas of involvement. B, Same patient showing a “kissing” lesion of oral candidiasis
on the hard palate.
Fig. 6-6 Angular cheilitis. Characteristic lesions appear as
ﬁssured, erythematous alterations of the skin at the corners
of the mouth.
Fig. 6-7 Cheilocandidiasis. The exfoliative lesions of the
vermilion zone and perioral skin are due to superﬁcial
candidal infection. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

218 ORAL AND MAXILLOFACIAL PATHOLOGY
Such lesions are usually located on the anterior buccal
mucosa and cannot clinically be distinguished from a
routine leukoplakia (Fig. 6-11). Often the leukoplakic
lesion associated with candidal infection has a ﬁne
intermingling of red and white areas, resulting in a
speckled leukoplakia (see page 392). Such lesions may
have an increased frequency of epithelial dysplasia
histopathologically.
A
B
C
Fig. 6-8 Denture stomatitis. A, Maxillary denture with
incomplete palatal vault associated with midline tissue
hyperplasia. B, Mucositis corresponds to the outline of the
prosthesis. C, Resolution of mucositis after antifungal therapy
and appropriate denture cleansing.
Fig. 6-9 Denture stomatitis. Denture stomatitis, not
associated with Candida albicans, conﬁned to the denture-
bearing mucosa of a maxillary partial denture framework.
Fig. 6-10 Denture stomatitis. This Sabouraud’s agar slant
has been streaked with swabs obtained from erythematous
palatal mucosa (left side of the slant) and the tissue-bearing
surface of the denture (right side of the slant). Extensive
colonization of the denture is demonstrated, whereas little
evidence of yeast associated with the mucosa is noted.
The diagnosis is conﬁrmed by the presence of can-
didal hyphae associated with the lesion and by com-
plete resolution of the lesion after antifungal therapy
(Fig. 6-12).
MUCOCUTANEOUS CANDIDIASIS
Severe oral candidiasis may also be seen as a compo-
nent of a relatively rare group of immunologic disor-
ders known as mucocutaneous candidiasis. Several distinct
immunologic dysfunctions have been identiﬁed, and
the severity of the candidal infection correlates with
the severity of the immunologic defect. Most cases are
sporadic, although an autosomal recessive pattern of
inheritance has been identiﬁed in some families. The
immune problem usually becomes evident during the
ﬁrst few years of life, when the patient begins to have `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 219
Fig. 6-11 Hyperplastic candidiasis. This lesion of the
anterior buccal mucosa clinically resembles a leukoplakia
because it is a white plaque that cannot be removed by
rubbing. With antifungal therapy, such a lesion should resolve
completely.
A B
Fig. 6-12 Hyperplastic candidiasis. A, These diffuse white plaques clinically appear as leukoplakia,
but they actually represent an unusual presentation of hyperplastic candidiasis. B, Treatment with
clotrimazole oral troches shows complete resolution of the white lesions within 2 weeks, essentially
conﬁrming the diagnosis of hyperplastic candidiasis. If any white mucosal alteration had persisted,
a biopsy of that area would have been mandatory.
candidal infections of the mouth, nails, skin, and other
mucosal surfaces. The oral lesions are usually described
as thick, white plaques that typically do not rub off
(essentially chronic hyperplastic candidiasis), although
the other clinical forms of candidiasis may also be
seen.
In some patients with mucocutaneous candidiasis,
mutations in the autoimmune regulator (AIRE) gene
have been documented, with the resultant formation
of autoantibodies directed against the person’s own
tissues (Fig. 6-13). In most instances the immunologic
attack is directed against the endocrine glands;
however, the reasons for this tissue speciﬁcity are
currently unclear. Young patients with mucocutaneous
candidiasis should be evaluated periodically because
any one of a variety of endocrine abnormalities (i.e.,
endocrine-candidiasis syndrome, autoimmune
polyendocrinopathy-candidiasis-ectodermal dys-
trophy [APECED] syndrome), as well as iron-
deﬁciency anemia, may develop in addition to the
candidiasis. These endocrine disturbances include
hypothyroidism, hypoparathyroidism, hypoadrenocor-
ticism (Addison’s disease), and diabetes mellitus. Typi-
cally, the endocrine abnormality develops months or
even years after the onset of the candidal infection.
One recent study has documented increased preva-
lence of oral and esophageal carcinoma in this condi-
tion, with these malignancies affecting approximately
10% of adults with APECED syndrome. This ﬁnding
represents another justiﬁcation for periodic reevalua-
tion of these individuals.
Interestingly, the candidal infection remains rela-
tively superﬁcial rather than disseminating through-
out the body. Both the oral lesions and any cutaneous
involvement (usually presenting as roughened, foul-
smelling cutaneous plaques and nodules) can be con-
trolled with continuous use of relatively safe systemic
antifungal drugs.
HISTOPATHOLOGIC FEATURES
The candidal organism can be seen microscopically in
either an exfoliative cytologic preparation or in tissue
sections obtained from a biopsy specimen. On staining
with the periodic acid-Schiff (PAS) method, the candi-
dal hyphae and yeasts can be readily identiﬁed (Fig. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

220 ORAL AND MAXILLOFACIAL PATHOLOGY
6-14). The PAS method stains carbohydrates, con-
tained in abundance by fungal cell walls; the organisms
are easily identiﬁed by the bright-magenta color
imparted by the stain. To make a diagnosis of candidia-
sis, one must be able to see hyphae or pseudohyphae
(which are essentially elongated yeast cells). These
hyphae are approximately 2 μm in diameter, vary in
their length, and may show branching. Often the
hyphae are accompanied by variable numbers of yeasts,
squamous epithelial cells, and inﬂammatory cells.
A 10% to 20% potassium hydroxide (KOH) prepara-
tion may also be used to rapidly evaluate specimens
for the presence of fungal organisms. With this tech-
nique, the KOH lyses the background of epithelial
cells, allowing the more resistant yeasts and hyphae to
be visualized.
The disadvantages of the KOH preparation include
the following:
●Lack of a permanent record
● Greater difﬁculty in identifying the fungal organ-
isms, compared with PAS staining
●Inability to assess the nature of the epithelial cell
population with respect to other conditions, such as
epithelial dysplasia or pemphigus vulgaris
The histopathologic pattern of oral candidiasis may
vary slightly, depending on which clinical form of the
infection has been submitted for biopsy. The features
that are found in common include an increased thick-
ness of parakeratin on the surface of the lesion in con-
junction with elongation of the epithelial rete ridges
(Fig. 6-15). Typically, a chronic inﬂammatory cell inﬁl-
trate can be seen in the connective tissue immediately
subjacent to the infected epithelium, and small
collections of neutrophils (microabscesses) are often
identiﬁed in the parakeratin layer and the superﬁcial
spinous cell layer near the organisms (Fig. 6-16). The
candidal hyphae are embedded in the parakeratin
layer and rarely penetrate into the viable cell layers
of the epithelium unless the patient is extremely
immunocompromised.
A
B
C
Fig. 6-13 Autoimmune polyendocrinopathy-candidiasis-
ectodermal dystrophy (APECED) syndrome.
A, Erythematous candidiasis diffusely involving the dorsal
tongue of a 32-year-old man. B, Same patient showing nail
dystrophy. C, Corneal keratopathy is also noted. Patient had
a history of the onset of hypoparathyroidism and
hypoadrenocorticism, both diagnosed in the second decade
of life.
Fig. 6-14 Candidiasis. This cytologic preparation
demonstrates tubular-appearing fungal hyphae and ovoid
yeasts of Candida albicans. (PAS stain.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 221
DIAGNOSIS
The diagnosis of candidiasis is usually established by
the clinical signs in conjunction with exfoliative cyto-
logic examination. Although a culture can deﬁnitively
identify the organism as C. albicans, this process may
not be practical in most ofﬁce settings. The cytologic
ﬁndings should demonstrate the hyphal phase of the
organism, and antifungal therapy can then be insti-
tuted. If the lesion is clinically suggestive of chronic
hyperplastic candidiasis but does not respond to anti-
fungal therapy, then a biopsy should be performed to
rule out the possibility of C. albicans superimposed on
epithelial dysplasia, squamous cell carcinoma, or lichen
planus.
The deﬁnitive identiﬁcation of the organism can be
made by means of culture. A specimen for culture is
obtained by rubbing a sterile cotton swab over the
lesion and then streaking the swab on the surface of a
Sabouraud’s agar slant. C. albicans will grow as creamy,
smooth-surfaced colonies after 2 to 3 days of incuba-
tion at room temperature.
TREATMENT AND PROGNOSIS
Several antifungal medications have been developed
for managing oral candidiasis, each with its advantages
and disadvantages (Table 6-2).
POLYENE AGENTS
NYSTATIN
In the 1950s the polyene antibiotic nystatin was the
ﬁrst effective treatment for oral candidiasis. Nystatin is
formulated for oral use as a suspension or pastille
(lozenge). Many patients report that nystatin has a very
bitter taste, which may reduce patient compliance;
therefore, the taste has to be disguised with sucrose
and ﬂavoring agents. If the candidiasis is due to xero-
stomia, the sucrose content of the nystatin preparation
may contribute to xerostomia-related caries in these
patients. The gastrointestinal tract poorly absorbs
nystatin and the other polyene antibiotic, amphoteri-
cin; therefore, their effectiveness depends on direct
contact with the candidal organisms. This necessitates
multiple daily doses so that the yeasts are adequately
exposed to the drug. Nystatin combined with triam-
cinolone acetonide cream or ointment can be applied
topically and is effective for angular cheilitis that does
not have a bacterial component.
AMPHOTERICIN B
For many years in the United States, the use of ampho-
tericin B was restricted to intravenous (IV) treatment
of life-threatening systemic fungal infections. This
medication subsequently became available as an oral
suspension for the management of oral candidiasis.
Unfortunately, the interest in this formulation of the
drug was scant, and it is no longer marketed in the
United States.
IMIDAZOLE AGENTS
The imidazole-derived antifungal agents were devel-
oped during the 1970s and represented a major step
forward in the management of candidiasis. The two
drugs of this group that are used most frequently are
clotrimazole and ketoconazole.
CLOTRIMAZOLE
Like nystatin, clotrimazole is not well absorbed and
must be administered several times each day. It is
formulated as a pleasant-tasting troche (lozenge) and
Fig. 6-15 Candidiasis. This medium-power
photomicrograph shows a characteristic pattern of
parakeratosis, neutrophilic microabscesses, a thickened
spinous layer, and chronic inﬂammation of the underlying
connective tissue associated with long-standing candidal
infection of the oral mucosa.
Fig. 6-16 Candidiasis. This high-power photomicrograph
shows the tubular hyphae of Candida albicans embedded in
the parakeratin layer. (PAS stain.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

222 ORAL AND MAXILLOFACIAL PATHOLOGY
Table 6-2 Antifungal Medications
Generic Name Trade Name Indications Dosage
Nystatin Mycostatin pastilles Oral candidiasis One or two pastilles (200,000-400,000 units) dissolved slowly
in the mouth 4-5 times daily for 10-14 days
Mycostatin oral suspension
Clotrimazole Mycelex oral troches Oral candidiasis Dissolve 1 troche (10 mg) slowly in the mouth, 5 times daily for
10-14 days
Ketoconazole Nizoral tablets Oral candidiasis Not to be used as initial therapy for oral candidiasis
Blastomycosis One tablet (200 mg) daily for 1-2 weeks for candidiasis
Coccidioidomycosis Minimum treatment period for systemic mycoses is 6 months
Histoplasmosis
Paracoccidioidomycosis
Fluconazole Diﬂucan tablets Oral candidiasis For oral candidiasis: 2 tablets (200 mg) on day 1 and then
1 tablet (100 mg) daily for 1-2 weeks
Cryptococcal meningitis
Itraconazole Sporanox capsules Blastomycosis
Histoplasmosis
Aspergillosis refractory to
For blastomycosis and histoplasmosis: two capsules
(200 mg) daily, increasing by 100-mg increments up to
400 mg daily in divided doses if no clinical response is noted
For aspergillosis: 200-400 mg daily
amphotericin B therapyFor life-threatening situations: loading dose of 200 mg TID for
ﬁrst 3 days, then dose can be reduced
Treatment should continue for at least 3 months for all of the
above
Itraconazole Sporanox oral solution Oral candidiasis 10 mL (100 mg) vigorously swished in the mouth and
swallowed, twice daily for 1-2 weeks
Amphotericin B Fungizone oral suspensionOral candidiasis 1 mL (100 mg) rinse and hold in the mouth for as long as
possible, QID, PC and HS for 2 weeks
TID, Three times a day; QID, four times a day; PC, after meals; HS, at bedtime.
produces few side effects. The efﬁcacy of this agent in
treating oral candidiasis can be seen in Fig. 6-12.
Clotrimazole cream is also effective treatment for
angular cheilitis, because this drug has antibacterial
and antifungal properties.
KETOCONAZOLE
Ketoconazole was the ﬁrst antifungal drug that could
be absorbed across the gastrointestinal tract, thereby
providing systemic therapy by an oral route of admin-
istration. The single daily dose was much easier for
patients to use; however, several disadvantages have
been noted. Patients must not take antacids or H
2-
blocking agents because an acidic environment is
required for proper absorption. If a patient is to take
ketoconazole for more than 2 weeks, then liver func-
tion studies are recommended because approximately
1 in 10,000 individuals will experience idiosyncratic
liver toxicity from the agent. For this reason, the U.S.
Food and Drug Administration has stated that ketocon-
azole should not be used as initial therapy for routine
oral candidiasis. Furthermore, ketoconazole has been `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 223
Side Effects/Adverse Reactions Drug Interactions
Nausea, diarrhea, vomiting with large doses None known
Mild elevations of liver enzymes in 15% of patients No signiﬁcant drug interactions
Periodic assessment of liver function in patients with hepatic
impairment
Nausea, vomiting
Serious hepatotoxicity in 1:10,000 patients Serious and/or life-threatening interactions with terfenadine, astemizole,
or cisapride
Monitoring of liver function is indicated for patients with
preexisting hepatic problems, patients who develop symptoms
of hepatic failure, or patients treated for >28 days
Metabolism of cyclosporine, tacrolimus, methylprednisolone, midazolam,
triazolam, coumarin-like drugs, phenytoin, and rifampin may be
altered
Serum testosterone is lowered
Nausea, vomiting
Anaphylaxis
Rare cases of hepatotoxicity, ranging from mild transient elevation
of liver enzymes to hepatic failure
Headache, nausea, vomiting, abdominal pain, diarrhea Clinically or potentially signiﬁcant side effects have been noted with the
following medications: oral hypoglycemic agents, coumarin-like drugs,
phenytoin, cyclosporine, rifampin, theophylline, terfenadine, cisapride,
astemizole, rifabutin, and tacrolimus
Rare cases of hepatoxicity Serious and/or life-threatening interactions with terfenadine,
astemizole, pimozide, quinidine, oral triazolam, oral midazolam, and
cisapride
Liver function should be monitored in patients with preexisting
hepatic problems on therapy for more than 1 month
Lovastatin and simvastatin should be discontinued
Nausea, diarrhea, vomiting Increased plasma concentrations may be seen with warfarin, ritonavir,
indinavir, vinca alkaloid agents, diazepam, cyclosporine,
dihydropyridine medications, tacrolimus, digoxin, and
methylprednisolone
Rare cases of hepatotoxicity Serious and/or life-threatening interactions with terfenadine, astemizole,
oral triazolam, oral midazolam, and cisapride
Liver function should be monitored in patients with preexisting
hepatic problems on therapy for more than 1 month
Lovastatin and simvastatin should be discontinued
Nausea, diarrhea, vomiting
Rash, gastrointestinal symptoms No signiﬁcant drug interactions
implicated in drug interactions with macrolide anti bi-
otics (e.g., erythromycin), the gastroin testinal motility–
enhancing agent cisapride, and the antihistamine
astemizole, all of which may produce potentially life-
threatening cardiac arrhythmias.
TRIAZOLES
The triazoles are the newest group of antifungal drugs.
Both ﬂuconazole and itraconazole have been approved
for treating candidiasis in the United States.
FLUCONAZOLE
Fluconazole appears to be more effective than ketocon-
azole; it is well absorbed systemically, and an acidic
environment is not required for absorption. A relatively
long half-life allows for once-daily dosing, and liver
toxicity is rare at the doses used to treat oral candidia-
sis. Some reports have suggested that ﬂuconazole may
not be appropriate for long-term preventive therapy
because resistance to the drug seems to develop in
some instances. Known drug interactions include a `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

224 ORAL AND MAXILLOFACIAL PATHOLOGY
potentiation of the effects of phenytoin (Dilantin), an
antiseizure medication; warfarin compounds (antico-
agulants); and sulfonylureas (oral hypoglycemic agents).
Other drugs that may interact with ﬂuconazole are
summarized in Table 6-2.
ITRACONAZOLE
Itraconazole has proven efﬁcacy against a variety of
fungal diseases, including histoplasmosis, blastomyco-
sis, and fungal conditions of the nails. Recently, itracon-
azole solution was approved for management of
oropharyngeal candidiasis, and this appears to have
an efﬁcacy equivalent to clotrimazole and ﬂuconazole.
As with ﬂuconazole, signiﬁcant drug interactions are
possible, and itraconazole is contraindicated for
patients taking astemizole, triazolam, midazolam, and
cisapride. (See Table 6-2 for other potential drug
interactions.)
POSACONAZOLE
This new triazole compound has been shown to be
effective in the management of oropharyngeal candi-
diasis in patients with HIV infection. Given the cost of
this drug and the proven effectiveness of other, less
expensive, oral antifungal agents, the use of this medi-
cation for treatment of routine oral candidiasis would
be difﬁcult to justify.
ECHINOCANDINS
This new class of antifungal drugs acts by interfering
with candidal cell wall synthesis. The formation of
β-1,3-glucan, which is a principal component of the
candidal cell wall, is disrupted and results in per-
meability of the cell wall with subsequent demise
of the candidal organism. These medications are not
well absorbed; consequently they must be adminis-
tered intravenously and are reserved for more life-
threatening candidal infections. Examples include
caspofungin, micafungin, and anidulafungin.
OTHER ANTIFUNGAL AGENTS
IODOQUINOL
Although not strictly an antifungal drug, iodoquinol
has antifungal and antibacterial properties. When
compounded in a cream base with a corticosteroid, this
material is very effective as topical therapy for angular
cheilitis.
In most cases, oral candidiasis is an annoying super-
ﬁcial infection that is easily resolved by antifungal
therapy. If infection should recur after treatment, then
a thorough investigation of potential factors that could
predispose to candidiasis, including immunosuppres-
sion, may be necessary. In only the most severely com-
promised patient will candidiasis cause deeply invasive
disease (Fig. 6-17).
HISTOPLASMOSIS
Histoplasmosis, the most common systemic fungal
infection in the United States, is caused by the organ-
ism Histoplasma capsulatum. Like several other patho-
genic fungi, H. capsulatum is dimorphic, growing as a
yeast at body temperature in the human host and as a
mold in its natural environment. Humid areas with soil
enriched by bird or bat excrement are especially suited
to the growth of this organism. This habitat preference
explains why histoplasmosis is seen endemically in
fertile river valleys, such as the region drained by the
Ohio and Mississippi Rivers in the United States. Air-
borne spores of the organism are inhaled, pass into the
terminal passages of the lungs, and germinate.
Approximately 500,000 new cases of histoplasmo-
sis are thought to develop annually in the United States.
Other parts of the world, such as Central and South
America, Europe, and Asia, also report numerous cases.
Epidemiologic studies in endemic areas of the United
States suggest that 80% to 90% of the population in
these regions has been infected.
CLINICAL AND RADIOGRAPHIC
FEATURES
Most cases of histoplasmosis produce either no symp-
toms or such mild symptoms that the patient does not
seek medical treatment. The expression of disease
depends on the quantity of spores inhaled, the immune
status of the host, and perhaps the strain of H. capsula-
Fig. 6-17 Candidiasis. This necrotic lesion of the upper lip
developed in a man with uncontrolled type I diabetes
mellitus. Biopsy and culture showed a rare example of
invasive oral infection by Candida albicans. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 225
tum. Most individuals who become exposed to the
organism are relatively healthy and do not inhale a
large number of spores; therefore, they have either
no symptoms or they have a mild, ﬂulike illness for
1 to 2 weeks. The inhaled spores are ingested by
macrophages within 24 to 48 hours, and speciﬁc
T-lymphocyte immunity develops in 2 to 3 weeks. Anti-
bodies directed against the organism usually appear
several weeks later. With these defense mechanisms,
the host is usually able to destroy the invading organ-
ism, although sometimes the macrophages simply sur-
round and conﬁne the fungus so that viable organisms
can be recovered years later. Thus patients who for-
merly lived in an endemic area may have acquired the
organism and later express the disease at some other
geographic site if they become immunocompromised.
Acute histoplasmosis is a self-limited pulmonary
infection that probably develops in only about 1% of
people who are exposed to a low number of spores.
With a high concentration of spores, as many as 50%
to 100% of individuals may experience acute symp-
toms. These symptoms (e.g., fever, headache, myalgia,
nonproductive cough, anorexia) result in a clinical
picture similar to that of inﬂuenza. Patients are usually
ill for 2 weeks, although calciﬁcation of the hilar lymph
nodes may be detected as an incidental ﬁnding on
chest radiographs years later.
Chronic histoplasmosis also primarily affects the
lungs, although it is much less common than acute
histoplasmosis. The chronic form usually affects older,
emphysematous, white men or immunosuppressed
patients. Clinically, it appears similar to tuberculosis.
Patients typically exhibit cough, weight loss, fever,
dyspnea, chest pain, hemoptysis, weakness, and fatigue.
Chest roentgenograms show upper-lobe inﬁltrates and
cavitation.
Disseminated histoplasmosis is even less common
than the acute and chronic types. It occurs in 1 of 2000
to 5000 patients who have acute symptoms. This con-
dition is characterized by the progressive spread of
the infection to extrapulmonary sites. It usually occurs
in either older, debilitated, or immunosuppressed
patients. In some areas of the United States, 2% to 10%
of patients with acquired immunodeﬁciency syn-
drome (AIDS) (see page 277) develop disseminated
histoplasmosis. Tissues that may be affected include
the spleen, adrenal glands, liver, lymph nodes, gastro-
intestinal tract, central nervous system (CNS), kidneys,
and oral mucosa. Adrenal involvement may produce
hypoadrenocorticism (Addison’s disease) (see page
841).
Most oral lesions of histoplasmosis occur with the
disseminated form of the disease. The most commonly
affected sites are the tongue, palate, and buccal mucosa.
The condition usually appears as a solitary, variably
painful ulceration of several weeks’ duration; however,
some lesions may appear erythematous or white with
an irregular surface (Fig. 6-18). The ulcerated lesions
have ﬁrm, rolled margins, and they may be indistin-
guishable clinically from a malignancy (Fig. 6-19).
HISTOPATHOLOGIC FEATURES
Microscopic examination of lesional tissue shows either
a diffuse inﬁltrate of macrophages or, more commonly,
collections of macrophages organized into granulomas
(Fig. 6-20). Multinucleated giant cells are usually seen
Fig. 6-18 Histoplasmosis. This ulcerated granular lesion
involves the maxillary buccal vestibule and is easily mistaken
clinically for carcinoma. Biopsy established the diagnosis.
(From Allen CM, Blozis GG: Oral mucosal lesions. In Cummings CW,
Fredrickson JM, Harker LA et al, editors: Otolaryngology: head and neck
surgery, ed 3, St Louis, 1998, Mosby.)
Fig. 6-19 Histoplasmosis. This chronic ulceration of the
ventral and lateral tongue represents an oral lesion of
histoplasmosis that had disseminated from the lungs. The
lesion clinically resembles carcinoma; because of this high-
risk site, biopsy is mandatory. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

226 ORAL AND MAXILLOFACIAL PATHOLOGY
in association with the granulomatous inﬂammation.
The causative organism can be identiﬁed with some
difﬁculty in the routine hematoxylin and eosin (H&E)-
stained section; however, special stains, such as the
PAS and Grocott-Gomori methenamine silver methods,
readily demonstrate the characteristic 1- to 2-μm yeasts
of H. capsulatum (Fig. 6-21).
DIAGNOSIS
The diagnosis of histoplasmosis can be made by histo-
pathologic identiﬁcation of the organism in tissue sec-
tions or by culture. Other helpful diagnostic studies
include serologic testing in which antibodies directed
against H. capsulatum are demonstrated and antigen
produced by the yeast is identiﬁed.
TREATMENT AND PROGNOSIS
Acute histoplasmosis, because it is a self-limited
process, generally warrants no speciﬁc treatment other
than supportive care with analgesic and antipyretic
agents. Often the disease is not treated because the
symptoms are so nonspeciﬁc and the diagnosis is not
readily evident.
Patients with chronic histoplasmosis require treat-
ment, despite the fact that up to half of them may
recover spontaneously. Often the pulmonary damage
is progressive if it remains untreated, and death may
result in up to 20% of these cases. The treatment of
choice is intravenous amphotericin B, particularly in
severe cases. However, signiﬁcant kidney damage can
result from this therapy; therefore, itraconazole may be
used in nonimmunosuppressed patients because it is as-
sociated with fewer side effects, but this medication
requires daily dosing for at least 3 months. Although
ketoconazole and ﬂuconazole have been used for treat-
ment of histoplasmosis, these agents appear to be less
effective than itraconazole and less likely to produce a
desired therapeutic response.
Disseminated histoplasmosis is a very serious condi-
tion that results in death in 80% to 90% of patients if
they remain untreated. Amphotericin B is usually indi-
cated for such patients; once the life-threatening phase
of the disease is under control, daily itraconazole is
necessary for 6 to 18 months. Despite therapy, however,
a mortality rate of 7% to 23% is observed. Itraconazole
alone may be used if the patient is nonimmunocom-
promised and has relatively mild to moderate disease;
however, the response rate is slower than for patients
receiving amphotericin B, and the relapse rate may be
higher.
BLASTOMYCOSIS
Blastomycosis is a relatively uncommon disease
caused by the dimorphic fungus known as Blastomyces
dermatitidis. Although the organism is rarely isolated
from its natural habitat, it seems to prefer rich, moist
soil, where it grows as a mold. Much of the region in
which it grows overlaps the territory associated with
H. capsulatum (affecting the eastern half of the United
States). The range of blastomycosis extends farther
north, however, including Wisconsin, Minnesota, and
the Canadian provinces surrounding the Great Lakes.
Sporadic cases have also been reported in Africa, India,
Europe, and South America. By way of comparison,
histoplasmosis appears to be at least ten times more
common than blastomycosis. In several series of cases,
a prominent adult male predilection has been noted,
often with a male-to-female ratio as high as 9:1.
Researchers have attributed this to the greater degree
Fig. 6-20 Histoplasmosis. This medium-power
photomicrograph shows scattered epithelioid macrophages
admixed with lymphocytes and plasma cells. Some
macrophages contain organisms of Histoplasma capsulatum
(arrows).
Fig. 6-21 Histoplasmosis. This high-power
photomicrograph of a tissue section readily demonstrates the
small yeasts of Histoplasma capsulatum. (Grocott-Gomori
methenamine silver stain.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 227
of outdoor activity (e.g., hunting, ﬁshing) by men in
areas where the organism grows. The occurrence of
blastomycosis in immunocompromised patients is
relatively rare.
CLINICAL AND RADIOGRAPHIC
FEATURES
Blastomycosis is almost always acquired by inhalation
of spores, particularly after a rain. The spores reach the
alveoli of the lungs, where they begin to grow as yeasts
at body temperature. In most patients, the infection is
probably halted and contained in the lungs, but it
may become hematogenously disseminated in a few
instances. In order of decreasing frequency, the sites of
dissemination include skin, bone, prostate, meninges,
oropharyngeal mucosa, and abdominal organs.
Although most cases of blastomycosis are either
asymptomatic or produce only very mild symptoms,
patients who do experience symptoms usually have
pulmonary complaints. Acute blastomycosis resem-
bles pneumonia, characterized by high fever, chest
pain, malaise, night sweats, and productive cough with
mucopurulent sputum. Rarely, the infection may pre-
cipitate life-threatening adult respiratory distress
syndrome.
Chronic blastomycosis is more common than
the acute form, and it may mimic tuberculosis; both
conditions are often characterized by low-grade fever,
night sweats, weight loss, and productive cough. Chest
radiographs may appear normal, or they may demon-
strate diffuse inﬁltrates or one or more pulmonary or
hilar masses. Unlike the situation with tuberculosis and
histoplasmosis, calciﬁcation is not typically present.
Cutaneous lesions usually represent the spread of
infection from the lungs, although occasionally they
are the only sign of disease. Such lesions begin as ery-
thematous nodules that enlarge, becoming verrucous
or ulcerated (Figs. 6-22 and 6-23).
Oral lesions of blastomycosis may result from either
extrapulmonary dissemination or local inoculation
with the organism. These lesions may have an irregu-
lar, erythematous or white intact surface, or they may
appear as ulcerations with irregular rolled borders and
varying degrees of pain (Figs. 6-24 and 6-25). Clini-
cally, because the lesions resemble squamous cell car-
cinoma, biopsy and histopathologic examination are
required.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of lesional tissue typically
shows a mixture of acute inﬂammation and granulo-
matous inﬂammation surrounding variable numbers of
yeasts. These organisms are 8 to 20 μm in diameter.
They are characterized by a doubly refractile cell wall
(Fig. 6-26) and a broad attachment between the
budding daughter cell and the parent cell. Like many
other fungal organisms, B. dermatitidis can be detected
more easily using special stains, such as the Grocott-
Gomori methenamine silver and PAS methods. Iden-
Fig. 6-22 Blastomycosis. This granular erythematous
plaque of cutaneous blastomycosis has affected the facial
skin. (Courtesy of Dr. William Welton.)
Fig. 6-23 Blastomycosis. Severe cutaneous infection by
Blastomyces dermatitidis. (Courtesy of Dr. Emmitt Costich.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

228 ORAL AND MAXILLOFACIAL PATHOLOGY
tiﬁcation of these organisms is especially important
because this infection often induces a benign reaction
of the overlying epithelium in mucosal or skin lesions
called pseudoepitheliomatous (pseudocarcinoma-
tous) hyperplasia. Because this benign elongation of
the epithelial rete ridges may look like squamous cell
carcinoma at ﬁrst glance under the microscope, careful
inspection of the underlying inﬂamed lesional tissue is
mandatory.
DIAGNOSIS
Rapid diagnosis of blastomycosis can be performed by
microscopic examination of either histopathologic sec-
tions or an alcohol-ﬁxed cytologic preparation. The
most rapid means of diagnosis, however, is the KOH
preparation, which may be used for examining scrap-
ings from a suspected lesion. The most accurate method
of identifying B. dermatitidis is by obtaining a culture
specimen from sputum or fresh biopsy material and
growing the organism on Sabouraud’s agar. This is a
slow technique, however, sometimes taking as long as
3 to 4 weeks for the characteristic mycelium-to-yeast
conversion to take place. A speciﬁc DNA probe has
been developed, allowing immediate identiﬁcation of
the mycelial phase that usually appears by 5 to 7 days
in culture. Serologic studies and skin testing are usually
not helpful because of lack of reactivity and speciﬁcity.
TREATMENT AND PROGNOSIS
As stated previously, most patients with blastomycosis
require no treatment. Even in the case of symptomatic
acute blastomycosis, administration of systemic ampho-
tericin B is indicated only if one or more of the follow-
ing is noted:
● Patient is seriously ill (AIDS, organ transplant
recipient, other immune suppression disorder)
●Patient is not improving clinically
●Patient is ill for more than 2 or 3 weeks
Patients with chronic blastomycosis or extrapulmo-
nary lesions need treatment. Itraconazole is generally
recommended, particularly if the infection is mild or
moderate. Although ketoconazole and ﬂuconazole are
active against B. dermatitidis, these drugs have been
shown to be less effective than itraconazole. Ampho-
tericin B is reserved for patients who are severely ill or
show no response to itraconazole.
Disseminated blastomycosis occurs in only a small
percentage of infected patients and, with proper treat-
ment, the outlook for the patient is reasonably good.
Still, mortality rates ranging from 4% to 22% have been
described over the past 20 years, with men, blacks, and
patients with HIV infection tending to have less favor-
able outcomes.
Fig. 6-24 Blastomycosis. These irregular ulcerations of the
tongue represent blastomycosis. Direct inoculation was
thought to have occurred from the patient’s habit of chewing
dried horse manure (“Kentucky ﬁeld candy”), in which the
organism was probably growing.
Fig. 6-25 Blastomycosis. Granular exophytic and indurated
mass on the buccal mucosa.
Fig. 6-26 Blastomycosis. This high-power photomicrograph
shows the large yeasts of Blastomyces dermatitidis (arrow) and
a pronounced host inﬂammatory response to the organism. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 229
PARACOCCIDIOIDOMYCOSIS (SOUTH
AMERICAN BLASTOMYCOSIS)
Paracoccidioidomycosis is a deep fungal infection
that is caused by Paracoccidioides brasiliensis. The condi-
tion is seen most frequently in patients who live in
either South America (primarily Brazil, Colombia,
Venezuela, Uruguay, and Argentina) or Central
America. However, immigrants from those regions and
visitors to those areas can acquire the infection. Within
some endemic areas, the nine-banded armadillo has
been shown to harbor P. brasiliensis (similar to the situ-
ation seen with leprosy) (see page 198). Although there
is no evidence that the armadillo directly infects
humans, it may be responsible for the spread of the
organism in the environment.
Paracoccidioidomycosis has a distinct predilection
for males, with a 15:1 male-to-female ratio typically
reported. This striking difference is thought to be
attributable to a protective effect of female hormones
(because β-estradiol inhibits the transformation of the
hyphal form of the organism to the pathogenic yeast
form). This theory is supported by the ﬁnding of an
equal number of men and women who have antibodies
directed against the yeast.
CLINICAL FEATURES
Patients with paracoccidioidomycosis are typically
middle-aged at the time of diagnosis, and most are
employed in agriculture. Most cases of paracoccidioi-
domycosis are thought to appear initially as pulmonary
infections after exposure to the spores of the organism.
Although infections are generally self-limiting, P. brasil-
iensis may spread by a hematogenous or lymphatic
route to a variety of tissues, including lymph nodes,
skin, and adrenal glands. Adrenal involvement often
results in hypoadrenocorticism (Addison’s disease)
(see page 841).
Oral lesions appear as mulberry-like ulcerations
that most commonly affect the alveolar mucosa,
gingiva, and palate (Fig. 6-27). The lips, tongue, oro-
pharynx, and buccal mucosa are also involved in a sig-
niﬁcant percentage of cases. In most patients with oral
lesions, more than one oral mucosal site is affected.
HISTOPATHOLOGIC FEATURES
Microscopic evaluation of tissue obtained from an oral
lesion may reveal pseudoepitheliomatous hyperplasia
in addition to ulceration of the overlying surface epi-
thelium. P. brasiliensis elicits a granulomatous inﬂam-
matory host response that is characterized by collections
of epithelioid macrophages and multinucleated giant
cells (Fig. 6-28). Scattered, large (up to 30 μm in diam-
eter) yeasts are readily identiﬁed after staining of the
tissue sections with the Grocott-Gomori methenamine
silver or PAS method. The organisms often show mul-
tiple daughter buds on the parent cell, resulting in an
appearance that has been described as resembling
“Mickey Mouse ears” or the spokes of a ship’s steering
wheel (“mariner’s wheel”).
DIAGNOSIS
Demonstration of the characteristic multiple budding
yeasts in the appropriate clinical setting is usually
adequate to establish a diagnosis of paracoccidioido-
mycosis. Specimens for culture can be obtained, but
P. brasiliensis grows quite slowly.
Fig. 6-27 Paracoccidioidomycosis. This granular,
erythematous, and ulcerated lesion of the maxillary alveolus
represents infection by Paracoccidioides brasiliensis. (Courtesy of
Dr. Ricardo Santiago Gomez.)
Fig. 6-28 Paracoccidioidomycosis. This high-power
photomicrograph shows a large yeast of Paracoccidioides
brasiliensis (arrow) within the cytoplasm of a multinucleated
giant cell. A section stained with the Grocott-Gomori
methenamine silver method (inset) illustrates the
characteristic “Mickey Mouse ears” appearance of the
budding yeasts. (Courtesy of Dr. Ricardo Santiago Gomez.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

230 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The method of management of patients with paracoc-
cidioidomycosis depends on the severity of the disease
presentation. Sulfonamide derivatives have been used
since the 1940s to treat this infection. These drugs are
still used today in many instances to treat mild-to-
moderate cases, particularly in developing countries
with limited access to the newer, more expensive anti-
fungal agents. For severe involvement, intravenous
amphotericin B is usually indicated. Cases that are not
life threatening are best managed by oral itraconazole,
although therapy may be needed for several months.
Ketoconazole can also be used, although the side effects
are typically greater than those associated with
itraconazole.
COCCIDIOIDOMYCOSIS
(SAN JOAQUIN VALLEY FEVER;
VALLEY FEVER; COCCI)
Coccidioides immitis is the fungal organism responsible
for coccidioidomycosis. C. immitis grows saprophyti-
cally in the alkaline, semiarid, desert soil of the south-
western United States and Mexico, with isolated regions
also noted in Central and South America. As with
several other pathogenic fungi, C. immitis is a dimor-
phic organism, appearing as a mold in its natural envi-
ronment of the soil and as a yeast in tissues of the
infected host. Arthrospores produced by the mold
become airborne and can be inhaled into the lungs of
the human host, producing infection.
Coccidioidomycosis is conﬁned to the Western
hemisphere and is endemic throughout the desert
regions of southwestern United States and Mexico;
however, with modern travel taking many visitors to
and from the Sunbelt, this disease can be encountered
virtually anywhere in the world. It is estimated that
100,000 people are infected annually in the United
States, although 60% of this group are asymptomatic.
CLINICAL FEATURES
Most infections with C. immitis are asymptomatic,
although approximately 40% of infected patients expe-
rience a ﬂulike illness and pulmonary symptoms within
1 to 3 weeks after inhaling the arthrospores. Fatigue,
cough, chest pain, myalgias, and headache are com-
monly reported, lasting several weeks with spontane-
ous resolution in most cases. Occasionally, the immune
response may trigger a hypersensitivity reaction that
causes the development of an erythema multiforme–
like cutaneous eruption (see page 776) or erythema
nodosum. Erythema nodosum is a condition that
usually affects the skin of the legs and is characterized
by the appearance of multiple painful erythematous
inﬂammatory nodules in the subcutaneous connec-
tive tissue. This hypersensitivity reaction occurring in
conjunction with coccidioidomycosis is termed valley
fever, and it resolves as the host cell–mediated immune
response controls the pulmonary infection.
Chronic progressive pulmonary coccidioidomy-
cosis is relatively rare. It mimics tuberculosis, with its
clinical presentation of persistent cough, hemoptysis,
chest pain, low-grade fever, and weight loss.
Disseminated coccidioidomycosis occurs when
the organism spreads hematogenously to extrapulmo-
nary sites. This occurs in less than 1% of cases, but it is
a more serious problem. The most commonly involved
areas include skin, lymph nodes (including cervical
lymph nodes), bone and joints, and the meninges.
Immunosuppression greatly increases the risk of dis-
semination. The following groups are particularly
susceptible:
●Patients taking large doses of systemic corticoste-
roids (organ transplant recipients)
●Patients who are being treated with cancer
chemotherapy
●Patients in the end stages of HIV infection
●Patients who are pregnant
Infants and older adult patients, both of whom may
have suboptimally functioning immune systems, also
may be at increased risk for disseminated disease.
Persons of color (e.g., blacks, Filipinos, Native Ameri-
cans) also seem to have an increased risk, but it is unclear
whether their susceptibility is due to genetic causes or
socioeconomic factors, such as poor nutrition.
The cutaneous lesions may appear as papules, sub-
cutaneous abscesses, verrucous plaques, and granulo-
matous nodules. Of prime signiﬁcance to the clinician
is the predilection for these lesions to develop in the
area of the central face, especially the nasolabial fold.
Oral lesions are distinctly uncommon, and these have
been described as ulcerated granulomatous nodules.
HISTOPATHOLOGIC FEATURES
Biopsy material shows large (20 to 60 μm), round
spherules that may contain numerous endospores. The
host response may be variable, ranging from a suppura-
tive, neutrophilic inﬁltrate to a granulomatous inﬂam-
matory response. In some cases the two patterns of
inﬂammation are seen concurrently. Special stains,
such as the PAS and Grocott-Gomori methenamine
silver methods, enable the pathologist to identify the
organism more readily.
DIAGNOSIS
The diagnosis of coccidioidomycosis can be conﬁrmed
by culture or identiﬁcation of characteristic organisms
in biopsy material. If the organisms do not have a `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 231
classic microscopic appearance, then in situ hybridiza-
tion studies using speciﬁc complementary DNA probes
for C. immitis can be performed to deﬁnitively identify
the fungus. Cytologic preparations from bronchial
swabbings or sputum samples may also reveal the
organisms.
Serologic studies are helpful in supporting the diag-
nosis, and they may be performed at the same time as
skin testing. Skin testing by itself may be of limited
value in determining the diagnosis because many
patients in endemic areas have already been exposed
to the organism and have positive test ﬁndings.
TREATMENT
The decision whether or not to treat a particular patient
affected by coccidioidomycosis depends on the sever-
ity and extent of the infection and the patient’s immune
status. Relatively mild symptoms in an immunocompe-
tent person do not warrant treatment. Amphotericin B
is administered for the following groups:
● Immunosuppressed patients
●Patients with severe pulmonary infection
●Patients who have disseminated disease
●Patients who are pregnant
●Patients who appear to be in a life-threatening
situation concerning the infection
For many cases of coccidioidomycosis, ﬂuconazole
or itraconazole is the drug of choice, usually given in
high doses for an extended period of time. Although
the response of the disease to these oral azole medica-
tions may be somewhat slower than that of amphoteri-
cin B, the side effects and complications of therapy
are far fewer. Ketoconazole also may be used as
an alternative treatment for mild-to-moderate cases of
coccidioidomycosis.
CRYPTOCOCCOSIS
Cryptococcosis is a relatively uncommon fungal
disease caused by the yeast Cryptococcus neoformans.
This organism normally causes no problem in immu-
nocompetent people, but it can be devastating to the
immunocompromised patient. The incidence of cryp-
tococcosis increased dramatically during the 1990s,
primarily because of the AIDS epidemic. At that time,
this was the most common life-threatening fungal
infection in these patients. However, with the advent
of highly active anti-retroviral therapy (HAART) (see
page 280), this complication has become less of a
problem in the United States. In countries where the
population cannot afford HAART, cryptococcosis
remains a signiﬁcant cause of death for AIDS patients.
The disease has a worldwide distribution because of its
association with the pigeon (with the organism living
in the deposits of excreta left by the birds). Unlike
many other pathogenic fungi, C. neoformans grows as a
yeast both in the soil and in infected tissue. The organ-
ism usually produces a prominent mucopolysaccha-
ride capsule that appears to protect it from host immune
defenses.
The disease is acquired by inhalation of C. neofor-
mans spores into the lungs, resulting in an immediate
inﬂux of neutrophils, which destroys most of the yeasts.
Macrophages soon follow, although resolution of infec-
tion in the immunocompetent host ultimately depends
on an intact cell-mediated immune system.
CLINICAL FEATURES
Primary cryptococcal infection of the lungs is often
asymptomatic; however, a mild ﬂulike illness may
develop. Patients complain of productive cough, chest
pain, fever, and malaise. Most patients with a diagnosis
of cryptococcosis have a signiﬁcant underlying medical
problem related to immune suppression (e.g., systemic
corticosteroid therapy, cancer chemotherapy, malig-
nancy, AIDS). It is estimated that 5% to 10% of AIDS
patients acquire this infection (see page 264).
Dissemination of the infection is common in these
immunocompromised patients, and the most frequent
site of involvement is the meninges, followed by skin,
bone, and the prostate gland.
Cryptococcal meningitis is characterized by head-
ache, fever, vomiting, and neck stiffness. In many
instances, this is the initial sign of the disease.
Cutaneous lesions develop in 10% to 15% of patients
with disseminated disease. These are of particular
importance to the clinician, because the skin of the
head and neck is often involved. The lesions appear as
erythematous papules or pustules that may ulcerate,
discharging a puslike material rich in cryptococcal
organisms (Fig. 6-29).
Although oral lesions are relatively rare, they have
been described either as craterlike, nonhealing ulcers
that are tender on palpation or as friable papillary ery-
thematous plaques. Dissemination to salivary gland
tissue also has been reported rarely.
HISTOPATHOLOGIC FEATURES
Microscopic sections of a cryptococcal lesion generally
show a granulomatous inﬂammatory response to the
organism. The extent of the response may vary,
however, depending on the host’s immune status and
the strain of the organism. The yeast appears as a
round-to-ovoid structure, 4 to 6 μm in diameter, sur-
rounded by a clear halo that represents the capsule.
Staining with the PAS or Grocott-Gomori methena-
mine silver method readily identiﬁes the fungus; `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

232 ORAL AND MAXILLOFACIAL PATHOLOGY
moreover, a mucicarmine stain uniquely demonstrates
its mucopolysaccharide capsule.
DIAGNOSIS
The diagnosis of cryptococcosis can be made by several
methods, including biopsy and culture. Detection of
cryptococcal polysaccharide antigen in the serum or
cerebrospinal ﬂuid is also useful as a diagnostic
procedure.
TREATMENT AND PROGNOSIS
Management of cryptococcal infections can be very
difﬁcult because most of the affected patients have an
underlying medical problem. Before amphotericin B
was developed, cryptococcosis was almost uniformly
fatal. For cryptococcal meningitis, a combination of
systemic amphotericin B and another antifungal drug
(ﬂucytosine) is used initially for 2 weeks in most cases
to treat this disease. Then, either ﬂuconazole or itra-
conazole is given for an additional minimal period of
10 weeks. For relatively mild cases of pulmonary cryp-
tococcosis, only ﬂuconazole or itraconazole may be
used. These drugs produce far fewer side effects than
do amphotericin B and ﬂucytosine, and they have
proven to be important therapeutic tools for managing
this type of infection.
ZYGOMYCOSIS (MUCORMYCOSIS;
PHYCOMYCOSIS)
Zygomycosis is an opportunistic, frequently fulminant,
fungal infection that is caused by normally saprobic
organisms of the class Zygomycetes, including such
genera as Absidia, Mucor, Rhizomucor, and Rhizopus.
These organisms are found throughout the world,
growing in their natural state on a variety of decaying
organic materials. Numerous spores may be liberated
into the air and inhaled by the human host.
Zygomycosis may involve any one of several areas of
the body, but the rhinocerebral form is most relevant
to the oral health care provider. Zygomycosis is noted
especially in insulin-dependent diabetics who have
uncontrolled diabetes and are ketoacidotic; ketoacido-
sis inhibits the binding of iron to transferrin, allowing
serum iron levels to rise. The growth of these fungi is
enhanced by iron, and patients who are taking defer-
oxamine (an iron-chelating agent used in the treatment
of diseases such as thalassemia) are also at increased
risk for developing zygomycosis. As with many other
fungal diseases, this infection affects immunocom-
p romised patients as well, including bone marrow
transplant recipients, patients with AIDS, and those
receiving systemic corticosteroid therapy. Only rarely
has zygomycosis been reported in apparently healthy
individuals.
CLINICAL AND RADIOGRAPHIC
FEATURES
The presenting symptoms of rhinocerebral zygomyco-
sis may be exhibited in several ways. Patients may
experience nasal obstruction, bloody nasal discharge,
facial pain or headache, facial swelling or cellulitis, and
visual disturbances with concurrent proptosis. Symp-
toms related to cranial nerve involvement (e.g., facial
paralysis) are often present. With progression of disease
into the cranial vault, blindness, lethargy, and seizures
may develop, followed by death.
If the maxillary sinus is involved, the initial presen-
tation may be seen as intraoral swelling of the maxil-
lary alveolar process, the palate, or both. If the condition
remains untreated, palatal ulceration may evolve, with
the surface of the ulcer typically appearing black and
necrotic. Massive tissue destruction may result if the
condition is not treated (Figs. 6-30 and 6-31).
Radiographically, opaciﬁcation of the sinuses may
be observed in conjunction with patchy effacement of
the bony walls of the sinuses (Fig. 6-32). Such a picture
may be difﬁcult to distinguish from that of a malig-
nancy affecting the sinus area.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of lesional tissue shows
extensive necrosis with numerous large (6 to 30 μm in
diameter), branching, nonseptate hyphae at the periph-
ery (Fig. 6-33). The hyphae tend to branch at 90-degree
angles. The extensive tissue destruction and necrosis
associated with this disease are undoubtedly attribut-
Fig. 6-29 Cryptococcosis. These papules of the facial skin
represent disseminated cryptococcal infection in a patient
infected with human immunodeﬁciency virus (HIV). (Courtesy
of Dr. Catherine Flaitz.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 233
able to the preference of the fungi for invasion of small
blood vessels. This disrupts normal blood ﬂow to the
tissue, resulting in infarction and necrosis. A neutro-
philic inﬁltrate usually predominates in the viable
tissue, but the host inﬂammatory cell response to the
infection may be minimal, particularly if the patient is
immunosuppressed.
DIAGNOSIS
Diagnosis of zygomycosis is usually based on the histo-
pathologic ﬁndings. Because of the grave nature of this
infection, appropriate therapy must be instituted in a
timely manner (often without the beneﬁt of deﬁnitive
culture results).
TREATMENT AND PROGNOSIS
Successful treatment of zygomycosis consists of rapid
accurate diagnosis of the condition, followed by radical
surgical débridement of the infected, necrotic tissue
and systemic administration of high doses of one of the
lipid formulations of amphotericin B. Magnetic reso-
nance imaging (MRI) of the head may be useful in
determining the extent of disease involvement so that
surgical margins can be planned. In addition, control
of the patient’s underlying disease (e.g., diabetic keto-
acidosis) must be attempted. Despite such therapy, the
prognosis is usually poor, with approximately 60% of
patients who develop rhinocerebral zygomycosis dying
of their disease. Should the patient survive, the massive
tissue destruction that remains presents a challenge
both functionally and aesthetically. Prosthetic obtura-
tion of palatal defects may be necessary.
Fig. 6-30 Zygomycosis. Diffuse tissue destruction involving
the nasal and maxillary structures caused by a Mucor species.
(Courtesy of Dr. Sadru Kabani.)
Fig. 6-31 Zygomycosis. The extensive black, necrotic
lesion of the palate represents zygomycotic infection that
extended from the maxillary sinus in a patient with poorly
controlled type I diabetes mellitus. (Courtesy of Dr. Michael Tabor.)
Fig. 6-32 Zygomycosis. This computed tomography (CT)
scan demonstrates the opaciﬁcation of the left maxillary sinus
(arrow).
Fig. 6-33 Zygomycosis. This high-power photomicrograph
shows the large, nonseptate fungal hyphae characteristic of
the zygomycotic organisms. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

234 ORAL AND MAXILLOFACIAL PATHOLOGY
ASPERGILLOSIS
Aspergillosis is a fungal disease that is characterized
by noninvasive and invasive forms. Noninvasive asper-
gillosis usually affects a normal host, appearing either
as an allergic reaction or a cluster of fungal hyphae.
Localized invasive infection of damaged tissue may be
seen in a normal host, but a more extensive invasive
infection is often evident in the immunocompromised
patient. With the advent of intensive chemotherapeu-
tic regimens, the AIDS epidemic, and both solid-organ
and bone marrow transplantation, the prevalence of
invasive aspergillosis has increased dramatically in the
past 20 years. Patients with uncontrolled diabetes mel-
litus are also susceptible to Aspergillus spp. infections.
Rarely, invasive aspergillosis has been reported to
affect the paranasal sinuses of apparently normal
immunocompetent individuals.
Normally, the various species of the Aspergillus genus
reside worldwide as saprobic organisms in soil, water,
or decaying organic debris. Resistant spores are
released into the air and inhaled by the human host,
resulting in opportunistic fungal infection second in
frequency only to candidiasis. Interestingly, most
species of Aspergillus cannot grow at 37° C; only the
pathogenic species have the ability to replicate at body
temperature.
The two most commonly encountered species of
Aspergillus in the medical setting are A. ﬂavus and A.
fumigatus, with A. fumigatus being responsible for 90%
of the cases of aspergillosis. The patient may acquire
such infections in the hospital (“nosocomial” infec-
tion), especially if remodeling or building construction
is being performed in the immediate area. Such activ-
ity often stirs up the spores, which are then inhaled by
the patient.
CLINICAL FEATURES
The clinical manifestations of aspergillosis vary,
depending on the host immune status and the pres-
ence or absence of tissue damage. In the normal host,
the disease may appear as an allergy affecting either
the sinuses (allergic fungal sinusitis) or the broncho-
pulmonary tract. An asthma attack may be triggered by
inhalation of spores by a susceptible person. Some-
times a low-grade infection becomes established in the
maxillary sinus, resulting in a mass of fungal hyphae
called an aspergilloma. Occasionally, the mass will
undergo dystrophic calciﬁcation, producing a radi-
opaque body called an antrolith within the sinus.
Another presentation that may be encountered by
the oral health care provider is aspergillosis after tooth
extraction or endodontic treatment, especially in the
maxillary posterior segments. Presumably, tissue
damage predisposes the sinus to infection, resulting in
symptoms of localized pain and tenderness accompa-
nied by nasal discharge. Immunocompromised patients
are particularly susceptible to oral aspergillosis, and
some investigators have suggested that the portal of
entry may be the marginal gingiva and gingival sulcus.
Painful gingival ulcerations are initially noted, and
peripherally the mucosa and soft tissue develops diffuse
swelling with a gray or violaceous hue (Fig. 6-34). If the
disease is not treated, extensive necrosis, seen clinically
as a yellow or black ulcer, and facial swelling evolve.
Disseminated aspergillosis occurs principally in
immunocompromised patients, particularly in those
who have leukemia or who are taking high daily
doses of corticosteroids. Such patients usually exhibit
symptoms related to the primary site of inoculation:
the lungs. The patient typically has chest pain, cough,
and fever, but such symptoms are vague. Therefore,
obtaining an early, accurate diagnosis may be difﬁcult.
Once the fungal organism obtains access to the blood-
stream, infection can spread to such sites as the CNS,
eye, skin, liver, gastrointestinal tract, bone, and thyroid
gland.
HISTOPATHOLOGIC FEATURES
Tissue sections of invasive Aspergillus spp. lesions show
varying numbers of branching, septate hyphae, 3 to
4 μm in diameter (Figs. 6-35 and 6-36). These hyphae
show a tendency to branch at an acute angle and to
invade adjacent small blood vessels. Occlusion of the
vessels often results in the characteristic pattern of
necrosis associated with this disease. In the immuno-
competent host, a granulomatous inﬂammatory
response—in addition to necrosis—can be expected. In
the immunocompromised patient, however, the inﬂam-
Fig. 6-34 Aspergillosis. This young woman developed a
painful purplish swelling of her hard palate after induction
chemotherapy for leukemia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 235
matory response is often weak or absent, leading to
extensive tissue destruction.
Noninvasive forms of aspergillosis have histopatho-
logic features that differ from invasive aspergillosis,
however. The aspergilloma, for example, is character-
ized by a tangled mass of hyphae with no evidence of
tissue invasion. Allergic fungal sinusitis, on the other
hand, histopathologically exhibits large pools of eosino-
philic inspissated mucin with interspersed sheetlike
collections of lymphocytes and eosinophils. Relatively
few fungal hyphae are identiﬁed, and then only
with careful examination after methenamine silver
staining.
DIAGNOSIS
Although the diagnosis of fungal infection can be
established by identiﬁcation of hyphae within tissue
sections, this ﬁnding is only suggestive of aspergillosis
because other fungal organisms may appear similar
microscopically. Ideally, the diagnosis should be sup-
ported by culture of the organism from the lesion;
however, from a practical standpoint, treatment may
need to be initiated immediately to prevent the patient’s
demise. Culture specimens of sputum and blood are of
limited value because they are often negative despite
disseminated disease.
TREATMENT AND PROGNOSIS
Treatment depends on the clinical presentation of
aspergillosis. For immunocompetent patients with a
noninvasive aspergilloma, surgical débridement may
be all that is necessary. Patients who have allergic
fungal sinusitis are treated with débridement and cor-
ticosteroid drugs. For localized invasive aspergillosis in
the immunocompetent host, débridement followed by
antifungal medication is indicated. Although systemic
amphotericin B therapy was considered appropriate
in the past, recent studies have shown that voricon-
azole, a triazole antifungal agent, is more effective
for treating these patients. In one large series of
patients with invasive aspergillosis, 71% of those
treated with voriconazole were alive after 12 weeks
of therapy, compared with 58% survival in the
group who received standard amphotericin B treat-
ment. Itraconazole has also been approved as an
alternative therapy. Immunocompromised patients
who have invasive aspergillosis should be treated
by aggressive débridement of necrotic tissue, com-
bined with systemic antifungal therapy as described
previously.
The prognosis for immunocompromised patients is
much worse compared with immunocompetent indi-
viduals, particularly if the infection is disseminated.
Even with appropriate therapy, only about one third of
these patients survive. Because aspergillosis in the
immunocompromised patient usually develops while
the individual is hospitalized, particular attention
should be given to the ventilation system in the hospital
to prevent patient exposure to the airborne spores of
Aspergillus spp.
TOXOPLASMOSIS
Toxoplasmosis is a relatively common disease caused
by the obligate intracellular protozoal organism Toxo-
plasma gondii. For normal, healthy adults, the organism
poses no problems, and an estimated 16% to 23% of
adults in the United States may have had asymptomatic
infection, based on an epidemiologic study that exam-
ined serologic samples from more than 4000 random-
ized individuals. However, the prevalence of infection
has considerable geographic variation around the
Fig. 6-35 Aspergillosis. This photomicrograph reveals
fungal hyphae and a fruiting body of an Aspergillus species.
Fig. 6-36 Aspergillosis. This high-power photomicrograph
shows the characteristic septate hyphae of Aspergillus
species. (Grocott-Gomori methenamine silver stain.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

236 ORAL AND MAXILLOFACIAL PATHOLOGY
world. Unfortunately, the disease can be devastating
for the developing fetus or the immunocompromised
patient. Other mammals, particularly members of the
cat family, are vulnerable to infection, and cats are
considered to be the deﬁnitive host. T. gondii multiplies
in the intestinal tract of the cat by means of a sexual
life cycle, discharging numerous oocysts in the cat
feces. Another animal or human can ingest these
oocysts, resulting in the production of disease.
CLINICAL FEATURES
In the normal, immunocompetent individual, infection
with T. gondii is often asymptomatic. If symptoms
develop, they are usually mild and resemble infectious
mononucleosis; patients may have a low-grade fever,
cervical lymphadenopathy, fatigue, and muscle or joint
pain. These symptoms may last from a few weeks to
a few months, although the host typically recovers
without therapy. Sometimes the lymphadenopathy
involves one or more of the lymph nodes in the para-
oral region, such as the buccal or submental lymph
node. In such instances, the oral health care provider
may discover the disease.
In immunosuppressed patients, toxoplasmosis may
represent a new, primary infection or, more frequently,
reactivation of previously encysted organisms. The
principal groups at risk include the following:
● AIDS patients
● Transplant recipients
● Cancer patients
Manifestations of infection can include necrotizing
encephalitis, pneumonia, and myositis or myocarditis.
In the United States, it is estimated that from 3% to 10%
of AIDS patients (see page 264) will experience CNS
involvement. CNS infection is very serious. Clinically,
the patient may complain of headache, lethargy, disori-
entation, and hemiparesis.
Congenital toxoplasmosis occurs when a nonim-
mune mother contracts the disease during her preg-
nancy and the organism crosses the placental barrier,
infecting the developing fetus. The potential effects of
blindness, mental retardation, and delayed psychomo-
tor development are most severe if the infection occurs
during the ﬁrst trimester of pregnancy.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of a lymph node obtained
from a patient with active toxoplasmosis shows charac-
teristic reactive germinal centers exhibiting an accu-
mulation of eosinophilic macrophages. The macro-
phages encroach on the germinal centers and
accumulate within the subcapsular and sinusoidal
regions of the node (Fig. 6-37).
DIAGNOSIS
The diagnosis of toxoplasmosis is usually established by
identiﬁcation of rising serum antibody titers to T. gondii
within 10 to 14 days after infection. Immunocompro-
mised patients, however, may not be able to generate
an antibody response; therefore, the diagnosis may rest
on the clinical ﬁndings and the response of the patient
to therapy.
Biopsy of an involved lymph node may suggest the
diagnosis, and the causative organisms can sometimes
be detected immunohistochemically using antibodies
directed against T. gondii–speciﬁc antigens (Fig. 6-38).
The diagnosis should also be conﬁrmed by serologic
studies, if possible.
TREATMENT AND PROGNOSIS
Most healthy adults with toxoplasmosis require no spe-
ciﬁc treatment because of the mild symptoms and self-
limiting course. Perhaps more importantly, pregnant
women should avoid situations that place them at
risk for the disease. Handling or eating raw meat or
cleaning a cat litter box should be avoided until after
delivery. If exposure during pregnancy is suspected,
treatment with a combination of sulfadiazine and pyri-
methamine often prevents transmission of T. gondii to
the fetus. Because these drugs act by inhibiting folate
metabolism of the protozoan, folinic acid is given con-
currently to help prevent hematologic complications
in the patient. A similar drug regimen is used to treat
immunosuppressed individuals with toxoplasmosis,
although clindamycin may be substituted for sulfadia-
zine in managing patients who are allergic to sulfa
drugs. Because most cases of toxoplasmosis in AIDS
patients represent reactivation of encysted organisms,
prophylactic administration of trimethoprim and sul-
Fig. 6-37 Toxoplasmosis. This high-power
photomicrograph shows an accumulation of eosinophilic
macrophages within a lymph node. (Courtesy of Dr. John Kalmar.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 6 FUNGAL AND PROTOZOAL DISEASES 237
famethoxazole is generally recommended, particularly
if the patient’s CD4+ T-lymphocyte count is less than
100 cells/μL.
BIBLIOGRAPHY
Candidiasis
Akpan A, Morgan R: Oral candidiasis, Postgrad Med J 78:455-
459, 2002.
Allen CM: Diagnosing and managing oral candidiasis, J Am Dent
Assoc 123:77-82, 1992.
Arendoff TM, Walker DM: The prevalence and intra-oral distri-
bution of Candida albicans in man, Arch Oral Biol 25:1-10,
1980.
Barbeau J, Séguin J, Goulet JP et al: Reassessing the presence of
Candida albicans in denture-related stomatitis, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 95:51-59, 2003.
Baughman RA: Median rhomboid glossitis: a developmental
anomaly? Oral Surg Oral Med Oral Pathol 31:56-65, 1971.
Bennett JE: Echinocandins for candidemia in adults without neu-
tropenia, N Engl J Med 355:1154-1159, 2006.
Bergendal T, Isacsson G: A combined clinical, mycological and
histological study of denture stomatitis, Acta Odontol Scand
41:33-44, 1983.
Blomgren J, Berggren U, Jontell M: Fluconazole versus nystatin
in the treatment of oral candidiasis, Acta Odontol Scand
56:202-205, 1998.
Eisenbarth GS, Gottlieb PA: Autoimmune polyendocrine syn-
dromes, N Engl J Med 350:2068-2079, 2004.
Fotos PG, Vincent SD, Hellstein JW: Oral candidosis: clinical,
historical and therapeutic features of 100 cases, Oral Surg
Oral Med Oral Pathol 74:41-49, 1992.
Heimdahl A, Nord CE: Oral yeast infections in immunocompro-
mised and seriously diseased patients, Acta Odontol Scand
48:77-84, 1990.
Holmstrup P, Axéll T: Classiﬁcation and clinical manifestations
of oral yeast infections, Acta Odontol Scand 48:57-59, 1990.
Kleinegger CL, Lockhart SR, Vargas K et al: Frequency, intensity,
species, and strains of oral Candida vary as a function of host
age, J Clin Microbiol 34:2246-2254, 1996.
Lehner T: Oral thrush, or acute pseudomembranous candidiasis:
a clinicopathologic study of forty-four cases, Oral Surg Oral
Med Oral Pathol 18:27-37, 1964.
Monaco JG, Pickett AB: The role of Candida in inﬂammatory
papillary hyperplasia, J Prosthet Dent 45:470-471, 1981.
Odds FC, Arai T, Disalvo AF et al: Nomenclature of fungal dis-
eases: a report and recommendations from a sub-committee
of the International Society for Human and Animal Mycology
(ISHAM), J Med Vet Mycol 30:1-10, 1992.
Öhman S-C, Dahlen G, Moller A et al: Angular cheilitis: a clinical
and microbial study, J Oral Pathol 15:213-217, 1986.
Peterson P, Pitkänen J, Sillanpää N et al: Autoimmune polyen-
docrinopathy candidiasis ectodermal dystrophy (APECED): a
model disease to study molecular aspects of endocrine auto-
immunity, Clin Exp Immunol 135:348-357, 2004.
Rautemaa R, Hietanen J, Niissalo S et al: Oral and oesophageal
squamous cell carcinoma—a complication or component
of autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy (APECED, APS-I), Oral Oncol 43:607-613, 2007.
Rodu B, Grifﬁn IL, Gockerman JP: Oral candidiasis in cancer
patients, South Med J 77:312-314, 1984.
Samaranayake LP, Cheung LK, Samaranayake YH: Candidiasis
and other fungal diseases of the mouth, Dermatol Ther 15:251-
269, 2002.
Sanguineti A, Carmichael JK, Campbell K: Fluconazole-resistant
Candida albicans after long-term suppressive therapy, Arch
Intern Med 153:1122-1124, 1993.
Sitheeque MAM, Samaranayake LP: Chronic hyperplastic candi-
dosis/candidiasis (candidal leukoplakia), Crit Rev Oral Biol
Med 14:253-267, 2003.
Terai H, Shimahara M: Atrophic tongue associated with Candida,
J Oral Pathol Med 34:397-400, 2005.
Terrell CL: Antifungal agents. II. The azoles, Mayo Clin Proc
74:78-100, 1999.
Vazquez JA, Skiest DJ, Nieto L et al: A multicenter randomized
trial evaluation posaconazole versus ﬂuconazole for the treat-
ment of oropharyngeal candidiasis in subjects with HIV/
AIDS, Clin Infect Dis 42:1179-1186, 2006.
Histoplasmosis
Bradsher RW: Histoplasmosis and blastomycosis, Clin Infect Dis
22(suppl 2):S102-111, 1996.
Couppié P, Clyti E, Nacher M et al: Acquired immunodeﬁciency
syndrome-related oral and/or cutaneous histoplasmosis: a
descriptive and comparative study of 21 cases in French
Guiana, Int J Dermatol 41:571-576, 2002.
Leal-Alcure M, Di Hipólito-Júnior O, Paes de Almeida O et al:
Oral histoplasmosis in an HIV-negative patient, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 101:E33-36, 2006.
Lortholary O, Denning DW, Dupont B: Endemic mycoses: a
treatment update, J Antimicrob Chemother 43:321-331, 1999.
Motta ACF, Galo R, Grupioni-Lourenço A et al: Unusual orofacial
manifestations of histoplasmosis in renal transplanted patient,
Mycopathologia 161:161-165, 2006.
Myskowski PL, White MH, Ahkami R: Fungal disease in the
immunocompromised host, Dermatol Clin 15:295-305,
1997.
Samaranayake LP: Oral mycoses in HIV infection, Oral Surg Oral
Med Oral Pathol 73:171-180, 1992.
Sarosi GA, Johnson PC: Disseminated histoplasmosis in patients
infected with human immunodeﬁciency virus, Clin Infect Dis
14(suppl 1):S60-67, 1992.
Sharma OP: Histoplasmosis: a masquerader of sarcoidosis, Sar-
coidosis 8:10-13, 1991.
Wheat LJ, Kauffman CA: Histoplasmosis, Infect Dis Clin North Am
17:1-19, 2003.
Fig. 6-38 Toxoplasmosis. In this high-power
photomicrograph, an encysted organism of toxoplasmosis is
highlighted by an immunohistochemical study. (Courtesy of Dr.
John Kalmar.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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238 ORAL AND MAXILLOFACIAL PATHOLOGY
Blastomycosis
Areno JP, Campbell GD, George RB: Diagnosis of blastomycosis,
Semin Respir Infect 12:252-262, 1997.
Assaly RA, Hammersley JR, Olson DE et al: Disseminated blas-
tomycosis, J Am Acad Dermatol 48:123-127, 2003.
Bradsher RW: Clinical features of blastomycosis, Semin Respir
Infect 12:229-234, 1997.
Bradsher RW, Chapman SW, Pappas PG: Blastomycosis, Infect
Dis Clin North Am 17:21-40, 2003.
Davies SF, Sarosi GA: Epidemiological and clinical features of
pulmonary blastomycosis, Semin Resp Infect 12:206-218,
1997.
Dworkin MS, Duckro AN, Proia L et al: The epidemiology of
blastomycosis in Illinois and factors associated with death,
Clin Infect Dis 41:e107-111, 2005.
Greenberg SB: Serious waterborne and wilderness infections,
Crit Care Clin 15:387-414, 1999.
Klein BS, Vergeront JM, Weeks RJ et al: Isolation of Blastomyces
dermatitidis in soil associated with a large outbreak of blasto-
mycosis in Wisconsin, N Engl J Med 314:529-534, 1986.
Lemos LB, Baliga M, Guo M: Blastomycosis: the great pretender
can also be an opportunist—initial clinical diagnosis and
underlying diseases in 123 patients, Ann Diagn Pathol 6:194-
203, 2002.
Meyer KC, McManus F-J, Maki DG: Overwhelming pulmonary
blastomycosis associated with the adult respiratory distress
syndrome, N Engl J Med 329:1231-1236, 1993.
Reder PA, Neel B: Blastomycosis in otolaryngology: review of a
large series, Laryngoscope 103:53-58, 1993.
Rose HD, Gingrass DJ: Localized oral blastomycosis mimicking
actinomycosis, Oral Surg Oral Med Oral Pathol 54:12-14,
1982.
Paracoccidioidomycosis
Bagagli E, Franco M, Bosco S et al: High frequency of Paracoc-
cidioides brasiliensis infection in armadillos (Dasypus novemcinc-
tus): an ecological study, Med Mycol 41:217-223, 2003.
Bethlem EP, Capone D, Maranhao B et al: Paracoccidioidomy-
cosis, Curr Opin Pulm Med 5:319-325, 1999.
Bruinmet E, Castaneda E, Restrepo A: Paracoccidioidomycosis:
an update, Clin Microbiol Rev 6:89-117, 1993.
Godoy H, Reichart PA: Oral manifestations of paracoccidioido-
mycosis. Report of 21 cases from Argentina, Mycoses 46:412-
417, 2003.
Gorete dos Santos-Nogueira M, Queiroz-Andrade GM, Tonelli E:
Clinical evolution of paracoccidioidomycosis in 38 children
and teenagers, Mycopathologia 161:73-81, 2006.
Paes de Almeida O, Jorge J, Scully C: Paracoccidioidomycosis of
the mouth: an emerging deep mycosis, Crit Rev Oral Biol Med
14:268-274, 2003.
San-Blas G: Paracoccidioidomycosis and its etiologic agent Para-
coccidioides brasiliensis, J Med Vet Mycol 31:99-113, 1993.
San-Blas G, Restrepo A, Clemons K et al: Paracoccidioidomyco-
sis, J Med Vet Mycol 30(suppl 1):59-71, 1992.
Sposto MR, Mendes-Giannini MJ, Moraes RA et al: Paracoccidi-
oidomycosis manifesting as oral lesions: clinical, cytological
and serological investigation, J Oral Pathol Med 23:85-87,
1994.
Sposto MR, Scully C, Paes de Almeida O et al: Oral paracoccidi-
oidomycosis: a study of 36 South American patients, Oral Surg
Oral Med Oral Pathol 75:461-465, 1993.
Coccidioidomycosis
Ampel NM, Dols CL, Galgiani JN: Coccidioidomycosis during
human immunodeﬁciency virus infection: results of a pro-
spective study in a coccidioidal endemic area, Am J Med
94:235-240, 1993.
Arnold MG, Arnold JC, Bloom DC et al: Head and neck mani-
festations of disseminated coccidioidomycosis, Laryngoscope
114:747-752, 2004.
Biller JA, Scheuller MC, Eisele DW: Coccidioidomycosis causing
massive cervical lymphadenopathy, Laryngoscope 114:1892-
1894, 2004.
Chiller TM, Galgiani JN, Stevens DA: Coccidioidomycosis, Infect
Dis Clin North Am 17:41-57, 2003.
Crum NF, Ballon-Landa G: Coccidioidomycosis in pregnancy:
case report and review of the literature, Am J Med 119:993.
e11-993.e17, 2006.
DiCaudo DJ: Coccidioidomycosis: a review and update, J Am
Acad Dermatol 55:929-942, 2006.
Galgiani JN, Ampel NM, Blair JE et al: Coccidioidomycosis, Clin
Infect Dis 41:1217-1223, 2005.
Galgiani JN, Catanzaro A, Cloud GA et al: Comparison of oral
ﬂuconazole and itraconazole for progressive, nonmeningeal
coccidioidomycosis, Ann Intern Med 133:676-686, 2000.
Kim A, Parker SS: Coccidioidomycosis: case report and update
on diagnosis and management, J Am Acad Dermatol 46:743-
747, 2002.
Rodriguez RA, Konia T: Coccidioidomycosis of the tongue, Arch
Pathol Lab Med 129:e4-e6, 2005.
Schneider E, Hajjeh RA, Spiegel RA et al: A coccidioidomycosis
outbreak following the Northridge, Calif, earthquake, J Am
Med Assoc 277:904-908, 1997.
Cryptococcosis
Christianson JC, Engber W, Andes D: Primary cutaneous cryp-
tococcosis in immunocompetent and immunocompromised
hosts, Med Mycol 41:177-188, 2003.
Leggiadro RJ, Barrett FF, Hughes WT: Extrapulmonary crypto-
coccosis in immunocompromised infants and children,
Pediatr Infect Dis J 11:43-47, 1992.
Levitz SM: The ecology of Cryptococcus neoformans and the epide-
miology of cryptococcosis, Rev Infect Dis 13:1163-1169,
1991.
Mehrabi M, Bagheri S, Leonard MK et al: Mucocutaneous mani-
festation of cryptococcal infection: report of a case and review
of the literature, J Oral Maxillofac Surg 63:1543-1549, 2005.
Monteil RA, Hofman P, Michiels JF et al: Oral cryptococcosis:
case report of salivary gland involvement in an AIDS patient,
J Oral Pathol Med 26:53-56, 1997.
Namiq AL, Tollefson T, Fan F: Cryptococcal parotitis presenting
as a cystic parotid mass: report of a case diagnosed by ﬁne-
needle aspiration cytology, Diagn Cytopathol 33:36-38, 2005.
Nosanchuk JD, Shoham S, Fries BC et al: Evidence of zoonotic
transmission of Cryptococcus neoformans from a pet cockatoo
to an immunocompromised patient, Ann Intern Med 132:205-
208, 2000.
Patz EF, Goodman PC: Pulmonary cryptococcosis, J Thorac
Imaging 7:51-55, 1992.
Perfect JR, Casadevall A: Cryptococcosis, Infect Dis Clin North Am
16:837-874, 2002.
Ruhnke M: Mucosal and systemic fungal infections in patients
with AIDS, Drugs 64:1163-1180, 2004.
Schmidt-Westhausen A, Grunewald T, Reichart PA et al: Oral
cryptococcosis in a patient with AIDS. A case report, Oral Dis
1:77-79, 1995.
Scully C, Paes De Almeida O: Orofacial manifestations of the
systemic mycoses, J Oral Pathol Med 21:289-294, 1992.
Subramanian S, Mathai D: Clinical manifestations and manage-
ment of cryptococcal infection, J Postgrad Med 51(suppl 1):
S21-S26, 2005.
Yao Z, Liao W, Chen R: Management of cryptococcosis in non-
HIV-related patients, Med Mycol 43:245-251, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 6 FUNGAL AND PROTOZOAL DISEASES 239
Zygomycosis
Chayakulkeeree M, Ghannoum MA, Perfect JR: Zygomycosis:
the re-emerging fungal infection, Eur J Clin Microbiol Infect Dis
25:215-229, 2006.
Gonzalez CE, Rinaldi MG, Sugar AM: Zygomycosis, Infect Dis Clin
North Am 16:895-914, 2002.
Greenberg RN, Mullane K, van Burik J-AH et al: Posaconazole
as salvage therapy for zygomycosis, Antimicrob Agents Che-
mother 50:126-133, 2006.
Huang J-S, Kok S-H, Lee J-J et al: Extensive maxillary sequestra-
tion resulting from mucormycosis, Br J Oral Maxillofac Surg
43:532-534, 2005.
Jayasuriya NSS, Tilakaratne WM, Amaratunga EAPD et al: An
unusual presentation of rhinofacial zygomycosis due to Cun-
ninghamella sp. in an immunocompetent patient: a case report
and literature review, Oral Dis 12:67-69, 2006.
Kyrmizakis DE, Doxas PG, Hajiioannou JK et al: Palate ulcer due
to mucormycosis, J Laryngol Otol 116:146-147, 2002.
Jones AC, Bentsen TY, Freedman PD: Mucormycosis of the oral
cavity, Oral Surg Oral Med Oral Pathol 75:455-460, 1993.
Lador N, Polacheck I, Gural A et al: A trifungal infection of the
mandible: case report and literature review, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 101:451-456, 2006.
Leitner C, Hoffmann J, Zerfowski M et al: Mucormycosis: necro-
tizing soft tissue lesion of the face, J Oral Maxillofac Surg
61:1354-1358, 2003.
O’Neill BM, Alessi AS, George EB et al: Disseminated rhinoce-
rebral mucormycosis: a case report and review of the litera-
ture, J Oral Maxillofac Surg 64:326-333, 2006.
Roden MM, Zaoutis TE, Buchanan WL et al: Epidemiology and
outcome of zygomycosis: a review of 929 reported cases, Clin
Infect Dis 41:634-653, 2005.
Schütz P, Behbhani JH, Khan ZU et al: Fatal rhino-orbito-cere-
bral zygomycosis caused by Apophysomyces elegans in a healthy
patient, J Oral Maxillofac Surg 64:1795-1802, 2006.
Spellberg B, Edwards J, Ibrahim A: Novel perspectives on mucor-
mycosis: pathophysiology, presentation and management,
Clin Microbiol Rev 18:556-569, 2005.
Aspergillosis
Clancy CJ, Nguyen MH: Invasive sinus aspergillosis in appar-
ently immunocompetent hosts, J Infect 37:229-240, 1998.
Correa MEP, Soares AB, de Souza CA et al: Primary aspergillosis
affecting the tongue of a leukemic patient, Oral Dis 9:49-53,
2003.
Falworth MS, Herold J: Aspergillosis of the paranasal sinuses. A
case report and radiographic review, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 81:255-260, 1996.
Karabulut AB, Kabakas F, Berköz Ö et al: Hard palate perforation
due to invasive aspergillosis in a patient with acute lympho-
blastic leukemia, Int J Pediatr Otorhinolaryngol 69:1395-1398,
2005.
Manuel RJ, Kibbler CC: The epidemiology and prevention of
invasive aspergillosis, J Hosp Infect 39:95-109, 1998.
Marr KA, Patterson T, Denning D: Aspergillosis: pathogenesis,
clinical manifestations, and therapy, Infect Dis Clin North Am
16:875-894, 2002.
Myoken Y, Sugata T, Fujita Y et al: Early diagnosis and successful
management of atypical invasive Aspergillus sinusitis in a
hematopoietic cell transplant patient: a case report, J Oral
Maxillofac Surg 64:860-863, 2006.
Myoken Y, Sugata T, Kyo T-I et al: Pathologic features of invasive
oral aspergillosis in patients with hematologic malignancies,
J Oral Maxillofac Surg 54:263-270, 1996.
Ogata Y, Okinaka Y, Takahashi M: Antrolith associated with
aspergillosis of the maxillary sinus: report of a case, J Oral
Maxillofac Surg 55:1339-1341, 1997.
Rhodes JC, Jensen HE, Nilius AM et al: Aspergillus and aspergil-
losis, J Med Vet Mycol 30(suppl 1):51-57, 1992.
Schubert MS: Allergic fungal sinusitis, Clin Rev Allergy Immunol
30:205-216, 2006.
Segal BH, Walsh TJ: Current approaches to diagnosis and treat-
ment of invasive aspergillosis, Am J Respir Crit Care Med
173:707-717, 2006.
Toxoplasmosis
Azaz B, Milhem I, Hasson O: Acquired toxoplasmosis of a sub-
mandibular lymph node in a 13-year-old boy: case report,
Pediatr Dent 16:378-380, 1994.
Beasley DM, Egerman RS: Toxoplasmosis, Semin Perinatol 22:332-
338, 1998.
García-Pola M-J, González-García M, García-Martín JM et al:
Submaxillary adenopathy as sole manifestation of toxoplas-
mosis: case report and literature review, J Otolaryngol 31:122-
125, 2002.
Luft BJ, Hafner R, Korzun AH et al: Toxoplasmic encephalitis in
patients with the acquired immunodeﬁciency syndrome, N
Engl J Med 329:995-1000, 1993.
Mamidi A, DeSimone JA, Pomerantz RJ: Central nervous system
infections in individuals with HIV-1 infection, J Neurovirol
8:158-167, 2002.
Montoya JG, Rosso F: Diagnosis and management of toxoplasmo-
sis, Clin Perinatol 32:705-726, 2005.
Moran WJ, Tom DWK, King D et al: Toxoplasmosis lymphadeni-
tis occurring in a parotid gland, Otolaryngol Head Neck Surg
94:237-240, 1986.
Rorman E, Zamir CS, Rilkis I et al: Congenital toxoplasmosis—
prenatal aspects of Toxoplasma gondii infection, Reprod Toxicol
21:458-472, 2006. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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240
7
Viral Infections
CHAPTER OUTLINE
Human Herpes Viruses
Herpes Simplex Virus
Varicella
Herpes Zoster
Infectious Mononucleosis
Cytomegalovirus
Enteroviruses
Herpangina
Hand-Foot-and-Mouth Disease
Acute Lymphonodular Pharyngitis
Rubeola
Rubella
Mumps
Human Immunodeﬁciency Virus and Acquired
Immunodeﬁciency Syndrome
Human herpesviruses 6 and 7 (HHV-6, HHV-7)
are closely related, commonly isolated from saliva,
usually transmitted by respiratory droplets, and exhibit
a prevalence rate of infection close to 90% by age 5 in
the United States. Both viruses are associated with a
primary infection that usually is asymptomatic but can
exhibit an erythematous macular eruption that may
demonstrate intermixed slightly elevated papules. The
cutaneous manifestation of HHV-6 creates a speciﬁc
pattern, roseola (exanthema subitum), whereas
HHV-7 may cause a similar roseola-like cutaneous
eruption. The primary latency resides in CD4 T lym-
phocytes, and reactivation occurs most frequently in
immunocompromised patients. Recurrences can result
in widespread multiorgan infection, including enceph-
alitis, pneumonitis, bone-marrow suppression, and
hepatitis.
Human herpesvirus 8 (HHV-8) appears to be
involved in the pathogenesis of Kaposi’s sarcoma
(KS) (see page 557) and has been termed Kaposi’s
sarcoma herpesvirus (KSHV). In patients with
normal immune systems, primary infection usually is
asymptomatic, with sexual contact (especially male
homosexual) being the most common pattern of trans-
mission. The virus has been found without difﬁculty in
saliva, suggesting another possible pattern of transmis-
sion. Associated symptoms such as transient fever,
lymphadenopathy, and arthralgias are rarely reported.
HUMAN HERPES VIRUSES
The term herpes comes from the ancient Greek word
meaning to creep or crawl. The human herpesvirus
(HHV) family is ofﬁcially known as Herpetoviridae,
and its best-known member is herpes simplex virus
(HSV), a DNA virus. Two types of HSV are known to
exist: type I (HSV-1 or HHV-1) and type 2 (HSV-2 or
HHV-2). Other members of the HHV family include
varicella-zoster virus (VZV or HHV-3), Epstein-Barr
virus (EBV or HHV-4), cytomegalovirus (CMV or
HHV-5), and several more recently discovered
members, HHV-6, HHV-7, and HHV-8.
Humans are the only natural reservoir for these
viruses, which are endemic worldwide and share many
features. All eight types cause a primary infection and
remain latent within speciﬁc cell types for the life of
the individual. On reactivation, these viruses are asso-
ciated with recurrent infections that may be symptom-
atic or asymptomatic. The viruses are shed in the saliva
or genital secretions, providing an avenue for infection
of new hosts. Each type is known to transform cells in
tissue culture, with several strongly associated with
speciﬁc malignancies. Of the various types, the follow-
ing sections will concentrate on the herpes simplex
viruses, varicella-zoster virus, cytomegalovirus, and
Epstein-Barr virus. Much less is known about herpes-
virus types 6, 7, and 8. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 7 VIRAL INFECTIONS 241
as old age, ultraviolet light, physical or emotional stress,
fatigue, heat, cold, pregnancy, allergy, trauma, dental
therapy, respiratory illnesses, fever, menstruation, sys-
temic diseases, or malignancy have been associated
with reactivation of the virus, but only ultraviolet light
exposure has been demonstrated unequivocally to
induce lesions experimentally. More than 80% of the
primary infections are purported to be asymptomatic,
and reactivation with asymptomatic viral shedding
greatly exceeds clinically evident recurrences.
HSV does not survive long in the external environ-
ment, and almost all primary infections occur from
contact with an infected person who is releasing the
virus. The usual incubation period is 3 to 9 days.
Because HSV-1 usually is acquired from contact with
contaminated saliva or active perioral lesions, crowd-
ing and poor hygiene promote exposure. Lower socio-
economic status correlates with earlier exposure. In
developing countries, more than 50% of the population
is exposed by 5 years of age, 95% by 15 years of age,
and almost universal exposure by 30 years of age. On
the other hand, upper socioeconomic groups in devel-
oped nations exhibit less than 20% exposure at 5 years
of age and only 50% to 60% in adulthood. Regardless of
the socioeconomic group, prevalence tends to increase
with age, and many investigators report a frequency of
prior infection that approaches 90% of the population
by age 60. The low childhood exposure rate in the
privileged groups is followed by a second peak during
the college years of life. The age of initial infection also
affects the clinical presentation of the symptomatic
primary infections. In symptomatic cases, individuals
exposed to HSV-1 at an early age tend to exhibit gingi-
vostomatitis; those initially exposed later in life often
demonstrate pharyngotonsillitis.
As mentioned previously, antibodies to HSV-1
decrease the chance of infection with HSV-2 or lessen
the severity of the clinical manifestations. The dramatic
increase recently seen in HSV-2 is due partly to lack of
prior exposure to HSV-1, increased sexual activity, and
lack of barrier contraception. HSV-2 exposure corre-
lates directly with sexual activity. Exposure of those
younger than age 14 is close to zero, and most initial
infections occur between the ages of 15 and 35. The
prevalence varies from near zero in celibate adults to
more than 80% in prostitutes. Because many of those
infected with HSV-2 refrain from sexual activity when
active lesions are present, many investigators believe
that at least 70% of primary infections are contracted
from individuals during asymptomatic viral shedding.
In addition to clinically evident infections, HSV has
been implicated in a number of noninfectious pro-
cesses. More than 15% of cases of erythema multi-
forme are preceded by a symptomatic recurrence of
HSV 3 to 10 days earlier (see page 776), and some
Circulating B lymphocytes appear to be the major cell
of latency. In addition to Kaposi’s sarcoma, HHV-8 also
has been associated with a small variety of lymphomas
and Castleman’s disease.
HERPES SIMPLEX VIRUS
The two herpes simplex viruses are similar structurally
but different antigenically. In addition, the two exhibit
epidemiologic variations.
HSV-1 is spread predominantly through infected
saliva or active perioral lesions. HSV-1 is adapted best
and performs more efﬁciently in the oral, facial, and
ocular areas. The pharynx, intraoral sites, lips, eyes, and
skin above the waist are involved most frequently.
HSV-2 is adapted best to the genital zones, is trans-
mitted predominantly through sexual contact, and
typically involves the genitalia and skin below the
waist. Exceptions to these rules do occur, and HSV-1
can be seen in a pattern similar to that of HSV-2 and
vice versa. The clinical lesions produced by both types
are identical, and both produce the same changes in
tissue. The viruses are so similar that antibodies
directed against one cross-react against the other. Anti-
bodies to one of the types decrease the chance of infec-
tion with the other type; if infection does occur, the
manifestations often are less severe.
Clinically evident infections with HSV-1 exhibit two
patterns. The initial exposure to an individual without
antibodies to the virus is called the primary infection.
This typically occurs at a young age, often is asymptom-
atic, and usually does not cause signiﬁcant morbidity.
At this point, the virus is taken up by the sensory nerves
and transported to the associated sensory or, less fre-
quently, the autonomic ganglia where the virus remains
in a latent state. With HSV-1 infection, the most fre-
quent site of latency is the trigeminal ganglion, but
other possible sites include the nodose ganglion of
the vagus nerve, dorsal root ganglia, and the brain. The
virus uses the axons of the sensory neurons to travel
back and forth to the peripheral skin or mucosa.
Secondary, recurrent, or recrudescent HSV-1
infection occurs with reactivation of the virus, although
many patients may show only asymptomatic viral shed-
ding in the saliva. Symptomatic recurrences are fairly
common and affect the epithelium supplied by the
sensory ganglion. Spread to an uninfected host can
occur easily during periods of asymptomatic viral shed-
ding or from symptomatic active lesions. When repeat-
edly tested, approximately one third of individuals with
HSV-1 antibodies occasionally shed infectious viral
particles, even without active lesions being present. In
addition, the virus may spread to other sites in the
same host to establish residency at the sensory gan-
glion of the new location. Numerous conditions such `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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242 ORAL AND MAXILLOFACIAL PATHOLOGY
investigators believe that up to 60% of mucosal ery-
thema multiforme may be triggered by HSV. In some
instances, the attacks of erythema multiforme are fre-
quent enough to warrant antiviral prophylaxis. An
association with cluster headaches and a number of
cranial neuropathies has been proposed, but deﬁnitive
proof is lacking.
On rare occasions, asymptomatic release of HSV
will coincide with attacks of aphthous ulcerations. The
ulcerations are not infected with the virus. In these rare
cases, the virus may be responsible for the initiation of
the autoimmune destruction; conversely, the immune
dysregulation that produces aphthae may have allowed
the release of the virions. In support of the lack of
association between HSV and aphthae in the general
population of patients with aphthous ulcerations, pro-
phylactic oral acyclovir does not decrease the recur-
rence rate of the aphthous ulcerations. Although the
association between HSV and recurrent aphthous
ulcerations is weak, it may be important in small subsets
of patients (see page 331).
HSV also has been associated with oral carcinomas,
but much of the evidence is circumstantial. The DNA
from HSV has been extracted from the tissues of some
tumors but not from others. HSV may aid carcinogen-
esis through the promotion of mutations, but the onco-
genic role, if any, is uncertain.
CLINICAL FEATURES
Acute herpetic gingivostomatitis (primary herpes)
is the most common pattern of symptomatic primary
HSV infection, and more than 90% are the result of
HSV-1. In a study of more than 4000 children with
antibodies to HSV-1, Juretic´ found that only 12% of
those infected had clinical symptoms and signs severe
enough to be remembered by the affected children or
their parents. Some health care practitioners suspect
that the percentage of primary infections that exhibit
clinical symptoms is much higher, whereas others
believe the prevalence is lower. Many primary infec-
tions may manifest as pharyngitis that mimics the
pattern seen in common colds. Further studies are
needed to fully answer this question.
Most cases of acute herpetic gingivostomatitis arise
between the ages of 6 months and 5 years, with the
peak prevalence occurring between 2 and 3 years of
age. In spite of these statistics, occasional cases have
been reported in patients over 60 years of age. Devel-
opment before 6 months of age is rare because of pro-
tection by maternal anti-HSV antibodies. The onset is
abrupt and often accompanied by anterior cervical
lymphadenopathy, chills, fever (103° to 105° F), nausea,
anorexia, irritability, and sore mouth lesions. The mani-
festations vary from mild to severely debilitating.
Initially the affected mucosa develops numerous
pinhead vesicles, which rapidly collapse to form numer-
ous small, red lesions. These initial lesions enlarge
slightly and develop central areas of ulceration, which
are covered by yellow ﬁbrin (Fig. 7-1). Adjacent ulcer-
ations may coalesce to form larger, shallow, irregular
ulcerations (Fig. 7-2). Both the movable and attached
oral mucosa can be affected, and the number of lesions
is highly variable. In all cases the gingiva is enlarged,
painful, and extremely erythematous (Fig. 7-3). In addi-
tion, the affected gingiva often exhibits distinctive
punched-out erosions along the midfacial free gingival
margins (Fig. 7-4). It is not unusual for the involvement
of the labial mucosa to extend past the wet line to
include the adjacent vermilion border of the lips.
Satellite vesicles of the perioral skin are fairly common.
Self-inoculation of the ﬁngers, eyes, and genital areas
can occur. Mild cases usually resolve within 5 to 7 days;
severe cases may extend to 2 weeks. Rare complica-
tions include keratoconjunctivitis, esophagitis, pneu-
monitis, meningitis, and encephalitis.
Fig. 7-1 Acute herpetic gingivostomatitis. Widespread
yellowish mucosal ulcerations. (Courtesy of Dr. David Johnsen.)
Fig. 7-2 Acute herpetic gingivostomatitis. Numerous
coalescing, irregular, and yellowish ulcerations of the dorsal
surface of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 243
As mentioned previously, when the primary infec-
tion occurs in adults, some symptomatic cases exhibit
pharyngotonsillitis. Sore throat, fever, malaise, and
headache are the initial symptoms. Numerous small
vesicles develop on the tonsils and posterior pharynx.
The vesicles rapidly rupture to form numerous shallow
ulcerations, which often coalesce with one another. A
diffuse, gray-yellow exudate forms over the ulcers in
many cases. Involvement of the oral mucosa anterior
to Waldeyer’s ring occurs in less than 10% of these
cases. HSV appears to be a signiﬁcant cause of pharyn-
gotonsillitis in young adults who are from the higher
socioeconomic groups with previously negative test
ﬁndings for HSV antibodies. Most of these infections
are HSV-1, but increasing proportions are HSV-2. The
clinical presentation closely resembles pharyngitis sec-
ondary to streptococci or infectious mononucleosis,
making the true frequency difﬁcult to determine.
Recurrent herpes simplex infections (secondary
herpes, recrudescent herpes) may occur either at the
site of primary inoculation or in adjacent areas of
surface epithelium supplied by the involved ganglion.
The most common site of recurrence for HSV-1 is the
vermilion border and adjacent skin of the lips. This is
known as herpes labialis (“cold sore” or “fever blister”).
Prevalence studies suggest that from 15% to 45% of the
United States population have a history of herpes labia-
lis. In some patients, ultraviolet light or trauma can
trigger recurrences. Prodromal signs and symptoms
(e.g., pain, burning, itching, tingling, localized warmth,
erythema of the involved epithelium) arise 6 to 24
hours before the lesions develop. Multiple small, ery-
thematous papules develop and form clusters of ﬂuid-
ﬁlled vesicles (Fig. 7-5). The vesicles rupture and crust
within 2 days. Healing usually occurs within 7 to 10
days. Symptoms are most severe in the ﬁrst 8 hours,
and most active viral replication is complete within 48
hours. Mechanical rupture of intact vesicles and the
release of the virus-ﬁlled ﬂuid may result in the spread-
ing of the lesions on lips previously cracked from sun
exposure (Fig. 7-6). Recurrences are observed less
commonly on the skin of the nose, chin, or cheek. The
Fig. 7-3 Acute herpetic gingivostomatitis. Painful,
enlarged, and erythematous palatal gingiva.
Fig. 7-4 Acute herpetic gingivostomatitis. Painful,
enlarged, and erythematous facial gingiva. Note erosions of
the free gingival margin.
Fig. 7-5 Herpes labialis. Multiple ﬂuid-ﬁlled vesicles on the
lip vermilion.
Fig. 7-6 Herpes labialis. Multiple sites of recurrent
herpetic infection secondary to spread of viral ﬂuid over
cracked lips. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

244 ORAL AND MAXILLOFACIAL PATHOLOGY
majority of those affected experience approximately
2 recurrences annually, but a small percentage may
experience outbreaks that occur monthly or even more
frequently.
On occasion, some lesions arise almost immediately
after a known trigger and appear without any preced-
ing prodromal symptoms. These rapidly developing
recurrences tend to respond less favorably to
treatment.
Recurrences also can affect the oral mucosa. In the
immunocompetent patient, involvement is limited
almost always to keratinized mucosa that is bound to
bone (attached gingiva and hard palate). These sites
often exhibit subtle changes, and the symptoms are less
intense. The lesions begin as 1- to 3-mm vesicles that
rapidly collapse to form a cluster of erythematous
macules that may coalesce or slightly enlarge (Figs. 7-7
and 7-8). The damaged epithelium is lost, and a central
yellowish area of ulceration develops. Healing takes
place within 7 to 10 days.
Less common presentations of HSV-1 do occur.
Infection of the thumbs or ﬁngers is known as herpetic
whitlow (herpetic paronychia), which may occur as
a result of self-inoculation in children with orofacial
herpes (Fig. 7-9). Before the uniform use of gloves,
medical and dental personnel could infect their digits
from contact with infected patients, and they were the
most likely group affected by this form of HSV-I infec-
tion. Recurrences on the digits are not unusual and
may result in paresthesia and permanent scarring.
Cutaneous herpetic infections also can arise in areas
of previous epithelial damage. Parents kissing areas
of dermatologic injury in children represent one
vector. Wrestlers and rugby players also may contami-
nate areas of abrasion, a lesion called herpes gladiato-
rum or scrumpox. On occasion, herpes simplex has
been spread over the bearded region of the face into
the minor injuries created by daily shaving, leading to
a condition known as herpes barbae (barbae is Latin
for “of the beard”). Ocular involvement may occur in
children, often resulting from self-inoculation. Patients
with diffuse chronic skin diseases, such as eczema,
pemphigus, and Darier’s disease, may develop diffuse
life-threatening HSV infection, known as eczema her-
peticum (Kaposi’s varicelliform eruption). New-
borns may become infected after delivery through a
birth canal contaminated with HSV, usually HSV-2.
Without treatment, there is greater than a 50% mortal-
ity rate.
HSV recurrence in immunocompromised hosts can
be signiﬁcant. Without proper immune function, recur-
rent herpes can persist and spread until the infection
is treated with antiviral drugs, until immune status
returns, or until the patient dies. On the skin, the lesions
Fig. 7-7 Intraoral recurrent herpetic infection. Early
lesions exhibiting as multiple erythematous macules on the
hard palate. Lesions appeared a few days after extraction of a
tooth.
Fig. 7-8 Intraoral recurrent herpetic infection. Multiple
coalescing ulcerations on the hard palate.
Fig. 7-9 Herpetic whitlow. Recurrent herpetic infection of
the ﬁnger. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 245
continue to enlarge peripherally, with the formation of
an increasing zone of superﬁcial cutaneous erosion.
Oral mucosa also can be affected and usually is present
in conjunction with herpes labialis. Although most oral
mucosal involvement begins on the bound mucosa, it
often is not conﬁned to these areas. The involved sites
begin as areas of necrotic epithelium that are brownish
and raised above the surface of the adjacent intact epi-
thelium. Typically, these areas are much larger than
the usual pinhead lesions found in immunocompetent
patients. With time, the area of involvement spreads
laterally. The enlarging lesion is a zone of superﬁcial
necrosis or erosion, often with a distinctive circinate,
raised, yellow border (Figs. 7-10 and 7-11). This border
represents the advancing margin of active viral destruc-
tion. Microscopic demonstration of HSV infection in a
chronic ulceration on the movable oral mucosa is
ominous, and all such patients should be evaluated
thoroughly for possible immune dysfunction or under-
lying occult disease processes.
Although a yellow curvilinear border often is present
in many chronic herpetic ulcerations noted in immu-
nocompromised patients, this distinctive feature might
be missing. Several authors have reported persistent
oral ulcerations in patients with acquired immunode-
ﬁciency syndrome (AIDS) that lack the distinctive
periphery, often are nonspeciﬁc clinically, and may
mimic aphthous ulcerations, necrotizing stomatitis, or
ulcerative periodontal disease. Biopsy of persistent
ulcerations in patients with AIDS is mandatory and
may reveal any one of a number of infectious or neo-
plastic processes. These ulcers may reveal histopatho-
logic evidence of herpesvirus, often combined with
diagnostic features of CMV (HHV-5) coinfection (see
page 255).
HISTOPATHOLOGIC FEATURES
The virus exerts its main effects on the epithelial cells.
Infected epithelial cells exhibit acantholysis, nuclear
clearing, and nuclear enlargement, which has been
termed ballooning degeneration (Fig. 7-12). The
acantholytic epithelial cells are termed Tzanck cells
(not speciﬁc for herpes; refers to a free-ﬂoating epithe-
lial cell in any intraepithelial vesicle). Nucleolar frag-
mentation occurs with a condensation of chromatin
around the periphery of the nucleus. Multinucleated,
infected epithelial cells are formed when fusion occurs
between adjacent cells (see Fig. 7-12). Intercellular
edema develops and leads to the formation of an
intraepithelial vesicle (Fig. 7-13). Mucosal vesicles
rupture rapidly; those on the skin persist and develop
secondary inﬁltration by inﬂammatory cells. Once they
have ruptured, the mucosal lesions demonstrate a
Fig. 7-10 Chronic herpetic infection. Numerous mucosal
erosions, each of which is surrounded by a slightly raised,
yellow-white border, in a patient with acute myelogenous
leukemia.
Fig. 7-11 Chronic herpetic infection. Numerous shallow
herpetic erosions with raised, yellow and circinate borders on
the maxillary alveolar ridge in an immunocompromised
patient.
Fig. 7-12 Herpes simplex. Altered epithelial cells
exhibiting ballooning degeneration, margination of chromatin,
and multinucleation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

246 ORAL AND MAXILLOFACIAL PATHOLOGY
surface ﬁbrinopurulent membrane. Often at the edge
of the ulceration or mixed within the ﬁbrinous exudate
are the scattered Tzanck or multinucleated epithelial
cells.
DIAGNOSIS
With a thorough knowledge of the clinical presenta-
tions, the clinician can make a strong presumptive
diagnosis of HSV infection. On occasion, HSV infec-
tions can be confused with other diseases, and labora-
tory conﬁrmation is desirable. Viral isolation from
tissue culture inoculated with the ﬂuid of intact vesi-
cles is the most deﬁnitive diagnostic procedure. The
problem with this technique in primary infections is
that up to 2 weeks can be required for a deﬁnitive
result. Laboratory tests to detect HSV antigens by direct
ﬂuorescent assay or viral DNA by polymerase chain
reaction (PCR) of specimens of active lesions also are
available. Serologic tests for HSV antibodies are posi-
tive 4 to 8 days after the initial exposure. Conﬁrmation
of primary infection by serology requires a specimen
obtained within 3 days of the presentation and a second
sample approximately 4 weeks later. In such cases the
initial specimen should be negative, with antibodies
discovered only in the convalescent sample. These
antibody titers are useful in documenting past expo-
sure and are used primarily in epidemiologic studies.
Intact vesicles are rare intraorally. Therefore, using
intraoral viral culture as the sole means of diagnostic
conﬁrmation of HSV infection is inappropriate.
Research has shown that asymptomatic oral HSV shed-
ding occurs in up to 9% of the general population.
During periods of mental or physical stress, asymptom-
atic viral shedding rises to approximately one third of
those previously exposed to the virus. In immunocom-
promised patients, the prevalence rises to 38%; this
percentage is low and most likely would double if
the investigation were restricted to those previously
exposed to the virus. Therefore, culture of lesions con-
taminated with saliva that might contain coincidentally
released HSV is meaningless unless supplemented by
additional diagnostic procedures.
Two of the most commonly used diagnostic proce-
dures are the cytologic smear and tissue biopsy, with
cytologic study being the least invasive and most cost-
effective. The virus produces distinctive histopatho-
logic alterations within the infected epithelium. Only
VZV produces similar changes, but these two infec-
tions usually can be differentiated on a clinical basis.
Fluorescent monoclonal antibody typing can be per-
formed on the direct smears or on infected cells
obtained from tissue culture.
If diagnostic features of herpesvirus are discovered
in a biopsy of a persistent ulceration in an immuno-
compromised patient, immunocytochemical studies
for CMV also should be performed to rule out coin-
fection. The histopathologic features of CMV can be
missed easily, resulting in patients not receiving the
most appropriate therapy.
TREATMENT AND PROGNOSIS
In the past, primary herpetic gingivostomatitis was
treated best symptomatically; however, if the infection
is diagnosed early, antiviral medications can have a
signiﬁcant inﬂuence. Patients should be instructed to
restrict contact with active lesions to prevent the spread
to other sites and people. As mentioned previously,
autoinoculation of the eyes can result in ocular involve-
ment with the possibility of recurrence. Repeated
ocular reinfection can produce permanent damage
and blindness. HSV is the leading infectious cause of
blindness in the United States.
When acyclovir suspension is initiated during the
ﬁrst 3 symptomatic days in a rinse-and-swallow tech-
nique ﬁve times daily for 5 days (children: 15 mg/kg
up to the adult dose of 200 mg), signiﬁcant accelera-
tion in clinical resolution is seen. Once therapy is initi-
ated, development of new lesions ceases. In addition,
the associated eating and drinking difﬁculties, pain,
healing time, duration of fever, and viral shedding are
shortened dramatically. The use of a topical spray with
0.5% or 1.0% dyclonine hydrochloride also dramati-
cally, but temporarily, decreases the mucosal discom-
fort. Compounding pharmacists also can provide
tetracaine lollipops that can be used for rapid and pro-
found numbing of the affected mucosa. Viscous lido-
caine and topical benzocaine should be avoided in
pediatric patients because of reports of lidocaine-
induced seizures in children and an association
between topical benzocaine and methemoglobinemia.
Fig. 7-13 Herpes simplex. Intraepithelial vesicle
demonstrating acantholytic and virally altered epithelial cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 247
Nonsteroidal antiinﬂammatory drugs (NSAIDs), such
as ibuprofen, also help alleviate the discomfort. Use of
antiviral medications in capsule or tablet form is much
less effective because of the increased time these for-
mulations require to exert a signiﬁcant effect.
Recurrent herpes labialis has been treated with
everything from ether to voodoo; nothing has solved
the problem for all patients. Of the antiherpetic medi-
cations, acyclovir ointment in polyethylene glycol was
the initial formulation available for topical therapy.
Acyclovir ointment has been of limited beneﬁt for
herpes labialis in immunocompetent patients, because
its base is thought to prevent signiﬁcant absorption.
Subsequently, penciclovir cream became available in
a base that allows increased absorption through the
vermilion border. Use of this formulation has resulted
in a statistically signiﬁcant, although clinically minimal,
reduction in healing time and pain (duration decreased
approximately 1 day). Although the best results are
obtained if use of penciclovir cream is initiated during
the prodrome, late application has produced a measur-
able clinical beneﬁt. Other current choices are acyclo-
vir cream and an over-the-counter formulation of 10%
n-docosanol cream. Although acyclovir cream does
appear more effective than n-docosanol, both of these
therapeutic choices are associated with statistically sig-
niﬁcant, but clinically minimal, reduction in healing
time and pain, but at a lesser degree than that associ-
ated with penciclovir cream.
Systemic acyclovir and the two newer related medi-
cations, valacyclovir and famciclovir, appear to demon-
strate similar effectiveness against HSV. However,
valacyclovir and famciclovir exhibit improved bioavail-
ability and more convenient oral dosing schedules. Of
the three medications, a dosing schedule with valacy-
clovir, consisting of an initial 2 g taken on recognition
of prodromal symptoms followed by another 2 g 12
hours later, has been most successful in minimizing the
recurrences. The effects of this treatment are reduced
signiﬁcantly if it is not initiated during the prodrome.
Although much less convenient, 400 mg of acyclovir
taken ﬁve times daily for 5 days appears to produce
similar results. For patients whose recurrences appear
to be associated with dental procedures, a regimen of
2 g of valacyclovir taken twice on the day of the proce-
dure and 1 g taken twice the next day may suppress or
minimize any associated attack. In individuals with a
known trigger that extends over a period of time (e.g.,
skiing, beach vacation), prophylactic short-term use of
one of the antivirals (acyclovir, 400 mg twice a day
[b.i.d.]; valacyclovir 1 g daily; or famciclovir 250 mg
b.i.d.) has been shown to reduce the prevalence and
severity of any associated recurrence.
Most cases of recurrent herpes labialis are infre-
quent; therefore, rarely can regular use of systemic
antiviral medications be justiﬁed in immunocompe-
tent individuals. Long-term suppression of recurrences
with an antiviral medication is reserved by many for
patients with more than six recurrences per year, those
suffering from HSV-triggered erythema multiforme,
and the immunocompromised. In recent years the
emergence of acyclovir-resistant HSV has been seen
with increasing frequency. Such resistance has arisen
almost ex clusively in immunocompromised patients
receiving intermittent therapy, and the use of prophy-
lactic therapy does not appear to be associated with
emergence of resistant strains. In immunocompro-
mised patients, the viral load tends to be high and
replication is not suppressed completely by antiviral
therapy, creating the environment for generating drug-
resistant mutants. Although resistance is seen primar-
ily in immunocompromised patients, cavalier use of
antiviral medications for mild cases of recurrent herpes
infection probably is inappropriate.
The pain associated with intraoral secondary herpes
usually is not intense, and many patients do not require
treatment. Some studies have shown chlorhexidine
to exert antiviral effects in vivo and in vitro. In addi-
tion, acyclovir appears to function synergistically with
chlorhexidine. Extensive clinical trials have not been
performed, but chlorhexidine alone or in combination
with acyclovir suspension may be beneﬁcial in patients
who desire or require therapy of intraoral lesions.
Immunocompromised hosts with HSV infections
often require intravenous (IV) antiviral medications to
control the problem. Furthermore, severely immuno-
suppressed individuals, such as bone marrow trans-
plant patients and those with AIDS, often need
prophylactic doses of oral acyclovir, valacyclovir, or
famciclovir. On occasion, viral resistance develops,
resulting in the onset of signiﬁcant herpetic lesions.
Any herpes lesions that do not respond to appropriate
therapy within 5 to 10 days most likely are the result
of resistant strains. At this point the initial antiviral
therapy should be repeated at an elevated dose. If this
intervention fails, IV trisodium phosphonoformate
hexahydrate (foscarnet) is administered. If the infec-
tion persists, IV cidofovir is recommended. Another
antiviral, adenine arabinoside (vidarabine), is reserved
for patients in whom all of the previously described
medications have failed. In resistant cases that have
been treated successfully, it appears that only the
peripheral virus mutates, because future recurrences
often are once again sensitive to the ﬁrst-line antivirals.
Ulcerations that reveal coinfection with HSV and CMV
respond well to ganciclovir, with foscarnet used in
refractory cases.
Although a successful live-virus vaccine has been
available for the closely related varicella virus for
over 25 years, similar approaches against HSV have `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

248 ORAL AND MAXILLOFACIAL PATHOLOGY
produced less satisfactory results. Signiﬁcant research
for a potential vaccine is ongoing and offers hope for
the future.
VARICELLA (CHICKENPOX)
The varicella-zoster virus (VZV, HHV-3) is similar to
herpes simplex virus (HSV) in many respects. Chick-
enpox represents the primary infection with the VZV;
latency ensues, and recurrence is possible as herpes
zoster, often after many decades. The virus is pre-
sumed to be spread through air droplets or direct
contact with active lesions. Most cases of chickenpox
arise between the ages of 5 and 9, with greater than
90% of the U.S. population being infected by 15 years
of age. In contrast to infection with HSV, most cases
are symptomatic. The incubation period is 10 to 21
days, with an average of 15 days.
CLINICAL FEATURES
The symptomatic phase of VZV infection usually begins
with malaise, pharyngitis, and rhinitis. In older chil-
dren and adults, additional symptoms (e.g., headache,
myalgia, nausea, anorexia, vomiting) occasionally are
seen. This is followed by a characteristic, intensely pru-
ritic exanthem. The rash begins on the face and trunk,
followed by involvement of the extremities. Each lesion
rapidly progresses through stages of erythema, vesicle,
pustule, and hardened crust (Figs. 7-14 and 7-15). The
early vesicular stage is the classic presentation. The
centrally located vesicle is surrounded by a zone of
erythema and has been described as “a dewdrop on a
rose petal.” In contrast to herpes simplex, the lesions
typically continue to erupt for 4 days; in some cases the
exanthem’s arrival may extend to 7 or more days. Old
crusted lesions intermixed with newly formed and
intact vesicles are commonplace. Affected individuals
are contagious from 2 days before the exanthem until
all the lesions crust. Fever usually is present during the
active phase of the exanthem. The severity of the cuta-
neous involvement is variable and often more severe
in adults and in household members secondarily
infected by the initial patient.
Perioral and oral manifestations are fairly common
and may precede the skin lesions. The vermilion border
of the lips and the palate are the most common sites
of involvement, followed by the buccal mucosa. Occa-
sionally, gingival lesions resemble those noted in
primary HSV infections, but distinguishing between
the two is not difﬁcult because the lesions of varicella
tend to be relatively painless. The lesions begin as 3- to
4-mm, white, opaque vesicles that rupture to form 1- to
3-mm ulcerations (Fig. 7-16). The prevalence and
number of the oral lesions correlate with the severity of
the extraoral infection. In mild cases, oral lesions are
present in about one third of affected individuals. Often
only 1 or 2 oral ulcers are evident, and typically these
heal within 1 to 3 days. In contrast, patients with severe
infections almost always have oral ulcerations, often
numbering up to 30 lesions and persisting for 5 to 10
days. In severe cases of chickenpox, old ruptured lesions
will often become intermixed with fresh vesicles.
Complications can occur, with the need for hospi-
talization in children approximating 1 in 600 in the
Fig. 7-14 Varicella. Infant with diffuse erythematous and
vesicular rash. (Courtesy of Dr. Sherry Parlanti.)
Fig. 7-15 Varicella. Numerous vesicles with surrounding
erythema and early crusting. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
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Chapter 7 VIRAL INFECTIONS 249
prevaccine era. Possible complications include Reye’s
syndrome, secondary skin infections, encephalitis,
cerebellar ataxia, pneumonia, gastrointestinal dis-
turbances (e.g., vomiting, diarrhea, associated dehydra-
tion), and hematologic events (i.e., thrombocytopenia,
pancytopenia, hemolytic anemia, sickle cell crisis).
In childhood the most frequent complications are
secondary skin infections, followed by encephalitis and
pneumonia. With enhanced public education and
decreased use of aspirin in children, the prevalence of
Reye’s syndrome is decreasing. Although associated
bacterial infections had decreased after the introduc-
tion of antibiotics, an increased prevalence of signiﬁ-
cant complications related to secondary infections
caused by group A, β-hemolytic streptococci was seen
during the 1990s. These organisms have created life-
threatening infections and areas of highly destructive
necrotizing fasciitis.
The prevalence of complications in adults exceeds
that noted in children. The most common and serious
complication is varicella pneumonitis, which features
dry cough, tachypnea, dyspnea, hemoptysis, chest pain,
and cyanosis. Encephalitis and clinically signiﬁcant
pneumonia are diagnosed in 1 in 375 affected adults
older than 20 years of age. The central nervous system
(CNS) involvement typically produces ataxia but may
result in headaches, drowsiness, convulsions, or coma.
The risk of death is reported to be 15 times greater in
adults compared with children, mostly because of an
increased prevalence of encephalitis.
Infection during pregnancy can produce congenital
or neonatal chickenpox. Involvement early in the preg-
nancy can result in spontaneous abortion or congenital
defects. Although complications can occur in new-
borns, the effects of maternal varicella infection appear
minimal. A multicenter prospective study of live births
associated with maternal varicella infection revealed
only a 1.2% prevalence of embryopathy. However,
infection of the mother close to delivery can result in
a severe fetal infection caused by a lack of maternal
antibodies.
Infection in immunocompromised patients also can
be most severe. The cutaneous involvement typically is
extensive and may be associated with high fever, hepa-
titis, pneumonitis, pancreatitis, gastrointestinal obstruc-
tion, and encephalitis. Before effective antiviral therapy,
the mortality rate in immunocompromised individuals
was approximately 7%. Secondary bacterial infections
often complicate the process.
HISTOPATHOLOGIC FEATURES
The cytologic alterations are virtually identical to those
described for HSV. The virus causes acantholysis, with
formation of numerous free-ﬂoating Tzanck cells,
which exhibit nuclear margination of chromatin and
occasional multinucleation.
DIAGNOSIS
The diagnosis of chickenpox usually can be made from
a history of exposure to VZV within the last 3 weeks
and the presence of the typical exanthem. Conﬁrma-
tion can be obtained through a demonstration of viral
cytopathologic effects present within the epithelial
cells harvested from the vesicular ﬂuid. These cytologic
changes are identical to those found in herpes simplex,
and further conﬁrmation sometimes is desired. Viral
isolation in cell culture or rapid diagnosis from ﬂuores-
cein-conjugated VZV monoclonal antibodies can be
performed. Finally, serum samples can be obtained
during the acute stage and 14 to 28 days later. The later
sample should demonstrate a signiﬁcant (fourfold)
increase in antibody titers to VZV.
TREATMENT AND PROGNOSIS
Before the current antiviral medications became avail-
able, the treatment of varicella primarily was symp-
tomatic. Warm baths with soap or baking soda,
application of calamine lotion, and systemic diphen-
hydramine still are used to relieve pruritus. VZV has a
lipid envelope that is destroyed rapidly by soap and
other detergents. Lotions with diphenhydramine are
not recommended because of reports of toxicity sec-
ondary to percutaneous absorption of the medication.
Antipyretics other than aspirin should be given to
reduce fever.
Use of peroral antiviral medications such as acyclo-
vir, valacyclovir, and famciclovir has been shown to
reduce the duration and severity of the infection if it is
administered within the ﬁrst 24 hours of the rash.
Routine use of these antiviral medications is not
Fig. 7-16 Varicella. White opaque vesicles on the hard
palate. (Courtesy of Tristan Neville.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

250 ORAL AND MAXILLOFACIAL PATHOLOGY
recommended in immunocompetent children with
uncomplicated chickenpox. Typically, such therapy is
reserved for patients at risk for more severe disease,
such as those over 13 years of age and individuals who
contract the disease from a family member. Intrave-
nous formulations are used in immunosuppressed
patients or those exhibiting a progressive, severe infec-
tion. Treatment with one of the available antiviral med-
ications does not alter the antibody response to VZV or
reduce immunity later in life.
In patients without evidence of immunity who
become exposed to VZV and are at high risk for
severe disease or complications, puriﬁed varicella-
zoster immune globulin can be given to modify the
clinical manifestations of the infection. Individuals at
risk include immunocompromised patients, pregnant
women, premature infants, and neonates whose
mothers do not have evidence of immunity. The U.S.-
licensed manufacturer of the immune globulin mar-
keted the material under the name VZIG but
discontinued production in October 2004. At the time
of this writing, the immune globulin is being made by
a Canadian company and is known as VariZIG. This
product has not completed full U.S. Food and Drug
Administration (FDA) approval and is currently classi-
ﬁed as an investigational new drug (IND). In an attempt
to improve access during this critical period of transi-
tion, an expanded access protocol has been approved
by a central institutional review board (IRB), with the
FDA not requiring additional local IRB approval at the
treatment site. VariZIG is most effective if adminis-
tered within 96 hours of initial exposure. In most
instances the material can be delivered from the dis-
tributor to the treatment site within 24 hours.
A live attenuated varicella vaccine has been avail-
able since 1974 and has been used extensively outside
the United States, especially in Japan. In 1995 the
vaccine was approved for use in the United States.
Before that time, the annual incidence of infection in
the United States was approximately 4 million, with an
associated 11,000 hospitalizations and 100 deaths.
Vaccination is recommended for children between 12
and 18 months of age, as well as for all susceptible
individuals over the age of 13. Although the vaccina-
tion rates vary by state, the national coverage is approx-
imately 85% and has led to a reduction of reported
infection rates that also is around 85%.
During the ﬁrst year after vaccination, the efﬁcacy
appears to be 100% but drops to 95% after 7 years.
When breakthrough infections do occur, they usually
are very mild. Because of continued exposure to wild
virus, previously vaccinated patients have not required
boosters to maintain immunity. As the prevalence of
the wild virus diminishes, booster vaccines may be
required to maintain lifelong immunity. Extensive
follow-up of vaccinated groups is ongoing; if antibody
levels wane with time, booster immunizations will be
recommended. It should be remembered that the
vaccine is a live virus that can be spread to individuals
in close contact. Vaccine recipients who develop a rash
should avoid contact with those at risk, such as immu-
nocompromised or pregnant individuals.
The national health objectives for 2010 included a
goal to obtain and maintain ≥95% vaccination coverage
among ﬁrst graders for hepatitis B, diphtheria, tetanus,
pertussis, poliovirus, measles, mumps, rubella, and
varicella. The measles, mumps, and rubella (MMR)
vaccine currently has achieved a 93% vaccination
rate, whereas the frequency for the varicella vaccine
remains below 90%. Use of a combined measles,
mumps, rubella, and varicella (MMRV) vaccine has
demonstrated comparable effectiveness and safety.
This approach would provide protection via a single
injection and have the potential to increase the vacci-
nation rate for varicella more rapidly.
HERPES ZOSTER (SHINGLES)
After the initial infection with VZV (chickenpox), the
virus is transported up the sensory nerves and presum-
ably establishes latency in the dorsal spinal ganglia.
Clinically evident herpes zoster occurs after reactiva-
tion of the virus, with the involvement of the distribu-
tion of the affected sensory nerve. Zoster occurs during
the lifetime of 10% to 20% of individuals, and the preva-
lence of attacks increases with age. With the increasing
average age of the population, an increased prevalence
of herpes zoster is expected. Unlike herpes simplex
virus (HSV), single rather than multiple recurrences
are the rule. Immunosuppression, HIV-infection, treat-
ment with cytotoxic or immunosuppressive drugs,
radiation, presence of malignancies, old age, alcohol
abuse, stress (emotional or physical), and dental manip-
ulation are predisposing factors for reactivation.
CLINICAL FEATURES
The clinical features of herpes zoster can be grouped
into three phases: (1) prodrome, (2) acute, and (3)
chronic. During initial viral replication, active gangli-
onitis develops with resultant neuronal necrosis and
severe neuralgia. This inﬂammatory reaction is respon-
sible for the prodromal symptoms of intense pain that
precedes the rash in more than 90% of the cases. As the
virus travels down the nerve, the pain intensiﬁes and
has been described as burning, tingling, itching, boring,
prickly, or knifelike. The pain develops in the area of
epithelium innervated by the affected sensory nerve
(dermatome). Typically, one dermatome is affected,
but involvement of two or more can occur. The tho- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 251
racic dermatomes are affected in about two thirds of
cases. This prodromal pain, which may be accompa-
nied by fever, malaise, and headache, normally is
present 1 to 4 days before the development of the
cutaneous or mucosal lesions. During this period
(before the exanthem) the pain may masquerade as
sensitive teeth, otitis media, migraine headache, myo-
cardial infarction, or appendicitis, depending on which
dermatome is affected.
Approximately 10% of affected individuals will
exhibit no prodromal pain. Conversely, on occasion
there may be recurrence in the absence of vesiculation
of the skin or mucosa. This pattern is called zoster sine
herpete (zoster without rash), and affected patients
have severe pain of abrupt onset and hyperesthesia
over a speciﬁc dermatome. Fever, headache, myalgia,
and lymphadenopathy may or may not accompany the
recurrence.
The acute phase begins as the involved skin devel-
ops clusters of vesicles set on an erythematous base
(Fig. 7-17). Within 3 to 4 days, the vesicles become
pustular and ulcerate, with crusts developing after 7 to
10 days. The lesions tend to follow the path of the
affected nerve and terminate at the midline (Fig. 7-18).
The exanthem typically resolves within 2 to 3 weeks in
otherwise healthy individuals. On healing, scarring
with hypopigmentation or hyperpigmentation is not
unusual.
Oral lesions occur with trigeminal nerve involve-
ment and may be present on the movable or bound
mucosa. The lesions often extend to the midline and
frequently are present in conjunction with involve-
ment of the skin overlying the affected quadrant. Like
varicella, the individual lesions manifest as 1- to 4-mm,
white, opaque vesicles that rupture to form shallow
ulcerations (Fig. 7-19). Involvement of the maxilla may
be associated with devitalization of the teeth in the
affected area.
Several reports have documented signiﬁcant bone
necrosis with loss of teeth in areas involved with herpes
zoster. Because of the close anatomic relationship
between nerves and blood vessels within neurovascu-
lar bundles, inﬂammatory processes within nerves
have the potential to extend to adjacent vessels. It is
postulated that the gnathic osteonecrosis may be sec-
ondary to damage of the blood vessels supplying the
alveolar ridges and teeth, leading to focal ischemic
Fig. 7-17 Herpes zoster. Cluster of vesicles with
surrounding erythema of the skin.
Fig. 7-18 Herpes zoster. Numerous crusting facial vesicles
that extend to the midline.
Fig. 7-19 Herpes zoster. Numerous white opaque vesicles
on the right buccal mucosa of the same patient depicted in
Fig. 7-18. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

252 ORAL AND MAXILLOFACIAL PATHOLOGY
necrosis. Of the reported cases, there is almost an equal
distribution between the maxilla and mandible, with
both sexes affected similarly. Although the average
patient age is approximately 55, a wide range has been
seen from the second to late eighth decade. The average
interval between the appearance of the exanthem and
the osteonecrosis is 21 days, but it has been reported
as late as 42 days.
Ocular involvement is not unusual and can be the
source of signiﬁcant morbidity, including permanent
blindness. The ocular manifestations are highly vari-
able and may arise from direct viral-mediated epithe-
lial damage, neuropathy, immune-mediated damage,
or secondary vasculopathy. If the tip of the nose is
involved, this is a sign that the nasociliary branch of the
ﬁfth cranial nerve is involved, suggesting the potential
for ocular infection. In these cases, referral to an oph-
thalmologist is mandatory.
Facial paralysis has been seen in association with
herpes zoster of the face or external auditory canal.
Ramsay Hunt syndrome is the combination of cuta-
neous lesions of the external auditory canal and involve-
ment of the ipsilateral facial and auditory nerves. The
syndrome causes facial paralysis, hearing deﬁcits,
vertigo, and a number of other auditory and vestibular
symptoms. In multiple studies of patients thought to
have Bell’s palsy (see page 859), evidenced of active
VZV infection was detected in approximately 30% of
patients by polymerase chain reaction (PCR) or via
demonstration of appropriate antibody titers, suggest-
ing an underlying viral cause for many cases of “idio-
pathic” facial paralysis. Similar associations also have
been demonstrated with HSV and EBV.
Approximately 15% of affected patients progress to
the chronic phase of herpes zoster, which is character-
ized by pain (postherpetic neuralgia) that persists
longer than 3 months after the initial presentation of
the acute rash. Postherpetic neuralgia is uncommon
in individuals under the age of 50 but affects at least
50% of patients older than 60 years of age. The pain is
described as burning, throbbing, aching, itching, or
stabbing, often with ﬂares caused by light stroking of
the area or from contact with adjacent clothing. Most
of these neuralgias resolve within 1 year, with half of
the patients experiencing resolution after 2 months.
Rare cases may last up to 20 years, and patients have
been known to commit suicide as a result of the severe,
lancinating quality of the pain. Although the cause is
unknown, some investigators believe chronic VZV gan-
glionitis is responsible. Clearance of the pain has been
reported within days after initiation of long-term fam-
ciclovir, with recurrence of the pain if the medication
is stopped. Additional double-blind, placebo-controlled
studies will need to be performed to conﬁrm this
observation.
HISTOPATHOLOGIC FEATURES
The active vesicles of herpes zoster are identical micro-
scopically to those seen in the primary infection, vari-
cella. For more information, refer to the previous
portions of the chapter on the histopathologic presen-
tation of varicella and herpes simplex.
DIAGNOSIS
The diagnosis of herpes zoster often can be made from
the clinical presentation, but other procedures may be
necessary in atypical cases. Viral culture can conﬁrm
the clinical impression but takes at least 24 hours.
Cytologic smears demonstrate viral cytopathologic
effects, as seen in varicella and HSV. In most cases the
clinical presentation allows the clinician to differenti-
ate zoster from HSV, but cases of zosteriform recurrent
HSV infection, although uncommon, do exist. A rapid
diagnosis can be obtained through the use of direct
staining of cytologic smears with ﬂuorescent monoclo-
nal antibodies for VZV. This technique gives positive
results in almost 80% of the cases. Molecular tech-
niques such as dot-blot hybridization and PCR also can
be used to detect VZV.
TREATMENT AND PROGNOSIS
Before the development of the current antiviral medi-
cations, therapy for herpes zoster was directed toward
supportive and symptomatic measures. Fever should
be treated with antipyretics that do not contain aspirin.
Antipruritics, such as diphenhydramine, can be admin-
istered to decrease itching. Skin lesions should be
kept dry and clean to prevent secondary infection;
antibiotics may be administered to treat such second-
ary infections.
Early therapy with appropriate antiviral medica-
tions such as acyclovir, valacyclovir, and famciclovir
has been found to accelerate healing of the cutaneous
and mucosal lesions, reduce the duration of the acute
pain, and decrease the duration of postherpetic neural-
gia. These medications are most effective if initiated
within 72 hours after development of the ﬁrst vesicle.
The newer generation of antiviral drugs, famciclovir
and valacyclovir, may be more successful than acyclo-
vir in reducing the prevalence of postherpetic
neuralgia.
Once the skin lesions have healed, the neuralgia
may become the worst aspect of the disease and often
is the most difﬁcult to resolve successfully. This intense
pain has been treated with variable results by a variety
of methods, including analgesics, narcotics, tricyclic
antidepressants, anticonvulsants, gabapentin, percuta-
neous electric nerve stimulation, biofeedback, nerve `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 253
blocks, and topical anesthetics. As mentioned previ-
ously, postherpetic neuralgia may be related to chronic
VZV ganglionitis and respond to long-term famciclovir.
In those who do not respond to famciclovir, IV acyclo-
vir often leads to clinical improvement.
One topical treatment, capsaicin, has had signiﬁcant
success, with almost 80% of patients experiencing some
pain relief; however, the medication’s effect often does
not occur until 2 weeks or more of therapy. Capsaicin
is derived from red peppers and is not recommended
for placement on mucosa or open cutaneous lesions.
Capsaicin has been associated with signiﬁcant burning,
stinging, and redness in 40% to 70% of patients, with up
to 30% discontinuing therapy because of this side effect.
After use, patients must be warned to wash their hands
and avoid contact with mucosal surfaces.
Corticosteroid therapy has been used in the hope
it might decrease the neural inﬂammation and
associated chronic pain. Although conﬂicting research
has been published, studies have shown no long-
term beneﬁt when corticosteroids are added to an
acyclovir regimen. In addition, an increased preva-
lence of side effects was noted in groups treated with
corticosteroids.
A live attenuated VZV vaccine has been approved
for use in adults 60 years of age or older. The vaccine,
Zostavax, is 14 times more potent than Varivax, the
vaccine for chickenpox. In a study of more than 38,000
adults, Zostavax markedly decreased the prevalence of
herpes zoster, as well as the morbidity and frequency
of postherpetic neuralgia in those who did develop the
infection. In an October 2006 press release, the Advi-
sory Committee on Immunization Practices of the
Centers for Disease Control and Prevention (CDC)
recommended that the vaccine be given to all people
60 years of age and older. This recommendation is
being reviewed and becomes ofﬁcial only when pub-
lished in the CDC’s Morbidity and Mortality Weekly
Report.
INFECTIOUS MONONUCLEOSIS
(MONO; GLANDULAR FEVER;
“KISSING DISEASE”)
Infectious mononucleosis is a symptomatic disease
resulting from exposure to Epstein-Barr virus (EBV,
HHV-4). The infection usually occurs by intimate
contact. Intrafamilial spread is common, and once a
person is exposed, EBV remains in the host for life.
Children usually become infected through contami-
nated saliva on ﬁngers, toys, or other objects. Adults
usually contract the virus through direct salivary trans-
fer, such as shared straws or kissing, hence, the nick-
name “kissing disease.” Exposure during childhood
usually is asymptomatic, and most symptomatic infec-
tions arise in young adults. In developing nations, expo-
sure usually occurs by age 3 and is universal by
adolescence. In the United States, introduction to the
virus often is delayed, with close to 50% of college stu-
dents lacking previous exposure. These unexposed
adults become infected at a rate of 10% to 15% per year
while in college. Infection in adulthood is associated
with a higher risk (i.e., 30% to 50%) for symptomatic
disease.
Besides infectious mononucleosis, EBV has been
demonstrated in the lesions of oral hairy leukoplakia
(OHL) (see page 268) and has been associated with a
number of lymphoproliferative disorders, a variety of
lymphomas (most notably African Burkitt’s lymphoma)
(see page 600), nasopharyngeal carcinoma (see page
428), some gastric carcinomas, possibly breast and
hepatocellular carcinomas, salivary lymphoepithelial
carcinomas, and occasional smooth muscle tumors.
However, direct proof of a cause-and-effect relation-
ship is lacking.
CLINICAL FEATURES
Most EBV infections in children are asymptomatic. In
children younger than 4 years of age with symptoms,
most have fever, lymphadenopathy, pharyngitis, hepa-
tosplenomegaly, and rhinitis or cough. Children older
than 4 years of age are affected similarly but exhibit a
much lower prevalence of hepatosplenomegaly, rhini-
tis, and cough.
Most young adults experience fever, lymphadenopa-
thy, pharyngitis, and tonsillitis. Hepatosplenomegaly
and rash are seen less frequently. In adults older than
40 years of age, fever and pharyngitis are the predomi-
nant ﬁndings, with less than 30% demonstrating lymph-
adenopathy. Less frequent signs and symptoms in this
group include hepatosplenomegaly, rash, and rhinitis
or cough. Possible signiﬁcant complications include
splenic rupture, thrombocytopenia, autoimmune hemo-
lytic anemia, aplastic anemia, and neurologic problems
with seizures. These complications are uncommon at
any age but more frequently develop in children.
In classic infectious mononucleosis in a young adult,
prodromal fatigue, malaise, and anorexia occur up to
2 weeks before the development of pyrexia. The body
temperature may reach 104° F and lasts from 2 to 14
days. Prominent lymphadenopathy is noted in more
than 90% of the cases and typically appears as enlarged,
symmetrical, and tender nodes, frequently with involve-
ment of the posterior and anterior cervical chains.
Enlargement of parotid lymphoid tissue rarely has
been reported and can be associated with facial nerve
palsy. More than 80% of affected young adults have
oropharyngeal tonsillar enlargement, sometimes with
diffuse surface exudates and secondary tonsillar `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

254 ORAL AND MAXILLOFACIAL PATHOLOGY
abscesses (Fig. 7-20). The lingual tonsils, which are
located on the base of the tongue and extend from the
circumvallate papilla to the epiglottis, can become
hyperplastic and compromise the airway. Rare fatalities
have been reported from respiratory difﬁculties second-
ary to the combined effects of hyperplasia of the lingual
and palatine tonsils, arytenoid hypertrophy, pharyngeal
edema, uvular edema, and epiglottal swelling.
Oral lesions other than lymphoid enlargement also
may be seen. Petechiae on the hard or soft palate are
present in about 25% of patients (Fig. 7-21). The pete-
chiae are transient and usually disappear within 24 to
48 hours. Necrotizing ulcerative gingivitis (NUG)
(see page 157) also is fairly common. NUG-like peri-
coronitis (see page 171) and necrotizing ulcerative
mucositis (see page 158) occur less frequently. Cases
of NUG that are refractory to normal therapy should
be evaluated to rule out the possibility of EBV.
A controversial symptom complex called chronic
fatigue syndrome has been described, and several
investigators have tried to associate EBV with this
problem. Patients complain of rather nonspeciﬁc
symptoms of chronic fatigue, fever, pharyngitis, myal-
gias, headaches, arthralgias, paresthesias, depression,
and cognitive defects. These patients often demonstrate
elevations in EBV antibody titers, but this ﬁnding alone
is insufﬁcient to prove a deﬁnite cause-and-effect rela-
tionship. Several studies have cast serious doubt on a
relationship between EBV and the chronic fatigue
syndrome.
DIAGNOSIS
The diagnosis of infectious mononucleosis is suggested
by the clinical presentation and should be conﬁrmed
through laboratory procedures. The white blood cell
(WBC) count is increased, with the differential count
showing relative lymphocytosis that can become as
high as 70% to 90% during the second week. Atypical
lymphocytes usually are present in the peripheral
blood. The classic serologic ﬁnding in mononucleosis
is the presence of Paul-Bunnell heterophil antibodies
(immunoglobulins that agglutinate sheep erythrocytes).
A rapid test for these antibodies is available and in-
expensive. More than 90% of infected young adults
have positive ﬁndings for the heterophil antibody, but
infected children younger than age 4 frequently have
negative results. Indirect immunoﬂuorescent testing to
detect EBV-speciﬁc antibodies should be used in those
suspected of having an EBV infection but whose ﬁnd-
ings were negative on the Paul-Bunnell test. Enzyme-
linked immunosorbent assays (ELISA) and recombinant
DNA-derived antigens also may be used in place of the
indirect immunoﬂuorescent test.
TREATMENT AND PROGNOSIS
In most cases, infectious mononucleosis resolves
within 4 to 6 weeks. Non–aspirin-containing antipyret-
ics and NSAIDs can be used to minimize the most
common symptoms. Infrequent complications include
splenic rupture, EBV-related hepatitis, and Bell’s palsy.
Patients with signiﬁcant enlargement of the spleen
should avoid contact sports to prevent the rare possibil-
ity of splenic rupture. On occasion, the fatigue may
become chronic. In immunocompromised patients, a
polyclonal B-lymphocyte proliferation may occur and
possibly lead to death.
The tonsillar involvement may, on occasion, resem-
ble streptococcal pharyngitis or tonsillitis (see page
183). However, treatment with ampicillin and penicil-
lin should be avoided because the use of these antibiot-
ics in infectious mononucleosis has been associated
with a higher than normal prevalence of allergic mor-
billiform skin rashes.
Corticosteroid use is the recommended therapy in
many textbooks. Such drugs, however, should not be
Fig. 7-20 Infectious mononucleosis. Hyperplastic
pharyngeal tonsils with yellowish crypt exudates. (Courtesy of
Dr. George Blozis.)
Fig. 7-21 Infectious mononucleosis. Numerous petechiae
of the soft palate. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 255
used indiscriminately because the person’s immune
response appears to be the most important factor in
ﬁghting the infection and preventing a potentially fatal
polyclonal B-lymphocyte proliferation. In addition, an
increased prevalence of encephalitis and myocarditis
has been noted in patients who have infectious mono-
nucleosis and are treated with steroids. Corticosteroid
use produces a shortened duration of fever and shrink-
age of enlarged lymphoid tissues, but its use should be
restricted to life-threatening cases (e.g., those with
upper-airway obstruction because of massive lymph-
adenopathy, tonsillar hyperplasia, and oropharyngeal
edema). If corticosteroid therapy fails to resolve the
airway obstruction, acute tonsillectomy and tracheos-
tomy may be necessary.
Although antiviral medications such as acyclovir,
valacyclovir, and famciclovir have been used success-
fully for temporary resolution of oral hairy leukoplakia,
these medications do not demonstrate clinically
obvious beneﬁt for patients with infectious mononucle-
osis. Although the medications most likely have an
effect on viral replication, the main clinical manifesta-
tions appear to be secondary to the immune response
to EBV-infected activated B lymphocytes and are not
altered by the medical intervention.
CYTOMEGALOVIRUS
Cytomegalovirus (CMV, HHV-5) is similar to the
other human herpes viruses (i.e., after the initial infec-
tion, latency is established and reactivation is possible
under conditions favorable to the virus). CMV can
reside latently in salivary gland cells, endothelium,
macrophages, and lymphocytes. Most clinically evident
disease is found in neonates or in immunosuppressed
adults. In infants, the virus is contracted through the
placenta, during delivery, or during breast-feeding. The
next peak of transmission occurs during adolescence,
predominantly from the exchange of bodily ﬂuids as
this group begins sexual activity. Transmission also has
been documented from blood transfusion and organ
transplantation. The prevalence of neonatal CMV
infection varies from 0.5% to 2.5%. By the age of 30,
almost 40% of the population is infected; by age 60,
80% to 100% are infected. Screening of healthy middle-
aged adult blood donors reveals that approximately
50% have been exposed to CMV.
CLINICAL FEATURES
At any age, almost 90% of CMV infections are asymp-
tomatic. In clinically evident neonatal infection, the
infant appears ill within a few days. Typical features
include hepatosplenomegaly, extramedullary cutane-
ous erythropoiesis, and thrombocytopenia (often with
associated petechial hemorrhages). Signiﬁcant enceph-
alitis frequently leads to severe mental and motor
retardation.
Although the majority of acute CMV infections are
asymptomatic, less than 10% may include a nonspeciﬁc
pattern of symptoms that ranges from an inﬂuenza-like
presentation to lethal multiorgan involvement. In a
review of 115 hospitalized immunocompetent adults
with CMV infection, the most common symptoms
(in order) include fever, joint and muscle pain, shiver-
ing, abdominal pain, nonproductive cough, cutane-
ous eruption (maculopapular rash), and diarrhea.
Associated signs include hepatomegaly, splenomegaly,
adenopathy, pharyngitis, jaundice, and evidence of
meningeal irritation. The authors stress that symptom-
atic CMV infection should not be dismissed in immu-
nocompetent patients and should be considered in any
patient with unexplained persistent fever.
In contrast to patients with infectious mononucleo-
sis, only about one third of patients with CMV infection
demonstrate pharyngitis and lymphadenopathy.
Rarely, immunocompetent patients may show signs of
an acute sialadenitis that diffusely involves all of the
major and minor salivary glands. In such cases, xero-
stomia often is noted and the affected glands are
painful. Involvement of the major glands usually results
in clinically obvious enlargements of the parotid and
submandibular glands. Unusual complications of
primary CMV infection include myocarditis, pneumo-
nitis, and septic meningitis.
Evident CMV involvement is not unusual in immu-
nocompromised transplant patients. In some cases a
temporary mild fever is the only evidence; in others,
the infection becomes aggressive and is characterized
by signiﬁcant hepatitis, leukopenia, pneumonitis, gas-
troenteritis, and, more rarely, a progressive wasting
syndrome.
CMV disease is common in patients with AIDS (see
page 264). CMV chorioretinitis affects almost one third
of patients with AIDS and tends to progress rapidly,
often resulting in blindness. Bloody diarrhea from
CMV colitis is fairly common but may respond to
appropriate antiviral medications.
Although oral lesions from CMV infection have
been documented in a number of immunosuppressive
conditions, reports of oral involvement by CMV
have been increasing since the advent of the AIDS
epidemic. Most affected patients have chronic mucosal
ulcerations, and CMV changes are found on biopsy.
Occasionally, chronic oral ulcerations in immunocom-
promised patients will demonstrate coinfection (usually
CMV combined with HSV).
Neonatal CMV infection also can produce develop-
mental tooth defects. Examination of 118 people with
a history of neonatal CMV infection revealed tooth `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

256 ORAL AND MAXILLOFACIAL PATHOLOGY
defects in 40% of those with symptomatic infections
and slightly more than 5% of those with asymptomatic
infections. The teeth exhibited diffuse enamel hypo-
plasia, signiﬁcant attrition, areas of enamel hypoma-
turation, and yellow coloration from the underlying
dentin.
HISTOPATHOLOGIC FEATURES
Biopsy specimens of intraoral CMV lesions usually
demonstrate changes within the vascular endothelial
cells. Scattered infected cells are extremely swollen,
showing both intracytoplasmic and intranuclear inclu-
sions and prominent nucleoli. This enlarged cell has
been called an “owl eye” cell. Gomori’s methenamine
silver and periodic acid-Schiff (PAS) stains demon-
strate the cytoplasmic inclusions but not the intranu-
clear changes. Salivary ductal epithelium also may be
affected and form “owl eye” cells (Fig. 7-22).
DIAGNOSIS
The diagnosis of CMV infection is made by considering
a combination of the clinical features and by conduct-
ing other examinations. Biopsy material can demon-
strate cellular changes that suggest infection. Because
effective therapies exist for CMV infections in immu-
nocompromised patients, biopsies are recommended
for chronic ulcerations that are not responsive to con-
servative therapy. More speciﬁc veriﬁcation can be
made by electron microscopy, detection of viral anti-
gens by immunohistochemistry, in situ hybridization,
polymerase chain reaction (PCR), demonstration of
rising viral antibody titers, or viral culture. Enzyme-
linked immunosorbent assay (ELISA) serologic testing
for CMV is inexpensive, demonstrates good speciﬁcity,
and should be considered in any patient with an unex-
plained fever or signs of CMV infection.
In immunocompromised patients with chronic
ulcerations, the typical “owl eye” cells may be few and
difﬁcult to discover on routine light microscopy. When
biopsy is performed on a chronic oral ulceration in
these patients, in situ hybridization or immunohisto-
chemical evaluation for CMV should be performed,
even in the absence of “owl eye” cells. In addition, close
examination to rule out coinfection by HSV also should
be performed.
TREATMENT AND PROGNOSIS
Although most CMV infections resolve spontaneously,
therapy often is required in the immunosuppressed
patient. Ganciclovir has resolved clinical symptoms
in more than 75% of treated immunocompromised
patients. However, the medication must be continued to
prevent a relapse if the immune dysfunction persists. In
patients with oral ulcerations coinfected with CMV and
HSV, intravenous (IV) ganciclovir will produce resolu-
tion in most instances. The development of resistance to
ganciclovir has been reported; other effective medica-
tions include foscarnet, cidofovir, and valganciclovir. In
spite of these antiviral medications, the best therapy in
immunocompromised patients remains improvement
of their immune status, such as that achieved with
highly active anti-retroviral therapy (HAART) therapy
in many patients with AIDS (see page 280).
Immunocompetent patients with clinically evident
CMV infection usually are treated symptomatically
with antipyretic medications and NSAIDs. Corticoste-
roids or IV gammaglobulins have been used in patients
with hemolytic anemia or severe thrombocytopenia.
There is no consensus related to the use of antiviral
agents in immunocompetent patients.
ENTEROVIRUSES
Human enterovirus infections traditionally have been
classiﬁed into echoviruses, coxsackieviruses A and B,
and polioviruses. Beginning in the 1960s, newly dis-
covered enteroviruses have been assigned a numeric
designation (e.g., enterovirus 71) rather than being
placed into one of the traditional groups. The clinical
presentations associated with these viruses are diverse
and vary from a minor febrile illness to a severe and
potentially fatal infection. In addition, some of these
viruses have been associated with an increased preva-
lence of type 1 diabetes mellitus and dilated cardiomy-
opathy. The estimated annual incidence of symptomatic
infections in the United States is 10 to 15 million.
Of the enteroviruses, more than 30 exist that can
result in symptomatic infections associated with rashes.
Few are distinctive enough clinically to allow differen-
tiation from one another. Most are asymptomatic or
Fig. 7-22 Cytomegalovirus (CMV) infection. Salivary
ductal epithelium exhibiting distinctive “owl eye” alterations. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 257
subclinical. These infections may arise at any age, but
most occur in infants or young children. Neonatal cases
also have been reported. Only herpangina, hand-
foot-and-mouth disease, and acute lymphonodular
pharyngitis deserve discussion. These three clinical
patterns are closely related and should not be consid-
ered as entirely separate infections. In reports of epi-
demics in which a large number of patients acquire the
same strain of the virus, the clinical presentations often
are variable and include both herpangina and hand-
foot-and-mouth disease.
Herpangina usually is produced by coxsackievirus
A1 to A6, A8, A10, or A22. However, it also may rep-
resent infection by coxsackievirus A7, A9, or A16; cox-
sackievirus B2 to 6; echovirus 9, 16, or 17; or enterovirus
71. Hand-foot-and-mouth disease usually is caused by
coxsackievirus A16, but may also arise from coxsackie-
virus A5, A9, or A10; echovirus 11; or enterovirus 71.
Acute lymphonodular pharyngitis is less recognized,
and coxsackievirus A10 has been found in the few
reported cases. The incubation period for these viruses
is 4 to 7 days.
Most cases arise in the summer or early fall in non-
tropical areas, with crowding and poor hygiene aiding
their spread. The fecal-oral route is considered the
major path of transmission, and frequent hand washing
is emphasized in an attempt to diminish spread during
epidemics. During the acute phase, the virus also can
be transmitted through saliva or respiratory droplets.
Infection confers immunity against reinfection to that
one strain. In spite of the developed immunity, people
may become infected numerous times with different
enterovirus types over several years while still remain-
ing susceptible to other different strains.
CLINICAL FEATURES
In many countries, epidemics occur every 2 to 3 years
and primarily affect children aged 1 to 4 years. The
timing of the epidemics appears to be correlated to the
accumulation of a new population of susceptible young
children. In all three clinical patterns, the severity and
signiﬁcant complications are variable and appear asso-
ciated with the particular strain that is responsible. In
general, most strains produce a self-limiting disease
that requires no therapy, but occasional strains can
produce epidemics with an increased number of sig-
niﬁcant complications and occasional mortalities. Sys-
temic complications include pneumonia, pulmonary
edema and hemorrhage, acute ﬂaccid paralysis,
encephalitis, meningitis, and carditis. Infection with
coxsackie B virus during pregnancy occasionally has
been associated with fetal and neonatal death, whereas
cardiac anomalies have been noted in infants who
survive the initial infection.
In 1998 a massive epidemic spread over Taiwan
(population 21,178,000), and it is estimated that
approximately 1.5 million people developed clinical
evidence of the infection. A group of sentinel physi-
cians (8.7% of primary physicians) documented
129,106 infected patients. Of these patients, the vast
majority were infected with enterovirus 71; a much
lesser number were infected with one of a number of
coxsackieviruses (predominantly A16). When patients
infected with the same strain were examined, clinical
patterns diagnostic of both herpangina and hand-foot-
and-mouth disease were detected. In this epidemic,
more than 75% had symptoms of hand-foot-and-mouth
disease, but it is clear these two clinical patterns repre-
sent variations of the same disorder.
In the surveillance document by the Centers for
Disease Control and Prevention (CDC) of the reported
enterovirus infections between 1970 and 2005, 44.2%
occurred in infants younger than 1 year of age, 15% in
children aged 1 to 4 years, 11.6% in children aged 5
to 9 years, 11.9% in those aged 10 to 19 years, and
17.3% in patients older than 20 years. During this
period, 131 deaths were reported secondary to com-
plications such as aseptic meningitis, encephalitis,
paralysis, myocarditis, and neonatal enteroviral sepsis.
The most common viruses to produce herpangina or
hand-foot-and-mouth disease were, in order, coxsacki-
eviruses B5, A9, B3, B1, and A16, followed by entero-
virus 71. In patients younger than the age of 20, there
was a male predominance. In those older than 20,
females were infected more frequently, most likely
because of exposure as the primary caregivers to
infected young children.
HERPANGINA
Herpangina begins with an acute onset of signiﬁcant
sore throat, dysphagia, and fever, occasionally accom-
panied by cough, rhinorrhea, anorexia, vomiting, diar-
rhea, myalgia, and headache. Most cases, however, are
mild or subclinical. A small number of oral lesions,
usually two to six, develop in the posterior areas of the
mouth, usually the soft palate or tonsillar pillars (Fig.
7-23). The affected areas begin as red macules, which
form fragile vesicles that rapidly ulcerate. The ulcer-
ations average 2 to 4 mm in diameter. The systemic
symptoms resolve within a few days; as would be
expected, the ulcerations usually take 7 to 10 days to
heal.
HAND-FOOT-AND-MOUTH DISEASE
Hand-foot-and-mouth disease is the most well-known
enterovirus infection. Like herpangina, the skin rash
and oral lesions typically are associated with ﬂulike
symptoms (e.g., sore throat, dysphagia, fever), occasion- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

258 ORAL AND MAXILLOFACIAL PATHOLOGY
ally accompanied by cough, rhinorrhea, anorexia, vom-
iting, diarrhea, myalgia, and headache.
The name fairly well describes the location of the
lesions. Oral lesions and those on the hands almost
always are present; involvement of other cutaneous
sites is more variable. The oral lesions arise without
prodromal symptoms and precede the development of
the cutaneous lesions. Sore throat and mild fever are
present. The cutaneous lesions range from a few to
dozens and primarily affect the borders of the palms
and soles and the ventral surfaces and sides of the
ﬁngers and toes (Fig. 7-24). Rarely other sites, espe-
cially the buttocks, external genitals, and legs, may be
involved. The individual cutaneous lesions begin as
erythematous macules that develop central vesicles
and heal without crusting (Fig. 7-25).
The oral lesions resemble those of herpangina but
may be more numerous and are not conﬁned to the
posterior areas of the mouth. The number of lesions
ranges from 1 to 30. The buccal mucosa, labial mucosa,
and tongue are the most common sites to be affected,
but any area of the oral mucosa may be involved (Fig.
7-26). The individual vesicular lesions rapidly ulcerate
and are typically 2 to 7 mm in diameter but may be
larger than 1 cm. Most of these ulcerations resolve
within 1 week.
ACUTE LYMPHONODULAR PHARYNGITIS
Acute lymphonodular pharyngitis is characterized by
sore throat, fever, and mild headache, which may last
from 4 to 14 days. Low numbers (one to ﬁve) of yellow
to dark-pink nodules develop on the soft palate or ton-
Fig. 7-23 Herpangina. Numerous aphthouslike ulcerations
of the soft palate.
Fig. 7-24 Hand-foot-and-mouth disease. Multiple vesicles
of the skin of the toe. (Courtesy of Dr. Samuel J. Jasper.)
Fig. 7-25 Hand-foot-and-mouth disease. Numerous
erythematous macules of the foot.
Fig. 7-26 Hand-foot-and-mouth disease. Multiple
aphthouslike ulcerations of the mucobuccal fold. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 259
sillar pillars (Fig. 7-27). The nodules represent hyper-
plastic lymphoid aggregates and resolve within 10 days
without vesiculation or ulceration. Few cases have
been described, and whether this represents a distinct
clinical entity is as yet unresolved. The possibility that
the sore throat and palatal lymphoid hyperplasia rep-
resent features of herpangina or some other infection
cannot be excluded without further documentation of
additional cases.
HISTOPATHOLOGIC FEATURES
In patients with herpangina and hand-foot-and-mouth
disease, the areas of affected epithelium exhibit intra-
cellular and intercellular edema, which leads to exten-
sive spongiosis and the formation of an intraepithelial
vesicle. The vesicle enlarges and ruptures through the
epithelial basal cell layer, with the resultant formation
of a subepithelial vesicle. Epithelial necrosis and ulcer-
ation soon follow. Inclusion bodies and multinucleated
epithelial cells are absent.
DIAGNOSIS
The diagnoses of herpangina, hand-foot-and-mouth
disease, and acute lymphonodular pharyngitis usually
are made from the distinctive clinical manifestations.
In patients with atypical presentations, laboratory con-
ﬁrmation appears prudent. Viral isolation from culture
can be performed, and analysis of stool specimens is
the best technique in patients with only mucosal
lesions. Throat culture ﬁndings tend to be positive pre-
dominantly during the early acute stage. The culture of
cutaneous lesions is best for the diagnosis of hand-foot-
and-mouth disease. A serologic demonstration of rising
enteroviral antibody titers between the acute and con-
valescent stages can be used to conﬁrm the diagnosis
in questionable cases. Polymerase chain reaction (PCR)
assay is increasingly available and replacing viral
culture in many diagnostic laboratories.
TREATMENT AND PROGNOSIS
In most instances, the infection is self-limiting and
without signiﬁcant complications. Therapy for patients
with an enterovirus infection is directed toward symp-
tomatic relief. Nonaspirin antipyretics and topical
anesthetics, such as dyclonine hydrochloride, often are
beneﬁcial.
Occasionally, certain strains produce infections with
a more aggressive clinical course. During the 1998
epidemic in Taiwan, a large group of physicians
reported 405 patients with severe disease and 78
deaths. Patients with more signiﬁcant complications
demonstrated higher body temperature (>102° F),
fever for longer than 3 days, more serious vomiting,
and greater lethargy. When these ﬁndings are present,
the physician must monitor the patient more closely
for the development of more serious complications.
RUBEOLA (MEASLES)
Rubeola is an infection produced by a virus in the
family Paramyxovirus, genus Morbillivirus, and exhibits
a variable prevalence that is correlated to the degree
of vaccine use. Measles vaccine has been in wide use
in the United States since 1963 and is 95% effective,
resulting in a 98% reduction in the prevalence of this
infection. Before 1963, virtually all children acquired
measles, but the vaccine produced a continued and
signiﬁcant decline until the late 1980s. From 1989 to
1991, a major resurgence occurred with an increas-
ing proportion of cases among unvaccinated pre-
school-aged children, particularly minority residents of
densely populated urban areas. In addition, a smaller
number of cases appeared to be associated with vaccine
failure.
CLINICAL FEATURES
Most cases of measles arise in the winter and are spread
through respiratory droplets. The incubation period is
from 10 to 12 days, and affected individuals are infec-
tious from 2 days before becoming symptomatic until
4 days after appearance of the associated rash. The
virus is associated with signiﬁcant lymphoid hyperpla-
sia that often involves sites such as the lymph nodes,
tonsils, adenoids, and Peyer’s patches. Giant cell inﬁl-
tration is noted in various tissues along with a vasculitis
that is responsible for the characteristic skin rash.
There are three stages of the infection, with each
stage lasting 3 days and justifying the designation nine-
day measles. The ﬁrst 3 days are dominated by the three
Fig. 7-27 Acute lymphonodular pharyngitis. Numerous
dark-pink and yellow lymphoid aggregates. (Courtesy of Dr.
George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

260 ORAL AND MAXILLOFACIAL PATHOLOGY
Cs: Coryza (runny nose), Cough (typically brassy and
uncomfortable), and Conjunctivitis (red, watery, and
photophobic eyes). Fever typically accompanies these
symptoms. During this initial stage, the most distinctive
oral manifestation, Koplik’s spots, is seen. Multiple
areas of mucosal erythema are visible on the buccal
and labial mucosa, and less often on the soft palate;
within these areas are numerous small, blue-white
macules (Fig. 7-28). In addition, similar spots rarely are
noted on the inner conjunctival folds of the eye or the
vaginal mucosa. These pathognomonic spots represent
foci of epithelial necrosis and have been described as
“grains of salt” on a red background.
As the second stage begins, the fever continues, the
Koplik’s spots fade, and a maculopapular and erythem-
atous (morbilliform) rash begins. The face is involved
ﬁrst, with eventual downward spread to the trunk and
extremities. Ultimately, a diffuse erythematous macu-
lopapular eruption is formed, which tends to blanch on
pressure (Fig. 7-29). Abdominal pain secondary to lym-
phatic involvement is not rare.
In the third stage, the fever ends. The rash begins to
fade and demonstrates a similar downward progres-
sion with replacement by a brown pigmentary staining.
Ultimately, desquamation of the skin is noted in the
areas previously affected by the rash.
Common complications in young children are otitis
media, pneumonia, persistent bronchitis, and diarrhea.
Acute appendicitis occasionally is seen secondary to
vascular obstruction created by the swelling of Peyer’s
patches. Encephalitis develops in approximately 1 in
1000 cases, often resulting in death or permanent
brain damage and mental retardation. In about 1 in
100,000 cases, a delayed complication termed sub-
acute sclerosing panencephalitis (SSPE) arises as
late as 11 years after the initial infection. This degen-
erative disorder of the CNS leads to personality
changes, seizures, coma, and death. Widespread
vaccine use has virtually eliminated SSPE in developed
nations. In the United States, one to two deaths occur
for every 1000 reported cases of measles. In develop-
ing countries, the infection often is more severe, and
the case-to-fatality rate can be as high as 25%. The most
common causes of death are pneumonia and acute
encephalitis.
Measles in immunocompromised patients can be
serious, with a high risk of complications and death.
Most of these patients exhibit either an atypical rash or
no exanthem. Pneumonitis is the primary complica-
tion. The fatality rate of measles in patients with a
malignancy is greater than 50%; AIDS-associated
measles results in the death of more than one third of
affected patients.
Koplik’s spots are not the only oral manifestation
that may be associated with measles. Candidiasis,
necrotizing ulcerative gingivitis (NUG), and necrotiz-
ing stomatitis may occur if signiﬁcant malnutrition also
is present. Severe measles in early childhood can affect
odontogenesis and result in pitted enamel hypoplasia
of the developing permanent teeth. Enlargement of
accessory lymphoid tissues such as the lingual and pha-
ryngeal tonsils also may be noted.
HISTOPATHOLOGIC FEATURES
Because of the reduced prevalence of measles and the
transient nature of Koplik’s spots, few oral and maxil-
lofacial pathologists have had the opportunity to view
these lesions microscopically. Initially, Koplik’s spots
represent areas of focal hyperparakeratosis in which
the underlying epithelium exhibits spongiosis, intercel-
lular edema, dyskeratosis, and epithelial syncytial giant
cells. The number of nuclei within these giant cells
ranges from three to more than 25. Close examination
of the epithelial cells often reveals pink-staining inclu-
sions in the nuclei or, less commonly, in the cytoplasm.
Fig. 7-28 Rubeola. Numerous blue-white Koplik’s spots of
buccal mucosa. (Courtesy of Dr. Robert J. Achterberg.)
Fig. 7-29 Rubeola. Erythematous maculopapular rash of
the face. (Courtesy of Dr. Robert J. Achterberg.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 261
On electron microscopy, the inclusions have been
shown to represent microtubular aggregates character-
istic of the causative paramyxovirus. As the spot ages,
the epithelium exhibits heavy exocytosis by neutrophils
leading to microabscess formation, epithelial necrosis,
and, ultimately, ulceration. Frequently, examination of
the epithelium adjacent to the ulceration will reveal
the suggestive syncytial giant cells.
Examination of hyperplastic lymphoid tissue during
the prodromal stage of measles often reveals a similar
alteration. In 1931, Warthin and Finkeldey, in two
separate publications, reported an unusual ﬁnding in
patients who had their tonsils removed within 1 to 5
days of the clinical appearance of measles. Within the
hyperplastic lymphoid tissue, there were numerous
multinucleated giant lymphocytes (Fig. 7-30). These
multinucleated cells subsequently have been termed
Warthin-Finkeldey giant cells and were thought for
a time to be speciﬁc for measles. Since that time,
however, similar-appearing cells have been noted in a
variety of lymphoproliferative conditions such as lym-
phoma, Kimura’s disease, AIDS-related lymphoprolif-
erative disease, and lupus erythematosus.
DIAGNOSIS
The diagnosis of typical measles in an epidemic setting
usually is straightforward and based on the clinical
features and history. Laboratory conﬁrmation can be of
value in isolated or atypical cases. Viral isolation or
rapid detection of viral antigens is possible, but conﬁr-
mation usually is established through a demonstration
of rising serologic antibody titers. The antibodies appear
within 1 to 3 days after the beginning of the exanthem
and peak in about 3 to 4 weeks.
TREATMENT AND PROGNOSIS
With a complication rate of 21%, the best treatment for
measles is a good vaccination program; rubeola is part
of the widely used MMR vaccine. In an attempt to stop
the resurgence of measles that began in 1989, the vac-
cination schedule was altered and the pockets of young,
unvaccinated children were targeted. This action
brought the transmission of indigenous measles to
record lows. Although the number is variable from
year to year, since 1993 the annual incidence of
reported cases in the United States typically is well
below 500. Total eradication of the infection is
technically feasible with existing vaccines but will
require universal cooperation and enthusiasm from
across the globe. Renewed emphasis in the noncompli-
ant sections of society must be stressed. In addition, a
new two-dose vaccination schedule has been adopted
in an attempt to decrease the vaccine failures. Cur-
rently, routine vaccination is recommended for all chil-
dren between the ages of 12 and 15 months, with a
second dose administered between the ages of 4 and 6
years.
In otherwise healthy patients with measles, ﬂuids
and nonaspirin antipyretics are recommended for
symptomatic relief. Immunocompromised patients
also may be treated with one of a number of medica-
tions that have shown promise but deﬁnitively have not
been proven to be efﬁcacious. The most promising is
ribavirin; however, immunoglobulin, interferon, and
vitamin A also are being used.
RUBELLA (GERMAN MEASLES)
Rubella is a mild viral illness that is produced by a
virus in the family Togavirus, genus Rubivirus. The
greatest importance of this infection lies not in its
effects on those who contract the acute illness, but in
its capacity to induce birth defects in the developing
fetus. The infection occurs primarily in the winter and
spring, is contracted through respiratory droplets, and
it is transmitted to nearly 100% of individuals in close
living conditions. The incubation time is from 14 to 21
days, and infected patients are contagious from 1 week
before the exanthem to about 5 days after the develop-
ment of the rash. Infants with a congenital infection
may release virus for up to 1 year.
In the past, this infection occurred in cycles, with
localized epidemics every 6 to 9 years and pandemics
every 10 to 30 years. The last pandemic occurred from
1962 to 1964. In 1964 and 1965, the United States
alone had more than 12.5 million cases, which resulted
in more than 10,000 fetal deaths (direct effects or sec-
ondary to therapeutic abortions) and 20,000 infants
born with congenital rubella syndrome (CRS).
Fig. 7-30 Rubeola. Histopathologic section of pharyngeal
tonsil demonstrating lymphoid hyperplasia with scattered
multinucleated giant cells. Inset reveals high-power
magniﬁcation of Warthin-Finkeldey giant cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

262 ORAL AND MAXILLOFACIAL PATHOLOGY
An effective vaccine, ﬁrst released in 1969, is used
widely and has dramatically affected the epidemiology
of the infection and broken the cycle of occurrences.
The vaccine is contraindicated in the following
groups:
● Pregnant women
● Immunodeﬁcient patients
●Patients with acute febrile illnesses
●Patients with a known allergy to components of
the vaccine
Researchers postulated that the protection of chil-
dren also would eliminate the risk of exposure to
women in the childbearing years. A 99% decrease in
the infection was seen between 1969 and 1988, but
young adults remain susceptible. Like rubeola, 1989
and 1990 demonstrated a slight resurgence of rubella,
which was the result of a lack of vaccination diligence.
More than 70% of the current cases occur in patients
older than 15 years of age, and 10% to 25% of young
adults remain susceptible. Of course, this should
change when the previously vaccinated children grow
into adults. For the present, the vaccination of postpu-
bertal females must be stressed. Persons are presumed
to be immune if they have received at least one dose
of the MMR or were born before 1957. For pregnant
females who have not received the vaccine, their
immunity should be conﬁrmed by demonstration of
serum rubella IgG.
Initially, a single dose of the vaccine was thought to
be sufﬁcient to confer permanent immunity. Contin-
ued immunity appears to be permanent only if expo-
sure to the virus occurs periodically, essentially serving
as “booster doses.” With almost total vaccination cover-
age throughout the population of the United States,
reexposures are not occurring and immunity is waning.
To combat this loss of immunity in a highly vaccinated
population, additional boosters may become necessary.
Already, two doses of MMR vaccine are recommended,
the ﬁrst at 12 to 15 months of age and the second at
the age of 4 to 6 years. Some believe a third dose may
become necessary in the future.
CLINICAL FEATURES
A large percentage of infections are asymptomatic; the
frequency of symptoms is greater in adolescents and
adults. Prodromal symptoms may be seen 1 to 5 days
before the exanthem and include fever, headache,
malaise, anorexia, myalgia, mild conjunctivitis, coryza,
pharyngitis, cough, and lymphadenopathy. The lymph-
adenopathy may persist for weeks and is noted primar-
ily in the suboccipital, postauricular, and cervical
chains. The most common complication is arthritis,
which increases in frequency with age and usually
arises subsequent to the rash. Rare complications
include encephalitis and thrombocytopenia.
The exanthematous rash is often the ﬁrst sign of the
infection and begins on the face and neck, with spread
to the entire body within 1 to 3 days. The rash forms
discrete pink macules, then papules, and ﬁnally fades
with ﬂaky desquamation. The rash fades as it spreads
and often exhibits facial clearing before the completion
of its spread into the lower body areas. Generally, the
rash is resolved completely by day 3, giving rise to the
designation three-day measles.
Oral lesions, known as Forchheimer’s sign, have
been reported to be present in about 20% of the cases.
These consist of small, discrete, dark-red papules that
develop on the soft palate and may extend onto the
hard palate. This enanthem arises simultaneously with
the rash, becoming evident in about 6 hours after the
ﬁrst symptoms and not lasting longer than 12 to 14
hours. Palatal petechiae also may occur.
The risk of CRS correlates with the time of infection.
The frequency of transmission from an infected mother
is greater than 80% during the ﬁrst 12 weeks of preg-
nancy, with the risk of fetal damage decreasing dra-
matically at 8 weeks and becoming rare after 20 weeks
of gestation. The classic triad of CRS consists of deaf-
ness, heart disease, and cataracts. Deafness is the most
common manifestation, affecting more than 80% of
patients. This hearing loss may not become evident
until 2 years of age and usually is bilateral. Less
common, late emerging complications include enceph-
alopathy, mental retardation, diabetes mellitus, and
thyroid disorders.
DIAGNOSIS
The diagnosis of rubella is contingent on laboratory
tests because the clinical presentation of the acquired
infection is typically subclinical, mild, or nonspeciﬁc.
Although viral culture is possible, serologic analysis is
the mainstay of diagnosis.
TREATMENT AND PROGNOSIS
Rubella is mild, and therapy usually is not required.
Nonaspirin antipyretics and antipruritics may be useful
in patients with signiﬁcant fever or symptomatic cuta-
neous involvement. Passive immunity may be provided
by the administration of human rubella immunoglobu-
lin. If immunoglobulin is given within a few days of
exposure, it decreases the severity of the infection. This
therapy typically is reserved for pregnant patients who
decline abortion.
During the 1962 to 1965 worldwide rubella epi-
demic, the estimated number of infections in the
United States was 12.5 million. These infections were `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 263
associated with 20,000 infants born with CRS, 11,250
fetal deaths, and 2100 neonatal deaths. Because of the
two-dose vaccination schedule with the MMR and at
least 95% vaccination coverage among school-aged
children, in 2004, rubella was declared no longer to be
endemic in the United States. The annual reported
incidence of rubella was 23 in 2001, 18 in 2002, 7 in
2003, and 9 in 2004. Approximately half of these
infections occurred in individuals born outside the
United States. Likewise, from 2001 to 2004, only four
cases of CRS were reported, and three of the mothers
of these infants were not born in the United States.
MUMPS (EPIDEMIC PAROTITIS)
Mumps is an infection caused by a virus in the family
Paramyxovirus, genus Rubulavirus, which causes a
diffuse disease of exocrine glands. Although the sali-
vary glands are the best known sites of involvement,
the pancreas, choroid plexus, and mature ovaries and
testes also frequently are involved. The involved glands
exhibit edema and lymphocytic inﬁltration. As with
measles and rubella, the epidemiology has been
affected dramatically by the MMR vaccine. Before the
advent of widespread vaccination, epidemics were
seen every 2 to 5 years; nearly everyone was exposed
with 90% of the infections occurring before age 15. The
vaccine directed against mumps was released in 1967,
but its use was not accepted nationally until 1977. At
that time, vaccination became the norm for children
12 to 15 months of age. The vaccine has a success rate
of 75% to 95%. Most individuals born before 1957 are
thought to have immunity from exposure to naturally
occurring mumps virus. Although most authorities
assume that natural infection is associated with lifelong
immunity, rare cases of recurrent mumps have been
well documented in patients with a conﬁrmed history
of prior natural infection.
The annual incidence of mumps decreased by 98%
and reached an all-time low in 1985. In 1986 a resur-
gence developed. In the past, most cases occurred in
children aged 5 to 9 years; during the resurgence, the
disease was more prevalent in 10- to 19-year-old
patients. Outbreaks have been reported in high schools,
on college campuses, and in the workplace. This
increased incidence has been attributed to lack of vac-
cination, not vaccine failure. Subsequently, in the early
1990s, isolated outbreaks were reported in highly vac-
cinated populations and thought to be the result of
large-scale vaccination failure. Not long after these
reports, a second immunization as part of the MMR
vaccine was recommended at 4 to 6 years of age. When
compared with the prevaccine era, the two-dose MMR
vaccination schedule has reduced the prevalence of
mumps by 99%. In addition, in an attempt to decrease
the prevalence in the older age groups, it is recom-
mended that individuals lacking a history of mumps or
MMR vaccination be immunized. This primarily affects
those born between 1967 and 1977 and, to a lesser
extent, those born between 1957 and 1967. For health
care workers born before 1957, a single dose of MMR
is recommended unless there is a physician’s diagn-
osis of mumps or laboratory evidence of mumps
immunity.
In 2006 an outbreak of mumps virus occurred in
the United States, with an epicenter in Iowa and sur-
rounding states. During this outbreak, only 7% of
infected individuals were proven to be unvaccinated,
and 49% had received at least the recommended two
doses of the MMR. After two doses of MMR, the vaccine
appears to be 98% effective against measles but only
90% effective against mumps. In spite of the vaccine
failures in the recent outbreak, the high vaccination
coverage most likely prevented thousands of additional
cases of mumps. Some investigators wonder if such
outbreaks may lead to a recommendation for a third
dose of the MMR vaccine in the future.
The mumps virus can be transmitted through urine,
saliva, or respiratory droplets. The incubation period
usually is 16 to 18 days, with a range of about 2 to 4
weeks. Patients are contagious from 1 day before the
clinical appearance of infection to 14 days after its
clinical resolution.
CLINICAL FEATURES
Approximately 30% of mumps infections are subclini-
cal. In symptomatic cases, prodromal symptoms of low-
grade fever, headache, malaise, anorexia, and myalgia
arrive ﬁrst. Most frequently, these nonspeciﬁc ﬁndings
are followed within 1 day by signiﬁcant salivary gland
changes. The parotid gland is involved most frequently,
but the sublingual and submandibular glands also can
be affected. Discomfort and swelling develop in the
tissues surrounding the lower half of the external ear
and extending down along the posterior inferior border
of the adjacent mandible (Fig. 7-31). The enlargement
typically peaks within 2 to 3 days, and the pain is most
intense during this period of maximal enlargement.
Chewing movements of the jaw or eating saliva-stimu-
lating foods tends to increase the pain. Enlargement of
the glands usually begins on one side and is followed
by contralateral glandular changes within a few days.
Unilateral involvement is seen in about 25% of
patients.
The second most common ﬁnding is epididymo-
orchitis, which occurs in about 25% of postpubertal
males. In those affected the testicle exhibits rapid
swelling, with signiﬁcant pain and tenderness. The
enlargement can range from a minimal swelling to a `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

264 ORAL AND MAXILLOFACIAL PATHOLOGY
fourfold increase in size. Unilateral involvement is
most common. On resolution of the swelling, atrophy
occurs in the affected testicle. Permanent sterility from
testicular changes is rare. Less commonly, oophoritis
and mastitis can be seen in postpubertal females. In
addition, spontaneous abortion occurs in approxi-
mately 25% of women who contract mumps during the
ﬁrst trimester of pregnancy.
Less commonly, meningoencephalitis (from involve-
ment of the choroid plexus), cerebellar ataxia, hearing
loss, pancreatitis, arthritis, carditis, and decreased renal
function may occur. The most common symptom asso-
ciated with CNS involvement is headache, whereas
involvement of the pancreas can lead to nausea
and vomiting. Isolated changes, such as orchitis or
meningitis, may occur in the absence of salivary gland
involvement, thereby making diagnosis difﬁcult in
nonepidemic settings. Mumps-related mortality is
exceedingly rare and most frequently associated with
mumps encephalitis.
The most frequently reported oral manifestation is
redness and enlargement of Wharton’s and Stensen’s
salivary gland duct openings. In addition, involvement
of the sublingual gland may produce bilateral enlarge-
ments of the ﬂoor of the mouth.
DIAGNOSIS
The diagnosis of mumps can be made easily from the
clinical presentation when the infection is occurring in
an epidemic fashion; however, isolated cases must be
differentiated from other causes. The most frequently
used conﬁrmatory measures are demonstration of
mumps-speciﬁc IgM or a fourfold rise of mumps-
speciﬁc IgG titers when measured during the acute
phase and about 2 weeks later. In addition, a swab
of secretions obtained from parotid or other affected
salivary gland ducts can be used for viral isolation
or reverse-transcriptase–polymerase chain reaction
testing.
TREATMENT AND PROGNOSIS
The treatment of mumps is palliative in nature. Fre-
quently, nonaspirin analgesics and antipyretics are
administered. In an attempt to minimize orchitis, bed
rest is recommended for males until the fever breaks.
Avoidance of sour foods and drinks helps to decrease
the salivary gland discomfort. As with measles and
rubella, the best results come from prior vaccination,
thereby preventing the infection.
HUMAN IMMUNODEFICIENCY
VIRUS AND ACQUIRED
IMMUNODEFICIENCY SYNDROME
During the last 2 decades, more articles have been
written on human immunodeﬁciency virus (HIV)
and its related disease states than any other infectious
process. A complete bibliography alone easily would
be thicker than this chapter. Entire texts dedicated to
HIV infection and acquired immunodeﬁciency syn-
drome (AIDS) are available and should be consulted
for more detailed information.
The ﬁrst cases of AIDS reported in the United States
were documented by the Centers for Disease Central
and Prevention (CDC) in the Morbidity and Mortality
Weekly Report on June 5, 1981. This publication detailed
Pneumocystis carinii pneumoniae in ﬁve previously
healthy men from Los Angeles, California. More than
25 years have passed. During this time, 65 million indi-
viduals worldwide have become infected with HIV and
more than 25 million individuals have died of AIDS.
Through 2004, a total of 529,113 deaths as a result of
AIDS in the United States have been reported to the
CDC, and more than 1 million individuals are living
with HIV. Worldwide in 2005 alone, 4.1 million new
infections occurred, 38.6 million were living with HIV,
and an estimated 2.8 million individuals died of AIDS.
At the time of publication of the ﬁrst edition of this
text, the infection was thought to be nearly 100% fatal.
Through treatment advances, the annual incidence of
Fig. 7-31 Mumps. Bilateral parotid enlargement. (From
Neville BW, Damm DD, White DK: Color atlas of clinical oral pathology,
ed 2, Hamilton, 1999, BC Decker.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 265
AIDS and related deaths have been altered dramati-
cally in the United States. Cases of AIDS in the United
States expanded rapidly during the 1980s, peaked in
1992 (estimated 78,000), and decreased each year
from that time until 1998 when the annual incidence
stabilized at about 40,000. Highly active anti-retroviral
therapy (HAART) (see Treatment and Prognosis
section) is changing the face of HIV infection, with
affected individuals demonstrating extended survival
(resulting in an increased percentage of the population
living with the virus). The percentage of individuals
surviving 2 years after the diagnosis of AIDS has
increased from 44% in 1981 to 1992, to 64% in 1993
to 1995, to 85% in 1996 to 2000.
In infected individuals, the virus can be found
in most bodily ﬂuids. HIV has been recovered from
serum, blood, saliva, semen, tears, urine, breast milk,
ear secretions, and vaginal secretions. The most fre-
quent routes of transmission are sexual contact, paren-
teral exposure to blood, or transmission from mother
to fetus during the perinatal period. Infection also has
been documented to be caused by artiﬁcial insemina-
tion, breast-feeding from infected mothers, and organ
transplantation. Although heterosexual transmission is
increasing, most of the adults infected in the United
States have been homosexual or bisexual men, intrave-
nous (IV) drug abusers, hemophiliac patients receiving
factor VIII before 1985, recipients of blood products, or
heterosexual contacts with one of the other high-risk
groups.
Researchers have debated the infectiousness of oral
ﬂuids. HIV has been found to be present in oral ﬂuids,
but saliva appears to reduce the ability of HIV to infect
its target cells, lymphocytes. Reports of transmission by
oral ﬂuids are rare, and it appears this is not a signiﬁ-
cant source for the transmission of AIDS. In spite of this,
anecdotal reports have documented the transmission
of AIDS during breast-feeding from the oral ﬂuids of
postpartum infected infants to their previously nonin-
fected mothers. In addition, rare examples have been
documented reporting the transmission of HIV infec-
tion by contamination of the oral ﬂuids during cunnilin-
gus or repeated passionate kissing. These rare anecdotal
reports point out that oral ﬂuids can be infectious and
are not completely protective against oral introduction
of HIV. Although saliva is known to contain a number
of anti-HIV inhibitory factors, the presence of aphthae,
erosions, ulcerations, and hemorrhagic inﬂammatory
pathoses (e.g., gingivitis, periodontitis) may predispose
an individual to oral transmission. In summary, the best
precaution against infection is avoidance of all body
ﬂuids of infected patients.
Initially in the United States, AIDS was thought to
be a disease that primarily affected whites and male
homosexuals. Although men who have sex with men
(MSM) remains the largest single risk factor, the nature
of the epidemic is shifting because of numerous public
health interventions directed against particularly vul-
nerable populations. These changing patterns are dem-
onstrated well by comparing the data related to the
early years of the infection with those noted in the
initial portion of the twenty-ﬁrst century (Table 7-1).
Since the initial years of the epidemic, blood-screen-
ing methods have improved dramatically and reduced
Table 7-1 Race/Ethnicity, Sex, and Transmission Category of AIDS Cases,
1981-1995 and 2001-2004
1981-1995 (%) 2001-2004 (%)
RACE
White, non-Hispanic 46.5 28.3
Black, non-Hispanic 34.6 49.5
Hispanic 17.9 20.3
Asian/Paciﬁc Islander 0.7 1.1
Native American/Alaska Native 0.3 0.5
SEX
Male 84.7 73.4
Female 15.3 26.6
TRANSMISSION CATEGORY
Male-to-male sexual contact 51.2 40.8
Injection-drug use 26.8 22.8
Male-to-male sexual contact/injection-drug use 7.8 4.9
Heterosexual contact 10.1 30.1
Perinatal 1.3 0.2
Other 2.9 1.3 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

266 ORAL AND MAXILLOFACIAL PATHOLOGY
the risk for HIV infection to as low as 1 in 2 million
blood donations. The risk of transmission from infected
mothers to newborns has been reduced from 25%-30%
to 2% (95% reduction) because of widespread prenatal
HIV testing, prophylactic use of antivirals, elective
cesarean section performed before onset of labor, and
avoidance of breast-feeding.
In the early years, non-Hispanic whites were the
predominant ethnic group diagnosed with AIDS;
however, with evolution of the epidemic, non-Hispanic
blacks have become the predominant racial group. In
addition, an increasing prevalence of HIV infection is
being seen in females and heterosexuals. Of 35 areas
reported to the CDC in 2004, 51% of all HIV infections
and cases of AIDS were documented in blacks, even
though this group accounted for only 13% of the popu-
lation in the United States. Of these, 11% of the black
men and 54% of the black women were infected
through heterosexual contact. During this time, HIV
infection was the leading cause of death for black
women aged 25 to 34 years; the rates of infection per
100,000 in blacks, Hispanics, and whites were 76.3,
29.5, and 9.0, respectively. In comparing the racial
rates of infection in the sexes in 2004, black males
were affected seven times more frequently than whites,
whereas black females demonstrated prevalence 21
times higher than white females.
The primary target cell of HIV is the CD4+ helper
T lymphocyte. The DNA of HIV is incorporated into
the DNA of the lymphocyte and is present for the life
of the cell. In most viral infections, host antibodies that
are protective against the organism usually are formed.
In people with HIV infection, antibodies are developed
but are not protective. The virus may remain silent,
cause cell death, or produce syncytial fusion of the
cells, which disrupts their normal function. A subse-
quent decrease in T-helper cell numbers occurs, with
a resultant loss in immune function. The normal
response to viruses, fungi, and encapsulated bacteria is
diminished.
On introduction of HIV, an indeﬁnite percentage of
those infected will have an acute self-limited viral syn-
drome. This is followed by an asymptomatic stage,
which averages 8 to 10 years. The length of the asymp-
tomatic period is variable and may be affected by the
nature of the virus, the host immune reaction, or
external factors that may delay or accelerate the
process. Almost inevitably, the ﬁnal symptomatic stage
develops.
CLINICAL FEATURES
HIV infection initially may be asymptomatic, or an
acute response may be seen. The acute viral syndrome
that occurs typically develops within 1 to 6 weeks after
exposure in 50% to 70% of infected patients. The symp-
toms bear some resemblance to those of infectious
mononucleosis (e.g., generalized lymphadenopathy,
sore throat, fever, maculopapular rash, headache,
myalgia, arthralgia, diarrhea, photophobia, peripheral
neuropathies). Oral changes may include mucosal ery-
thema and focal ulcerations.
The acute viral syndrome clears within a few weeks;
during this period, HIV infection usually is not consid-
ered or investigated. A variable asymptomatic period
follows. Some patients have persistent generalized
lymphadenopathy (PGL), which may later resolve. In
some patients (before development of overt AIDS),
there is a period of chronic fever, weight loss, diarrhea,
oral candidiasis, herpes zoster, and/or oral hairy leuko-
plakia (OHL). This has been termed AIDS-related
complex (ARC).
The presentation of symptomatic, overt AIDS is
highly variable and often is affected by a person’s prior
exposure to a number of chronic infections. The signs
and symptoms described under ARC are often present,
along with an increasing number of opportunistic
infections or neoplastic processes. In 50% of the cases,
pneumonia caused by the protozoan Pneumocystis
carinii is the presenting feature leading to the diagnosis.
Other infections of diagnostic signiﬁcance include dis-
seminated cytomegalovirus (CMV) infection, severe
herpes simplex virus (HSV) infection, atypical myco-
bacterial infection, cryptococcal meningitis, and cen-
tral nervous system (CNS) toxoplasmosis. Persistent
diarrhea is commonplace and may be bacterial or pro-
tozoal in origin. Clinically signiﬁcant neurologic dys-
function is present in 30% to 50% of patients, and the
most common manifestation is a progressive encepha-
lopathy known as AIDS-dementia complex.
The most widely accepted classiﬁcation of the oral
manifestations of AIDS was compiled by the EC-Clear-
inghouse on Problems Related to HIV Infection and
the WHO Collaborating Centre on Oral Manifesta-
tions of the Immunodeﬁciency Virus. This classiﬁca-
tion divided the manifestations into three groups: (1)
strongly associated, (2) less commonly associated, and
(3) seen in patients HIV infection (Box 7-1). The dis-
cussion here concentrates primarily on the clinical
presentations. (For detailed information on the histo-
pathology, diagnosis, and treatment of each condition,
see the text covering the individual disease.) When the
infections are treated differently in HIV-infected
patients, these variations are presented here. The most
common manifestations are presented ﬁrst, followed
by a selection of the less frequently encountered
disorders.
The prevalence and mixture of oral manifestations
noted in HIV-infected patients has been altered dra-
matically by the current antiretroviral therapies. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 267
Numerous investigations of patients receiving HAART
(see Treatment and Prognosis section) have demon-
strated an increase in CD4+ count and a reduction in
viral load that appear to be correlated with a reduced
prevalence of many oral manifestations. Other factors
that appear to affect the frequency of oral manifesta-
tions include xerostomia, poor oral hygiene, and
smoking. Subsequent to HAART, the overall preva-
lence of oral manifestations decreased, including sig-
niﬁcant reductions in the frequency of oral candidiasis,
OHL, HIV-associated periodontal disease, and Kaposi’s
sarcoma. Although the prevalence of certain lympho-
mas has decreased because of HAART, the frequency
of all HIV-related lymphomas has not demonstrated
signiﬁcant change. In contrast, many researchers have
reported an increased prevalence of benign human
papillomavirus (HPV)-induced pathoses. A similar
increased frequency of HIV-related salivary gland
disease has been noted by some, but disputed by
others.
The detection of oral manifestations can be critical,
because it may suggest possible HIV infection in an
unaware individual. The discovery in a patient with
known HIV infection who is not yet on active therapy
may signal progression of HIV disease. Finally, if new
oral manifestations surface in a patient receiving anti-
retroviral therapy, it may lead to reevaluation and pos-
sible adjustment of the therapeutic regimen
ORAL AND MAXILLOFACIAL LESIONS
STRONGLY ASSOCIATED WITH
HIV INFECTION
CANDIDIASIS
Oral candidiasis is the most common intraoral mani-
festation of HIV infection and often is the presenting
sign that leads to the initial diagnosis (Fig. 7-32).
Although a number of Candida species have been
encountered intraorally, the most common organism
identiﬁed in association with oral candidiasis is Candida
albicans. The presence of oral candidiasis in a patient
infected with HIV is not diagnostic of AIDS but appears
to be predictive for the subsequent development of
full-blown AIDS in untreated patients within 2 years.
Prevalence studies vary widely, but approximately one
third of HIV-infected individuals and more than 90%
of patients with AIDS develop oral candidiasis at some
Fig. 7-32 HIV-associated candidiasis. Extensive removable
white plaques of the left buccal mucosa.
Box 7-1
EC-Clearinghouse Classiﬁcation of
the Oral Manifestations of HIV
Disease in Adults
GROUP 1: STRONGLY ASSOCIATED WITH
HIV INFECTION
●Candidiasis: erythematous, pseudomembranous,
angular cheilitis
● Hairy leukoplakia
●Kaposi’s sarcoma (KS)
● Non-Hodgkin’s lymphoma
●Periodontal diseases: linear gingival erythema, necro-
tizing gingivitis, necrotizing periodontitis
GROUP 2: LESS COMMONLY ASSOCIATED WITH
HIV INFECTION
● Bacterial infections: Mycobacterium avium-intracellu-
lare, Mycobacterium tuberculosis
● Melanotic hyperpigmentation
●Necrotizing ulcerative stomatitis
●Salivary gland disease: dry mouth, unilateral or bilat-
eral swelling of major salivary glands
● Thrombocytopenia purpura
●Oral ulcerations NOS (not otherwise speciﬁed)
●Viral infections: herpes simplex, human
papillomavirus, varicella-zoster
GROUP 3: SEEN IN HIV INFECTION
● Bacterial infections: Actinomyces israelii, Escherichia
coli, Klebsiella pneumonia
● Cat-scratch disease (Bartonella henselae)
●Epithelioid (bacillary) angiomatosis (Bartonella
henselae)
●Drug reactions: ulcerative, erythema multiforme,
lichenoid, toxic epidermolysis
●Fungal infections other than candidiasis: Cryptococcus
neoformans, Geotrichum candidum, Histoplasma capsu-
latum, Mucoraceae (mucormycosis/zygomycosis),
Aspergillus ﬂavus
●Neurologic disturbances: facial palsy, trigeminal
neuralgia
●Recurrent aphthous stomatitis
●Viral infections: cytomegalovirus, molluscum
contagiosum
HIV, Human immunodeﬁciency virus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

268 ORAL AND MAXILLOFACIAL PATHOLOGY
time during their disease course. The following four
clinical patterns are seen:
1. Pseudomembranous candidiasis
2. Erythematous candidiasis
3. Hyperplastic candidiasis
4. Angular cheilitis
The ﬁrst two variants constitute most of the cases
(see page 213). Although infrequently seen in immu-
nocompetent patients, chronic multifocal oral involve-
ment is common in patients who are infected with
HIV. Erythematous candidiasis typically begins to
appear when the CD4 lymphocyte count drops below
400 cells/mm
3
, with the pseudomembranous pattern
being noted when the counts drop below 200 cells/
mm
3
. When comparing immunocompromised patients
of different causations, those secondary to HIV infec-
tion have a greater prevalence of oral candidiasis, sug-
gesting that HIV may play a role in initiation of the
infection. Some studies have shown that development
of candidiasis may be associated more closely with
viral load than CD4 cell count. Oral candidiasis can be
painful and associated with a reduction in taste and
smell, which may lead to decreased intake of food and
further wasting.
The diagnosis of candidiasis often is obvious from
the clinical presentation but can be conﬁrmed by cyto-
logic smear or biopsy. Biopsy specimens of involved
mucosa demonstrate the candidal organisms embed-
ded in the superﬁcial keratin, but the typical inﬂamma-
tory reaction often is deﬁcient (Fig. 7-33). Because
C. albicans is a portion of the normal ﬂora in 60% of
healthy adults, positive microbiological cultures do not
necessarily imply an active infection.
Treatment is much more difﬁcult in patients with
AIDS. Nystatin often is ineffective. Topical clotrimazole
is associated with an improved response and typically
produces a clinical cure rate that equals that of the
systemic azoles. In spite of this success, topical therapy
is associated with a high recurrence rate. The systemic
azoles (i.e., ﬂuconazole, ketoconazole, itraconazole)
produce longer disease-free intervals but are associ-
ated with another set of problems. Itraconazole and
ketoconazole require gastric acidity for adequate
absorption, and all three agents are associated with a
number of drug interactions. In addition, widespread
use of systemic azoles has led to an increased preva-
lence of drug-resistant candidiasis in this patient popu-
lation. In an attempt to reduce recurrences, patients
have been encouraged to improve oral hygiene and
assist mechanical cleansing of the mouth by rinsing
with normal saline or home-made salt water several
times daily.
In patients who are receiving effective antiretroviral
therapy, have a CD4+ count exceeding 50 cells/mm
3
,
and have no signs of esophageal involvement, topical
clotrimazole is the treatment of choice. Systemic
therapy is recommended for patients not receiving
effective antiretroviral therapy or for those with
either esophageal involvement, a CD4+ count below
50 cells/mm
3
, or a high viral load. Fluconazole is con-
sidered by many to be the drug of choice and has been
shown to be the most effective prophylactic medica-
tion. In spite of this, non-albicans species such as Candida
glabrata and Candida krusei have been isolated in HIV-
infected patients, and these organisms are less suscep-
tible to ﬂuconazole. In many patients, itraconazole in
an oral solution has been shown to be particularly
effective in a swish-and-swallow method. Although
gentian violet is not widely used, its effectiveness is
better than nystatin and approaches the azoles, making
this therapy a low-cost alternative in areas with inade-
quate funding or insufﬁcient access to many of the
newer medications. In several studies, antiretroviral
protease inhibitors have been shown to exhibit a syn-
ergistic effect with the antifungal azoles and are thought
possibly to interfere directly with candidal secretory
aspartyl protease, an important virulence factor.
Patients failing systemic azole therapy are candidates
for intravenous amphotericin B if the patient’s health
supports its use. Amphotericin B oral suspension is
available but reserved by many for azole-resistant can-
didiasis. Prophylactic antifungal therapy is not recom-
mended unless frequent and severe recurrences are
present.
ORAL HAIRY LEUKOPLAKIA
Although EBV is thought to be associated with several
forms of lymphoma in HIV-infected patients, the most
common EBV-related lesion in patients with AIDS is
oral hairy leukoplakia (OHL). This lesion clinically
presents as a white mucosal plaque that does not rub
off and is characterized histopathologically by a some-
Fig. 7-33 HIV-associated candidiasis. Periodic acid-Schiff
(PAS) stain of histopathologic section exhibiting numerous
fungal organisms embedded in superﬁcial keratin. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 269
what distinctive (but not diagnostic) pattern of hyper-
keratosis and epithelial hyperplasia.
Most cases of OHL occur on the lateral border of the
tongue and range in appearance from faint white verti-
cal streaks to thickened and furrowed areas of leuko-
plakia, exhibiting a shaggy keratotic surface (Fig. 7-34).
The lesions infrequently may become extensive and
cover the entire dorsal and lateral surfaces of the
tongue. Rarely, the buccal mucosa, soft palate, pharynx,
or esophagus may be involved.
Histopathologically, OHL exhibits thickened para-
keratin that demonstrates surface corrugations or thin
projections (Fig. 7-35). The epithelium is acanthotic
and exhibits a bandlike zone of lightly stained cells
with abundant cytoplasm (“balloon cells”) in the upper
spinous layer (Fig. 7-36). Close examination of the
superﬁcial epithelium reveals scattered cells with
nuclear clearing and a characteristic pattern of periph-
eral margination of chromatin termed nuclear beading
(see Fig. 7-36, inset), caused by extensive EBV replica-
tion that displaces the chromatin to the nuclear margin.
Dysplasia is not noted. Heavy candidal infestation of
the parakeratin layer is typical, although the normal
inﬂammatory reaction to the fungus usually is absent.
In the routine management of patients with HIV
infection, the clinical features of OHL typically are suf-
ﬁcient for a presumptive diagnosis. When deﬁnitive
diagnosis is necessary, demonstration of EBV within
the lesion is required and can be achieved by in situ
hybridization, PCR, immunohistochemistry, Southern
blotting, or electron microscopy (Fig. 7-37).
Treatment of OHL usually is not needed, although
slight discomfort or aesthetic concerns may necessitate
therapy. Systemic antiherpesviral drugs produce rapid
Fig. 7-34 HIV-associated oral hairy leukoplakia (OHL).
Vertical streaks of keratin along the lateral border of the
tongue.
Fig. 7-35 HIV-associated oral hairy leukoplakia (OHL).
Oral mucosa exhibiting hyperparakeratosis with surface
corrugations.
Fig. 7-36 HIV-associated oral hairy leukoplakia (OHL).
Oral epithelium exhibiting hyperparakeratosis and layer of
“balloon cells” in the upper spinous layer. Inset reveals high-
power magniﬁcation of epithelial cells that demonstrate
nuclear beading.
Fig. 7-37 HIV-associated oral hairy leukoplakia (OHL).
Immunoperoxidase evaluation for Epstein-Barr virus (EBV)
revealing positive reaction within numerous epithelial cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

270 ORAL AND MAXILLOFACIAL PATHOLOGY
resolution, but recurrence is expected with discontinu-
ation of therapy. Topical treatment with retinoids or
podophyllum resin has resulted in temporary remis-
sions. Surgical excision or cryotherapy has been used
by some. A signiﬁcantly reduced prevalence of OHL
has been noted in patients on HAART who have dem-
onstrated decreased viral load and an improved CD4
count. In underdeveloped countries with patients
located great distances from urban health centers, the
presence or absence of OHL can be used along with
oral candidiasis as a clinical guide to assist in judging
the effectiveness of antiviral therapy.
Although rare instances of OHL have been reported
in immunocompetent individuals, most cases arise in
immunocompromised persons. OHL also has been
reported in heart, kidney, liver, and bone marrow
transplant recipients, but its presence in the absence of
a known cause of immunosuppression strongly sug-
gests HIV infection. Discovery of OHL in “normal”
patients mandates a thorough physical evaluation to
rule out immunocompromised status. The presence of
OHL in HIV-infected patients is a signal of severe
immune suppression and more advanced disease.
KAPOSI’S SARCOMA
Kaposi’s sarcoma (KS) is a multifocal neoplasm of
vascular endothelial cell origin that was described ini-
tially in patients over the age of 60 (see page 557).
However, since the beginning of the AIDS epidemic,
most cases in the United States have been seen in asso-
ciation with HIV infection, with about 15% to 20% of
patients with AIDS demonstrating KS. Human herpes-
virus type 8 (HHV-8, Kaposi’s sarcoma– associated her-
pesvirus [KSHV]) is noted within the tumor and
believed to be responsible for the neoplasm’s develop-
ment. In Western countries, AIDS-associated KS has
been reported primarily in homosexuals and is thought
to be related to sexual transmission of HHV-8. Further
evidence from Africa has demonstrated acquisition of
HHV-8 infection before sexual activity and suggests
alternate transmission pathways. HHV-8 has been
found in saliva, serum, plasma, throat swabs, and bron-
choalveolar lavage ﬂuids. In Africa, HIV-related KS
does not demonstrate a strong association with homo-
sexual activity, exhibits an equal prevalence in men
and women, and is not rare in children. In a recent
North American study of healthy adults, HHV-8 was
detected in oral epithelial cells and in the oropharynx,
suggesting that the oral cavity may represent the pre-
dominant reservoir of infectious virus. These studies
suggest that saliva represents an important route for
transmission of HHV-8 in both heterosexual and homo-
sexual populations.
KS typically manifests as multiple lesions of the skin
or oral mucosa, although occasionally a solitary lesion
is identiﬁed ﬁrst. The trunk, arms, head, and neck are
the most commonly involved anatomic sites (Fig. 7-38).
Approximately 70% of individuals with HIV-related KS
of skin or viscera demonstrate oral lesions; in 22% the
oral cavity is the initial site of involvement. Although
any mucosal site may be involved, the hard palate,
gingiva, and tongue are affected most frequently (Figs.
7-39 and 7-40). When present on the palate or gingiva,
the neoplasm can invade bone and create tooth mobil-
ity. The lesions begin as brown or reddish purple
macular lesions that do not blanch with pressure. With
time, the macules typically develop into plaques or
nodules (Fig. 7-41). Pain, bleeding, and necrosis may
become a problem and necessitate therapy (Fig.
7-42).
A biopsy is required to make the deﬁnitive diagno-
sis, although a presumptive diagnosis is sometimes
made from the clinical presentation and history.
Lesions that have a similar clinical appearance can
Fig. 7-38 HIV-associated Kaposi’s sarcoma (KS). Multiple
purple macules on the right side of the face.
Fig. 7-39 HIV-associated Kaposi’s sarcoma (KS). Large
zones of KS exhibiting as a ﬂat, brownish, and M-shaped
discoloration of the hard palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 271
occur in HIV-infected patients who exhibit bacillary
angiomatosis, the multifocal vascular proliferation
associated with the cat-scratch bacillus (see page 206).
HIV-related lymphomas also may resemble KS at
times.
Before HAART, KS was considered a progressive
malignancy that often disseminated widely to lymph
nodes and various organ systems. HAART with prote-
ase inhibitors has been associated with a 30% to 50%
reduction in the prevalence of KS and has produced
signiﬁcant regression of lesions in patients already
affected. Because KS typically arises in immunocom-
promised patients and frequently demonstrates
regression on return of immunocompetence, many
researchers question whether KS is a true sarcoma. In
cases not responding to HAART, single-agent chemo-
therapy such as alkaloids, bleomycin, doxorubicin,
epirubicin, etoposide, and paclitaxel have shown effec-
tiveness. Multiagent combinations have an increased
effect but are associated with more severe adverse
reactions and poor results in patients with widespread
disease.
Oral lesions are frequently a cause of major morbid-
ity, as a result of pain, bleeding, and functional interfer-
ences. Problematic lesions may be removed surgically
or with cryotherapy. Intralesional injection of oral
lesions with vinblastine (a chemotherapeutic agent) is
effective. Intralesional injection of sodium tetradecyl
sulfate, a sclerosing agent, has been effective for prob-
lematic intraoral lesions less than 2.5 cm in diameter.
Laser ablation or electrosurgery have been used to
treat KS, although theoretical concerns have been
raised with respect to aerosolization of viral particles,
which may place the surgical team at risk.
PERSISTENT GENERALIZED
LYMPHADENOPATHY
After seroconversion, HIV disease often remains silent
except for persistent generalized lymphadenopa-
thy (PGL). The prevalence of this early clinical sign
varies; however, in several studies it approaches 70%.
PGL consists of lymphadenopathy that has been present
for longer than 3 months and involves two or more
extrainguinal sites. The most frequently involved sites
are the posterior and anterior cervical, submandibular,
occipital, and axillary nodes. Nodal enlargement ﬂuc-
tuates, usually is larger than 1 cm, and varies from 0.5
to 5.0 cm (Fig. 7-43).
Because lymphoma is known to occur in this popu-
lation, a lymph node biopsy may be indicated for local-
ized or bulky adenopathy, when cytopenia or an
elevated erythrocyte sedimentation rate is present, or
when requested for patient reassurance. Histopatho-
logic examination reveals ﬂorid follicular hyperplasia.
Although not as predictive as oral candidiasis or hairy
Fig. 7-40 HIV-associated Kaposi’s sarcoma (KS). Raised,
dark-red enlargement of the mandibular anterior facial
gingiva on the left side.
Fig. 7-41 HIV-associated Kaposi’s sarcoma (KS). Diffuse,
red-blue nodular enlargement of the left hard palate.
Fig. 7-42 HIV-associated Kaposi’s sarcoma (KS). Diffuse,
red-blue gingival enlargement that demonstrates widespread
necrosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

272 ORAL AND MAXILLOFACIAL PATHOLOGY
leukoplakia, PGL does warn of progression to AIDS;
almost one third of affected and untreated patients will
have diagnostic features of AIDS within 5 years.
NON-HODGKIN’S LYMPHOMA
Non-Hodgkin’s lymphoma (NHL) is the second most
common malignancy in HIV-infected individuals. This
neoplasm occurs in approximately 3% to 5% of those
with the virus, a prevalence 60 times greater than the
normal population. Typically, NHL in patients with
AIDS presents as a high-grade and aggressive disease
that frequently is associated with widespread involve-
ment and short survival times. In AIDS the relative risk
for developing a low-grade NHL is 15 times greater,
compared with a 400 times greater risk for a high-grade
NHL. The majority of the NHLs are B-cell lymphomas
and include AIDS Burkitt’s lymphoma, anaplastic large
cell lymphoma, diffuse large cell lymphoma, immuno-
plasmacytoid lymphoma, primary effusion lymphoma,
and plasmablastic lymphoma. Although a large number
of these neoplasms demonstrate a relationship with
EBV, studies have suggested that plasmablastic lym-
phoma and primary effusion lymphoma may be associ-
ated with both EBV and HHV-8.
Lymphoma in patients with AIDS usually occurs in
extranodal locations, with the CNS being the most
common site. Oral lesions are seen in approximately
4% of patients with AIDS-related NHL and most fre-
quently involve the gingiva, palate, tongue, tonsil, or
maxillary sinus (Fig. 7-44). Intraosseous involvement
also has been documented and may resemble diffuse
progressive periodontitis with loss of periodontal
attachment and loosening of teeth. In these cases, wid-
ening of the periodontal ligament and loss of lamina
dura frequently are noted and represent clues to the
diagnosis.
The treatment usually is combination chemother-
apy, and radiation is reserved for local control of the
disease. These malignancies are aggressive, and sur-
vival usually is measured in months from the date of
discovery. Although HAART has dramatically reduced
the prevalence of many opportunistic infections and
KS in HIV-infected patients, the effect on NHL appears
to vary with the type of lymphoma and has been incon-
sistent. Although many forms of NHL continue to con-
tribute to the morbidity and mortality of HIV-infected
patients, others categories of NHL, such as plasmablas-
tic lymphoma, have declined signiﬁcantly because of
HAART.
HIV-ASSOCIATED PERIODONTAL DISEASE
Three atypical patterns of periodontal disease are asso-
ciated strongly with HIV infection:
1. Linear gingival erythema
2. Necrotizing ulcerative gingivitis
3. Necrotizing ulcerative periodontitis
Linear gingival erythema initially was termed
HIV-related gingivitis, but ultimately was noted in asso-
ciation with other disease processes. This unusual
pattern of gingivitis appears with a distinctive linear
band of erythema that involves the free gingival margin
and extends 2 to 3 mm apically (Fig. 7-45). In addition,
the alveolar mucosa and gingiva may demonstrate
punctate or diffuse erythema in a signiﬁcant percent-
age of the cases. This diagnosis should be reserved for
gingivitis that does not respond to improved plaque
control and exhibits a greater degree of erythema than
would be expected for the amount of plaque in the
area. The literature related to linear gingival erythema
is difﬁcult to evaluate, because it appears that conven-
tional marginal gingivitis often is misinterpreted as
linear gingival erythema. Although some investigators
Fig. 7-43 HIV-associated lymphadenopathy. Enlarged
cervical lymph nodes in a patient with persistent generalized
lymphadenopathy (PGL).
Fig. 7-44 HIV-associated lymphoma. Erythematous and
ulcerated soft tissue enlargement of the posterior mandibular
gingiva and mucobuccal fold on the right side. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 273
believe linear gingival erythema results from an abnor-
mal host immune response to subgingival bacteria,
data suggest that this pattern of gingivitis may repre-
sent an unusual pattern of candidiasis. Most instances
respond to systemic antifungal medications such as ﬂu-
conazole or ketoconazole.
Necrotizing ulcerative gingivitis (NUG) (see page
157) refers to ulceration and necrosis of one or more
interdental papillae with no loss of periodontal attach-
ment. Patients with NUG have interproximal gingival
necrosis, bleeding, pain, and halitosis (Fig. 7-46).
Necrotizing ulcerative periodontitis (NUP) previ-
ously was termed HIV-associated periodontitis; however,
it has not been deemed to be speciﬁc for HIV infection.
NUP is characterized by gingival ulceration and necro-
sis associated with rapidly progressing loss of periodon-
tal attachment. Although severe cases can affect all
teeth, multiple isolated defects often are seen and con-
trast with the diffuse pattern associated with typical
chronic periodontitis. Edema, severe pain, and sponta-
neous hemorrhage are common and often lead affected
patients to seek care. Deep pocketing usually is not
seen because extensive gingival necrosis typically coin-
cides with loss of the adjacent alveolar bone (Fig. 7-47).
Loss of more than 6 mm of attachment within a
6-month period is not unusual. HIV-associated peri-
odontitis does not respond to conventional periodontal
therapy.
The treatment of NUG and NUP revolves around
débridement, antimicrobial therapy, immediate follow-
up care, and long-term maintenance. The initial re-
moval of necrotic tissue is necessary, combined with
povidone-iodine irrigation. The use of systemic antibi-
otics usually is not necessary, but metronidazole
(narrow spectrum to suppress periodontal pathogens
without strongly promoting candidal overgrowth) has
been administered to patients with extensive involve-
ment that is associated with severe acute pain. All
patients should use chlorhexidine mouth rinses ini-
tially and for long-term maintenance. After initial
débridement, follow-up removal of additional diseased
tissue should be performed within 24 hours and again
every 7 to 10 days for two to three appointments,
depending on the patient’s response. At this point,
monthly recalls are necessary until the process stabi-
lizes; evaluations then are performed every 3 months.
In patients with gingival necrosis, the process occa-
sionally extends away from the alveolar ridges and
creates massive areas of tissue destruction termed nec-
rotizing stomatitis (Fig. 7-48). The process clinically
resembles noma (see page 201) and may involve pre-
dominantly soft tissue or extend into the underlying
bone, resulting in extensive sequestration (Fig. 7-49).
Although this process initially was thought to be an
extension of NUP, necrotizing stomatitis has arisen on
Fig. 7-45 HIV-associated gingivitis. Band of erythema
involving the free gingival margin.
Fig. 7-46 HIV-associated necrotizing ulcerative gingivitis
(NUG). Multiple punched-out interdental papillae of the
mandibular gingiva. Note diffuse pseudomembranous
candidiasis of the surrounding mucosa.
Fig. 7-47 HIV-associated periodontitis. Extensive loss of
periodontal support without deep pocketing. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

274 ORAL AND MAXILLOFACIAL PATHOLOGY
the oral mucosa separate from the gingiva (not overly-
ing bone).
In the absence of gingival involvement, the clinical
features of necrotizing stomatitis are nonspeciﬁc and
mandate biopsy. In many instances, the areas of soft
tissue ulceration and necrosis demonstrate infection
with one of more agents, such as HSV, CMV, and
EBV.
In addition to these three atypical forms of HIV-
related periodontal disease, patients also may demon-
strate conventional gingivitis, chronic periodontitis,
and progressive nonnecrotizing periodontitis. Studies
have shown that periodontal attachment loss can be
combated successfully with regular professional
removal of supra- and subgingival plaque in patients
who optimize their personal oral hygiene techniques.
Because smoking has been associated strongly with all
forms of periodontal disease, patients should be encour-
aged to discontinue their tobacco habit.
LESS COMMON ORAL AND
MAXILLOFACIAL MANIFESTATIONS OF
HIV INFECTION
MYCOBACTERIAL INFECTION
The best known mycobacterial infection is tuberculo-
sis (TB), which typically is caused by Mycobacterium
tuberculosis (see page 195). Infections with other myco-
bacteria include M. avium and M. intracellulare (M.
avium-intracellulare complex), M. bovis, M. scrofulaceum,
M. africanum, and M. haemophilum, although these
usually are found only in the immunocompromised
patient. Worldwide, one in three individuals contracts
TB sometime during their life, with more than 2 million
associated deaths each year. Those coinfected with
HIV are at greater risk of death and account for 15% of
AIDS-related deaths worldwide. It is estimated that
more than 4.4 million individuals are coinfected with
TB and HIV, with more than half a million individuals
exhibiting active TB.
Oral lesions are uncommon and occur in less than
5% of individuals with active TB. When present, the
tongue is affected most frequently, but lesions also can
develop on the buccal mucosa, gingiva, ﬂoor of mouth,
lips, and palate. The affected areas present as chronic
ulcerations, granular leukoplakias, or exophytic prolif-
erative masses. Jaw involvement also has been reported.
Conﬁrming the diagnosis of TB often can be difﬁcult
in AIDS patients, because up to 80% do not react to
tuberculin skin tests. In such cases, identifying the
organism by examining AFB-stained sections of biopsy
material and conﬁrming its presence on culture of
infected tissue are important.
Management is difﬁcult because of increasing drug
resistance and difﬁculty in ensuring patient compli-
ance with the extended treatment protocols. Agents
frequently used in the triple-drug regimens include
rifampicin, isoniazid, and pyrazinamide, with etham-
butol added when isoniazid resistance is likely.
HYPERPIGMENTATION
Hyperpigmentation of the skin, nails, and mucosa
has been reported in HIV-infected patients. The
changes are similar microscopically to focal melanosis,
with increased melanin pigmentation observed in the
basal cell layer of the affected epithelium. Several med-
ications taken by AIDS patients (e.g., ketoconazole,
clofazimine, pyrimethamine, zidovudine) may cause
the increased melanin pigmentation. Adrenocortical
destruction has been reported from several of the
infections associated with AIDS, resulting in an addi-
sonian pattern of pigmentation. Finally, pigmentation
with no apparent cause has arisen in HIV-infected
patients, and some investigators have theorized that
this may be a direct result of the HIV infection.
Fig. 7-48 HIV-associated periodontitis with necrotizing
stomatitis. Diffuse gingival necrosis with extension onto
alveolar mucosa.
Fig. 7-49 HIV-associated necrotizing stomatitis. Massive
necrosis of soft tissue and bone of the anterior maxilla. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 275
HIV-ASSOCIATED SALIVARY GLAND DISEASE
HIV-associated salivary gland disease also can arise
anytime during infection. Clinically obvious salivary
gland disease is noted in approximately 5% to 10% of
HIV-infected patients, with a greater prevalence noted
in children. The main clinical sign is salivary gland
enlargement, particularly affecting the parotid. Bilat-
eral involvement is seen in about 60% of patients with
glandular changes and often is associated with cervical
lymphadenopathy.
As a result of a genetically inﬂuenced alteration of
the immune response to HIV infection, some patients
develop diffuse inﬁltrative lymphocytosis syn-
drome (DILS), which is associated with a more
favorable prognosis for their HIV infection but also
associated with a forty-fourfold greater chance of lym-
phoma. Affected individuals reveal CD8 lymphocyto-
sis and lymphadenopathy, along with salivary gland
enlargement. Although the pathosis may involve any
of the major or minor salivary glands, the parotid is
affected most commonly. Other sites of involvement
include the lacrimal glands, kidneys, muscles, nerves,
and lungs. The glandular involvement arises from
CD8-lymphocytic inﬁltration and often is followed by
lymphoepithelial cyst formation in the parotid.
The most widely accepted therapy for DILS is oral
prednisone or antiretroviral therapy, although some
patients have been treated with parotidectomy or radi-
ation therapy. The effect of HAART is unclear. Some
investigators have reported an increased prevalence
(possibly because of partial immune reconstitution),
whereas others have noted regression after initiation of
antiviral therapy. Because of the increased risk for
B-cell lymphoma, observation with histopathologic
monitoring by ﬁne-needle aspiration is recommended
by some. In patients with large lymphoepithelial
cysts, aspiration or sclerotherapy with tetracycline or
doxycycline has been associated with temporary
improvement. Associated xerostomia is variable and
treated in a manner similar to that of cases associated
with non-HIV disease (i.e., maintenance of good
oral health and the use of sialogogues and saliva
substitutes).
THROMBOCYTOPENIA
Thrombocytopenia (see page 584) has been reported
in up to 40% of patients with HIV infection, may occur
at any time during the course of the disease, and
frequently is the ﬁrst clinical manifestation of HIV
infection. The causes are diverse and include direct
infection by HIV, immune dysfunction, alteration of
platelet production, loss because of associated infec-
tious diseases, and drug reactions. Cutaneous lesions
are present in most cases, but oral lesions do occur
with petechiae, ecchymosis, or spontaneous gingival
hemorrhage.
Platelets have been shown to engulf HIV and play
an important role in the immune response to the virus.
HIV-infected patients with extended thrombocytope-
nia have demonstrated decreased survival. HAART
has reduced the prevalence of thrombocytopenia
and is the ﬁrst line of defense. Additional therapies
used in nonresponsive patients include splenectomy,
intravenous immunoglobulin (IVIG), IV anti-Rho
immunoglobulin (anti-D), and transfusion of platelets.
Corticosteroids, danazol, and vinca alkaloids are addi-
tional approaches proven to be effective in the general
population but associated with increased risks in HIV-
infected patients.
HERPES SIMPLEX VIRUS
Recurrent HSV infections occur in about the same
percentage of HIV-infected patients as they do in the
immunocompetent population (10% to 15%); however,
the lesions are more widespread, occur in an atypical
pattern, and may persist for months (Fig. 7-50). The
prevalence of HSV lesions increases signiﬁcantly once
the CD4+ count drops below 50 cells/mm
3
. Herpes
labialis may extend to the facial skin and exhibit exten-
sive lateral spread. Persistence of active sites of HSV
infection for more than 1 month in a patient infected
with HIV is one accepted deﬁnition of AIDS. The clini-
cal presentations of recurrences in immunocom-
promised patients and appropriate therapy and
maintenance have been discussed in the text on her-
pesvirus (see page 244).
As mentioned in the discussion of necrotizing sto-
matitis, evaluation for HSV should be performed in all
persistent oral ulcerations in HIV-infected individuals.
In these ulcerations, investigators have discovered
HSV in 10% to 19% (with an additional 10% to 28%
exhibiting coinfection by HSV and CMV).
Fig. 7-50 HIV-associated recurrent herpetic infection.
Mucosal erosion of the anterior dorsal surface of the tongue
on the left side. Note the yellowish circinate border. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

276 ORAL AND MAXILLOFACIAL PATHOLOGY
VARICELLA-ZOSTER VIRUS
Recurrent varicella-zoster virus (VZV) infection
(herpes zoster) is fairly common in HIV-infected
patients, but the course is more severe, with increased
morbidity and mortality rates. Many of these patients
are younger than age 40, in contrast to cases in immu-
nocompetent patients that usually arise later in life. In
the early stages of HIV-related immunosuppression,
herpes zoster usually is conﬁned to a dermatome but
persists longer than usual. In full-blown AIDS, herpes
zoster usually begins in a classic dermatomal distribu-
tion; however, subsequent cutaneous dissemination is
not unusual. When present intraorally, the involve-
ment often is severe and occasionally leads to bone
sequestration and loss of teeth. In many instances, the
associated osteonecrosis and tooth exfoliation may be
delayed a month or more after the initial onset of the
herpes zoster. Associated pain typically is intense.
Although peroral antiviral medications are beneﬁcial
in immunocompetent patients, intravenous acyclovir is
recommended for severe herpes zoster in the absence
of an intact immune system.
HUMAN PAPILLOMAVIRUS
Human papillomavirus (HPV) is responsible for several
facial and oral lesions in immunocompetent patients,
the most frequent of which are the verruca vulgaris
(common wart) (see page 364) and oral squamous
papilloma (see page 362). An increased prevalence of
HPV-related lesions is noted in HIV-infected patients,
and most are located in the anogenital areas. Oral
involvement also may be seen. Although usual types of
HPV may be present in intraoral lesions, HIV-infected
patients often demonstrate more unusual variants such
as HPV-7 (associated with butcher’s warts) or HPV-32
(often noted in multifocal epithelial hyperplasia) (see
page 367).
An increased prevalence of HPV-related lesions has
been reported from several centers in patients respond-
ing to HAART. Although the exact cause is not clear,
some wonder if the virus remains latent in many
patients until partial immune reconstitution leads to a
local inﬂammatory response, viral reactivation, and the
initiation of clinically evident lesions. In several cohorts,
the risk of oral HPV lesions increased with the effec-
tiveness of the antiretroviral therapy.
The oral lesions usually are multiple and may be
located on any mucosal surface. The labial mucosa,
tongue, buccal mucosa, and gingiva are frequent sites.
The lesions may exhibit a cluster of white, spikelike
projections, pink cauliﬂower-like growths, or slightly
elevated sessile papules (Fig. 7-51).
Histopathologically, the lesions may be sessile or
papillary and covered by acanthotic or even hyperplas-
tic stratiﬁed squamous epithelium (Fig. 7-52). The
A
B
Fig. 7-51 HIV-associated human papillomavirus (HPV)
infection. Multiple exophytic and somewhat papillary
nodules of the lip, buccal mucosa, and gingiva.
Fig. 7-52 HIV-associated human papillomavirus (HPV)
infection. Oral mucosa exhibiting acanthosis and mild
nuclear pleomorphism. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 277
affected epithelium often demonstrates vacuolization
of numerous epithelial cells (i.e., koilocytosis) and occa-
sionally may exhibit mild variation in nuclear size (Fig.
7-53). Immunohistochemistry or DNA in situ hybrid-
ization often is used to conﬁrm the presence and type
of HPV within histopathologic specimens (Fig. 7-54).
Dysplasia has been noted within HPV-related lesions
in patients with AIDS and mandates close observation
of affected patients for development of squamous cell
carcinoma. The treatment of choice is surgical removal;
however, recurrences are common, especially in
patients with signiﬁcant immune deﬁciency. Other
therapeutic modalities that have been used include
topical podophyllin, imiquimod, interferon, cryosur-
gery, laser ablation, and electrocoagulation. If one of
the latter two choices is used, the surgical team must
be wary of the resultant plume that may contain infec-
tious HPV.
OTHER ORAL AND MAXILLOFACIAL
LESIONS SEEN IN HIV INFECTION
HISTOPLASMOSIS
Histoplasmosis, the most common endemic respira-
tory fungal infection in the United States, is produced
by Histoplasma capsulatum (see page 224). In healthy
patients the infection typically is subclinical and self-
limiting, but clinically evident infections do occur in
immunocompromised individuals. Although a number
of deep fungal infections are possible in patients with
AIDS, histoplasmosis is the most common, with dis-
seminated disease noted in approximately 5% of AIDS
patients residing in areas where the fungus is endemic.
In patients with AIDS, diagnosis of histoplasmosis also
has been documented in nonendemic areas, possibly
from reactivation of a previous subclinical infection.
The signs and symptoms associated with dissemina-
tion are nonspeciﬁc and include fever, weight loss,
splenomegaly, and pulmonary inﬁltrates. Oral lesions
are not uncommon and usually are caused by blood-
borne organisms or spread from pulmonary involve-
ment. On occasion, the initial diagnosis is made from
the oral changes, with some patients demonstrating
involvement isolated to the oral cavity. Although intra-
bony infection in the jaws has been reported, the most
common oral presentation of histoplasmosis is a
chronic, indurated mucosal ulceration with a raised
border (Fig. 7-55). The oral lesions may be single or
multiple, and any area of the oral mucosa may be
involved.
Microscopically, the small fungal organisms are
visible within the cytoplasm of histiocytes and
Fig. 7-53 HIV-associated human papillomavirus (HPV)
infection. Oral mucosa exhibiting extensive koilocytosis in
the superﬁcial spinous cell layer.
Fig. 7-54 HIV-associated human papillomavirus (HPV)
infection. DNA in situ hybridization of oral mucosal biopsy
that reveals diffuse cellular positivity for HPV.
Fig. 7-55 HIV-associated histoplasmosis. Indurated
ulceration with a rolled border on the dorsal surface of the
tongue on the right side. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

278 ORAL AND MAXILLOFACIAL PATHOLOGY
multinucleated giant cells. These phagocytic cells may
be present in sheets or in organized granulomas (Fig.
7-56). The therapy of choice for disseminated histo-
plasmosis has been intravenous amphotericin B, but
itraconazole has been shown to be effective with fewer
adverse reactions and better patient compliance. Keto-
conazole is another alternative, but its hepatotoxicity
makes this approach a less desirable form of therapy.
APHTHOUS ULCERATIONS
Lesions that are clinically similar to aphthous ulcer-
ations occur with increased frequency in patients
infected with HIV. All three forms (minor, major, and
herpetiform) are seen; surprisingly, however, almost
two thirds of the patients have the usually uncom-
mon herpetiform and major variants (Fig. 7-57). As
immunosuppression becomes more profound, major
aphthous ulcerations demonstrate an increased
prevalence.
Treatment with potent topical or intralesional corti-
costeroids has been successful in a number of patients.
Not all lesions respond, and recurrences are common.
Secondary candidiasis may be a complication of
therapy. Systemic corticosteroid drugs also may prove
beneﬁcial but typically are avoided in an attempt to
prevent further immune depression. For lesions non-
responsive to topical corticosteroids, thalidomide has
been found to be advantageous in many patients. Tha-
lidomide must be used cautiously for only a short term
because of its association with an irreversible periph-
eral neuropathy and its ability to enhance the produc-
tion of HIV. In a limited number of patients, granulocyte
colony-stimulating factor (G-CSF) has produced rapid
and sustained resolution of aphthous ulcerations that
were resistant to therapy with topical corticosteroids,
cyclosporine, and thalidomide.
Biopsy of any chronic mucosal ulceration clinically
diagnosed as an aphthous ulceration should be consid-
ered if the lesion is atypical clinically or does not
respond to therapy (Fig. 7-58). In such cases, biopsy
often reveals another cause, such as HSV, CMV, deep
fungal infection, or neoplasia. (For further information
on aphthous ulcerations and the pathogenesis of these
lesions in patients infected with HIV, see page 331.)
MOLLUSCUM CONTAGIOSUM
Molluscum contagiosum is an infection of the skin
caused by a poxvirus (see page 371). The lesions are
small, waxy, dome-shaped papules that often demon-
strate a central depressed crater. In immunocompe-
tent individuals, the lesions are self-limiting and
typically involve the genital region or trunk. In patients
with AIDS, hundreds of lesions may be present, with
many exhibiting little tendency to undergo spontane-
ous resolution, and some occasionally obtaining large
size. Approximately 5% to 10% of HIV-infected patients
Fig. 7-56 HIV-associated histoplasmosis. Mucosal biopsy
in which the connective tissue is ﬁlled with numerous
clusters of small fungal organisms.
Fig. 7-57 HIV-associated aphthous ulceration. Large
superﬁcial ulceration of the posterior soft palate.
Fig. 7-58 HIV-associated ulceration. Atypical mucosal
ulceration that mandates biopsy and may be attributable to a
variety of causes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 279
are affected, and the facial skin commonly is involved
(Fig. 7-59). Rare intraoral examples of molluscum con-
tagiosum have been reported, appearing as erythema-
tous papules. These lesions may involve either the
keratinized or nonkeratinized mucosa.
Histopathologically, the surface epithelium forms
several hyperplastic downgrowths. This involuting epi-
thelium contains numerous large, intracytoplasmic
inclusions known as molluscum bodies (Fig. 7-60). In
the center of the lesion, the keratin layer often disinte-
grates and releases the adjacent molluscum bodies,
hence the central crater.
Numerous reports have documented resolution of
widespread and recalcitrant lesions after successful
initiation of HAART. It is not known if these responses
are secondary to immune reconstitution or the antivi-
ral effects of the therapy. Because viral particles have
been identiﬁed in perilesional skin of HIV-infected
patients, local therapy (e.g., curettage, cryosurgery,
cautery, photodynamic therapy, podophyllotoxin) often
is associated with recurrences. Anecdotal reports of
positive responses to immunomodulatory (imiquimod)
or antiviral therapy (cidofovir) have been documented
in severely immunocompromised patients with previ-
ously recalcitrant disease.
ORAL SQUAMOUS CELL CARCINOMA
Squamous cell carcinoma of the oral cavity, pharynx,
and larynx has been reported in HIV-infected patients.
These neoplasms are associated with the same cancer
risk factors as the general population but tend to occur
at a younger age. Similar clinical presentations and
anatomic distribution of these carcinomas are noted
(Fig. 7-61). It appears that HIV infection may acceler-
ate the development of squamous cell carcinoma, pos-
sibly because of impaired immune surveillance.
Treatment of squamous cell carcinoma is not signiﬁ-
cantly different for HIV-infected patients and consists
of surgical resection, radiation therapy, or combined
radiation and chemotherapy. Clinical staging can be
problematic because of HIV-related cervical lymph-
adenopathy. In these cases, cross-sectional computed
tomography (CT) or magnetic resonance imaging (MRI)
could be performed in an attempt to distinguish lymph
nodes enlarged by lymphoproliferative disease from
those containing metastatic carcinoma. The majority of
HIV-infected patients with a diagnosis of squamous
cell carcinoma have advanced disease and exhibit a
less favorable prognosis.
Fig. 7-59 HIV-associated molluscum contagiosum.
Numerous perioral papules.
Fig. 7-60 HIV-associated molluscum contagiosum.
Downgrowth of surface epithelium exhibiting numerous
“molluscum bodies.”
Fig. 7-61 HIV-associated squamous cell carcinoma.
Ulceration with raised, indurated borders on the lateral
tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

280 ORAL AND MAXILLOFACIAL PATHOLOGY
DIAGNOSIS
Conﬁrmation of HIV infection can be made by viral
culture or by detection of HIV antibodies or antigens.
The standard screening tool is the enzyme immunoas-
say (EIA) for antibodies to HIV. This test can have false-
positive results or cross-reactions; therefore, it should
be repeated and followed by the more accurate
Western blot antibody assay. Other alternatives include
radioimmunoprecipitation (RIPA), rapid latex aggluti-
nation assay, and dot-blot immunobinding assay. All
of these evaluations are used to detect antibodies to
HIV.
In an attempt to improve the safety of the blood
supply, a few assays have been approved by the FDA
to detect viral antigens before development of anti-HIV
antibodies. These tests are not used widely and include
the p24 antigen capture assay and polymerase chain
reaction (PCR) for detection of HIV DNA that may be
integrated into the host DNA. This latter method may
be used to identify someone who was infected recently
or HIV carriers who otherwise have negative antigen
or antibody ﬁndings.
The diagnosis of AIDS is indicated if the patient has
laboratory evidence of HIV infection combined with
documentation of less than 200 CD4+ T lymphocytes
per microliter or a CD4+ T-lymphocyte percentage of
total lymphocytes that is less than 14. In addition, the
diagnosis of AIDS can be made in an HIV-infected
person if one of the indicator diseases listed in Box 7-2
has been documented.
TREATMENT AND PROGNOSIS
As mentioned previously, HIV infection initially was
considered fatal; however, the introduction of HAART
has altered the course of the epidemic. A wide variety
of antiretroviral agents is available and continues to
expand (Box 7-3), increasing the effectiveness of
medical therapy. Although numerous drug combina-
tions are possible, HAART often consists of two nucleo-
side analogue reverse-transcriptase inhibitors, at least
one protease inhibitor, and/or one nonnucleoside
analogue reverse-transcriptase inhibitor. Alternatively,
one nucleoside analogue reverse-transcriptase inhibi-
tor can be combined with one nonnucleoside ana-
logue reverse-transcriptase inhibitor and one protease
inhibitor.
The current therapeutic approaches have driven
HIV to undetectable levels in many patients, with a
resultant clinically signiﬁcant reconstitution of the
immune system. With the current antiretroviral medi-
cations, total HIV eradication would take at least a
decade and presently is not a realistic goal. Although
no cure exists, survival times are increasing as a result
of earlier diagnosis and improved therapy.
Although antiretroviral therapy is effective for many
patients, it is expensive. In addition, this treatment
often is associated with signiﬁcant adverse reactions,
may not be effective in all patients, or may fail after a
period of initial success. Work is proceeding toward
the development of a safe and effective vaccine against
HIV infection, but complex issues slow the progress.
Advances in therapy and prevention of HIV infection
occur daily; however, the best defense against the
disease is prevention of the initial infection.
Despite the continuing advances in medical therapy
and the ongoing work toward a successful vaccine,
many of the positive gains against the epidemic have
been achieved through epidemiologically directed
public health interventions. The ever-changing data
Box 7-2
Indicator Diseases Used in the
Diagnosis of Acquired
Immunodeﬁciency Syndrome
1.Candidiasis of bronchi, trachea, or lungs
2.Candidiasis, esophageal
3.Cervical cancer, invasive
4.Coccidioidomycosis, disseminated or
extrapulmonary
5.Cryptococcosis, extrapulmonary
6.Cryptosporidiosis, chronic intestinal (>1 month’s
duration)
7.Cytomegalovirus disease (other than liver, spleen,
or nodes)
8.Cytomegalovirus-induced retinitis (with loss of
vision)
9.Encephalopathy, HIV-related
10.Herpes simplex: chronic ulcer or ulcers (>1
month’s duration) or bronchitis, pneumonitis, or
esophagitis
11.Histoplasmosis, disseminated or extrapulmonary
12.Isosporiasis, chronic intestinal (>1 month’s duration)
13.Kaposi’s sarcoma (KS)
14.Lymphoma, Burkitt’s (or equivalent term)
15.Lymphoma, immunoblastic (or equivalent term)
16.Lymphoma, primary, of brain
17.Mycobacterium avium complex or M. kansasii,
disseminated or extrapulmonary
18.Mycobacterium tuberculosis, any site (pulmonary or
extrapulmonary)
19.Mycobacterium, other species or unidentiﬁed
species, disseminated, or extrapulmonary
20.Pneumocystis carinii pneumonia
21.Pneumonia, recurrent
22.Progressive multifocal leukoencephalopathy
23.Salmonella septicemia, recurrent
24.Toxoplasmosis of brain
25.Wasting syndrome as a result of AIDS
HIV, Human immunodeﬁciency virus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 281
continue to be important and highlight increasingly
important areas (e.g., increasing prevalence in hetero-
sexuals and blacks) for present and future interven-
tions. Routine HIV testing is critical, because it
represents the best avenue toward life-saving early
therapy and prevention of HIV transmission to others.
It is estimated that more than 300,000 individuals in
the United States are unaware that they are infected
with HIV. To appropriately emphasize early diagnosis
and prevention, the CDC recommends HIV testing
as a part of routine clinical care in all health care
settings.
Some health professionals have been concerned
about the risk of occupational transmission of HIV. The
average risk of seroconversion after a percutaneous
exposure to HIV-infected blood is estimated to be
approximately 0.3%. Mucous membrane exposure to
HIV-infected blood results in seroconversion in only
0.09% of cases, and the rate is even lower after a non-
intact skin exposure. The risk of transmission after
exposure to ﬂuids or tissues other than blood has not
been quantiﬁed but most likely is considerably lower.
On exposure to HIV-contaminated material, the risk of
seroconversion can be reduced by greater than 75%
through postexposure prophylaxis (PEP) with antiret-
roviral medications if initiated within hours of the
event. Four weeks of therapy is recommended;
however, this often is difﬁcult to complete because of
adverse reactions; therefore, the regimen probably
should not be used for exposures that pose a negligible
risk for transmission. The basic PEP consists of a two-
drug regimen that may be expanded to a three-drug
combination for more severe exposures. Because of the
complexity of choosing and administering the regimen,
involvement of an infectious disease specialist or a phy-
sician experienced in antiretroviral therapy is strongly
recommended. Regardless, promptness in the initia-
tion of the therapy is paramount.
BIBLIOGRAPHY
Herpes Simplex Virus
Amir J: Clinical aspects and antiviral therapy in primary herpetic
gingivostomatitis, Paediatr Drugs 3:593-597, 2001.
Arduino PG, Porter SR: Oral and perioral herpes simplex virus
type I (HSV-I) infection: review of its management, Oral Dis
12:254-270, 2006.
Chilukuri S, Rosen T: Management of acyclovir-resistant herpes
simplex virus, Dermatol Clin 21:311-320, 2003.
Cohen PR, Kazi S, Grossman ME: Herpetic geometric glossitis:
a distinctive pattern of lingual herpes simplex virus infection,
South Med J 88:1231-1235, 1995.
Cohen SG, Greenberg MS: Chronic oral herpes simplex virus
infection in immunocompromised patients, Oral Surg Oral
Med Oral Pathol 59:465-471, 1985.
Flaitz CM, Nichols CM, Hicks MJ: Herpesviridae-associated per-
sistent mucocutaneous ulcers in acquired immunodeﬁciency
syndrome: a clinicopathologic study, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 81:433-441, 1996.
Hess GP, Walson PD: Seizures secondary to oral viscous lido-
caine, Ann Emerg Med 17:725-727, 1988.
Huber MA: Herpes simplex type-1 virus infection, Quintessence
Int 34:453-457, 2003.
Juretic´ M: Natural history of herpetic infection, Helv Paediatr Acta
21(4):356-368, 1966.
Kameyama T, Futami M, Nakayoshi N et al: Shedding of herpes
simplex virus type I into saliva in patients with orofacial frac-
ture, J Med Virol 28:78-80, 1989.
Kameyama T, Sujaku C, Yamamoto S et al: Shedding of herpes
simplex virus type 1 into saliva, J Oral Pathol 17:478-481,
1988.
Kolokotronis A, Doumas S: Herpes simplex virus infection, with
particular reference to the progression and complications of
primary herpetic gingivostomatitis, Clin Microbiol Infect
12:202-211, 2006.
Krause PR, Straus SE: Herpesvirus vaccines. Development, con-
troversies, and applications, Infec Dis Clin North Am 13:61-81,
1999.
Jensen LA, Hoehns JD, Squires CL: Oral antivirals for the acute
treatment of recurrent herpes labialis, Ann Pharmacother
38:705-709, 2004.
Nahmias AJ: Sero-epidemiological and -sociological patterns of
herpes simplex virus infection in the world, Scand J Infect Dis
Suppl 69:19-36, 1990.
Nesbit SP, Gobetti JP: Multiple recurrence of oral erythema
multiforme after secondary herpes simplex: report of case
and review of literature, J Am Dent Assoc 112:348-352,
1986.
Overall JC: Oral herpes simplex: pathogenesis, clinical and viro-
logic course, approach to treatment. In Hooks JJ, Jordan G:
Viral infections in oral medicine, pp 53-78, New York, 1982,
Elsevier.
Park JB, Park N: Effect of chlorhexidine on the in vitro and in
vivo herpes simplex virus infection, Oral Surg Oral Med Oral
Pathol 67:149-153, 1989.
Box 7-3
Antiretroviral Therapy
1. Nucleoside reverse-transcriptase inhibitors
●Abacavir, didanosine, emtricitabine, lamivudine,
stavudine, tenofovir, zalcitabine, or zidovudine
2. Nucleotide reverse-transcriptase inhibitors
●Adefovir or tenofovir
3. Nonnucleoside reverse-transcriptase inhibitors
●Capravirine, delavirdine, efavirenz, emivirine, or
nevirapine
4. Protease inhibitors
●Amprenavir, atazanavir, darunavir, fosamprenavir,
indinavir, lopinavir/ritonavir, nelﬁnavir, ritonavir,
saquinavir, saquinavir-SGC, or tipranavir
5. Fusion inhibitors
● Enfuvirtide
6. Integrase inhibitors
● MK-0518 (experimental)
7. CCR5 inhibitors
●Maraviroc (experimental), vicriviroc (experimental) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

282 ORAL AND MAXILLOFACIAL PATHOLOGY
Parlette EC, Polo JM: Inoculation herpes barbae, Skinmed 4:186-
187, 2005.
Raborn GW, Grace MGA: Recurrent herpes simplex labialis:
selected therapeutic options, J Can Dent Assoc 69:498-503,
2003.
Raborn GW, Martel AY, Lassonde M et al: Effective treatment of
herpes simplex labialis with penciclovir cream. Combined
results of two trials, J Am Dent Assoc 133:303-309, 2002.
Scott DA, Coulter WA, Lamey P-J: Oral shedding of herpes
simplex virus type 1: a review, J Oral Pathol Med 26:441-447,
1997.
Spruance SL, Freeman DJ, Stewart JC et al: The natural history
of ultraviolet radiation–induced herpes simplex labialis and
response to therapy with perioral and topical formulations of
acyclovir, J Infect Dis 163:728-734, 1991.
Spruance SL, Nett R, Marbury T et al: Acyclovir cream for treat-
ment of herpes simplex labialis: results of two randomized,
double-blind, vehicle-controlled, multicenter clinical trials,
Antimicrob Agents Chemother 46:2238-2243, 2002.
Starr JR, Daling JR, Fitzgibbons ED et al: Serologic evidence of
herpes simplex virus 1 infection and oropharyngeal cancer
risk, Cancer Res 61:8459-8464, 2001.
Stanberry LR: Herpes: vaccines for HSV, Dermatol Clin 16:811-
816, 1998.
Stoopler ET, Greenberg MS: Update on herpesvirus infections,
Dent Clin North Am 47:517-532, 2003.
Weathers DR, Grifﬁn JW: Intraoral ulcerations of recurrent
herpes simplex and recurrent aphthae: two distinct clinical
entities, J Am Dent Assoc 81:81-88, 1970.
Woo, S-K, Challacombe SJ: Management of recurrent oral herpes
simplex infections, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 103(suppl 1):S12.e1-S12.e18, 2007.
Wormser GP, Mack L, Lenox T et al: Lack of effect of oral acy-
clovir on prevention of aphthous stomatitis, Otolaryngol Head
Neck Surg 98:14-17, 1988.
Varicella-Zoster Virus
Alper BS, Lewis PR: Does treatment of acute herpes zoster
prevent or shorten postherpetic neuralgia? J Fam Pract
49:255-264, 2000.
Badger GR: Oral signs of chickenpox (varicella): report of two
cases, J Dent Child 47:349-351, 1980.
Balfour HH Jr, Bean B, Laskin OL et al: Acyclovir halts progres-
sion of herpes zoster in immunocompromised patients, N
Engl J Med 308:1448-1453, 1983.
Barrett AP, Katelaris CH, Morris JGL et al: Zoster sine herpete
of the trigeminal nerve, Oral Surg Oral Med Oral Pathol 75:173-
175, 1993.
Centers for Disease Control and Prevention: Decline in annual
incidence of varicella-selected states, MMWR Morb Mortal
Wkly Rep 52:884-885, 2003.
Centers for Disease Control and Prevention: A new product
(VariZIG) for postexposure prophylaxis of varicella available
under an investigational new drug application expanded
access protocol, MMWR Morb Mortal Wkly Rep 55:209-210,
2006.
Centers for Disease Control and Prevention: CDC’s advisory com-
mittee recommends “shingles” vaccination. Available at http://
www.cdc.gov/od/media/pressrel/r061026.htm. Accessed
December 21, 2007.
Dunkle LM, Arvin AM, Whitley RJ et al: A controlled trial of
acyclovir for chickenpox in normal children, N Engl J Med
325:1539-1544, 1991.
Furuta Y, Ohtani F, Aizawa H et al: Varicella-zoster virus reacti-
vation is an important cause of acute peripheral facial paraly-
sis in children, Pedatric Infect Dis 24:97-101, 2005.
Gilden DH, Cohrs RJ, Hayward AR et al: Chronic varicella-zoster
virus ganglionitis—possible cause of postherpetic neuralgia,
J Neurovirol 9:404-407, 2003.
Kolokotronis A, Louloudiadis K, Fotiou G et al: Oral manifesta-
tions of infections due to varicella zoster virus in otherwise
healthy children, J Clin Pediatr Dent 25:107-112, 2001.
Lieberman JM, Williams WR, Miller JM et al: The safety and
immunogenicity of a quadrivalent measles, mumps, rubella
and varicella vaccine in healthy children. A study of manu-
facturing consistency and persistence of antibody, Pediatr
Infect Dis J 25:615-622, 2006.
Meer S, Coleman H, Altini M et al: Mandibular osteomyelitis and
tooth exfoliation following zoster-CMV co-infection, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 101:70-75, 2006.
Mendieta C, Miranda J, Brunet LI et al: Alveolar bone necrosis
and tooth exfoliation following herpes zoster infection: a
review of the literature and case report, J Periodontol 76:148-
153, 2005.
Ogita S, Terada K, Niizuma T et al: Characteristics of facial nerve
palsy during childhood in Japan: frequency of varicella-zoster
virus association, Pediatr Int 48:245-249, 2006.
Oxman MN, Levin MJ, Johnson GR et al: A vaccine to prevent
herpes zoster and postherpetic neuralgia in older adults, N
Engl J Med 352:2271-2284, 2005.
Stankus SJ, Dlugopolski M, Packer D: Management of herpes
zoster (shingles) and postherpetic neuralgia, Am Fam Physi-
cian 61:2437-2448, 2000.
Straus SE, Ostrove JM, Inchauspe G et al: NIH conference.
Varicella-zoster virus infections. Biology, natural history,
treatment and prevention, Ann Intern Med 108:221-237,
1988.
Wutzler P: Antiviral therapy of herpes simplex and varicella-
zoster virus infections, Intervirology 40:343-356, 1997.
Infectious Mononucleosis
Courant P, Sobkov T: Oral manifestations of infectious mononu-
cleosis, J Periodontol 40:279-283, 1979.
Fraser-Moodie W: Oral lesions in infectious mononucleosis, Oral
Surg Oral Med Oral Pathol 12:685-691, 1959.
Har-EI G, Josephsen JS: Infectious mononucleosis complicated
by lingual tonsillitis, J Laryngol Otol 104:651-653, 1990.
Niedobitek G, Meru N, Delecluse H-J: Epstein-Barr virus infec-
tion and human malignancies, Int J Exp Pathol 82:149-170,
2001.
Roberge RJ, Simon M, Russell M et al: Lingual tonsillitis: an
unusual presentation of mononucleosis, Am J Emerg Med
19:173-175, 2001.
Ryan C, Dutta C, Simo R: Role of screening for infectious mono-
nucleosis in patients admitted with isolated, unilateral peri-
tonsillar abscess, J Laryngol Otol 118:362-365, 2004.
Slote J, Saygun I, Sabeti M et al: Epstein-Barr virus in oral dis-
eases, J Periodontol Res 41:235-244, 2006.
Torre D, Tambini R: Acyclovir for treatment of infectious mono-
nucleosis: a meta-analysis, Scand J Infect Dis 31:543-547,
1999.
van der Horst C, Joncas J, Ahronheim G et al: Lack of effect of
peroral acyclovir for the treatment of acute infectious mono-
nucleosis, J Infect Dis 164:788-791, 1991.
Cytomegalovirus
Bonnet F, Neau D, Viallard J-F et al: Clinical and laboratory ﬁnd-
ings of cytomegalovirus infection in 115 hospitalized non-
immunocompromised adults, Ann Med Interne (Paris)
152:227-235, 2001.
Epstein JB, Scully C: Cytomegalovirus: a virus of increasing rele-
vance to oral medicine and pathology, J Oral Pathol Med
22:348-353, 1993. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 7 VIRAL INFECTIONS 283
Epstein JB, Sherlock CH, Wolber RA: Oral manifestations of
cytomegalovirus infection, Oral Surg Oral Med Oral Pathol
75:443-451, 1993.
Flaitz CM, Nichols CM, Hicks MJ: Herpesviridae-associated per-
sistent mucocutaneous ulcers in acquired immunodeﬁciency
syndrome: a clinicopathologic study, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 81:433-441, 1996.
Guntinas-Lichius O, Wagner M, Krueger GRF et al: Severe acute
cytomegalovirus sialadenitis in an immunocompetent adult:
case report, Clin Infect Dis 22:1117-1118, 1996.
Jones AC, Freedman PD, Phelan JA et al: Cytomegalovirus infec-
tions of the oral cavity: a report of six cases and review of the
literature, Oral Surg Oral Med Oral Pathol 75:76-85, 1993.
Regezi JA, Eversole LR, Barker BF et al: Herpes simplex and
cytomegalovirus coninfected oral ulcers in HIV-infected
patients, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
81:55-62, 1996.
Schubert MM, Epstein JB, Lloid ME: Oral infections due to cyto-
megalovirus in immunocompromised patients, J Oral Pathol
Med 22:268-273, 1993.
Slots J: Update on human cytomegalovirus in destructive peri-
odontal disease, Oral Microbiol Immunol 19:217-223, 2004.
Stagno S, Pass RF, Thomas JP et al: Defects of tooth structure in
congenital cytomegalovirus infection, Pediatrics 69:646-648,
1982.
Torres R, Cottrell D, Reebye UN: Ulcerative tongue lesion sec-
ondary to cytomegalovirus, J Mass Dent Soc 53:36-37, 2004.
Enteroviruses
Buchner A: Hand, foot, and mouth disease, Oral Surg Oral Med
Oral Pathol 41:333-337, 1976.
Khetsuriani N, Lamonte-Fowlkes A, Oberst S et al: Enterovirus
surveillance—United States, 1970-2005, MMWR Surveill
Summ 55:1-20, 2006.
Chang L-Y, Lin T-Y, Huang Y-C et al: Comparison of enterovirus
71 and coxsackievirus A16 clinical illnesses during the
Taiwan enterovirus epidemic, 1998, Pediatr Infect Dis J
18:1092-1096, 1999.
Ho M, Hsu K-H, Twu S-J et al: An epidemic of enterovirus 71
infection in Taiwan, N Engl J Med 341:929-935, 1999.
Ornoy A, Tenenbaum A: Pregnancy outcome following infec-
tions by coxsackie, echo, measles, mumps, hepatitis, polio and
encephalitis viruses, Reprod Toxicol 21:446-457, 2006.
Steigman AJ, Lipton MM, Braspennickx H: Acute lymphonodu-
lar pharyngitis: a newly described condition due to coxsackie
virus, J Pediatr 61:331-336, 1962.
Rubeola
Kaplan LJ, Daum RS, Smaron M et al: Severe measles in immu-
nocompromised patients, JAMA 267:1237-1241, 1992.
Koplik H: The diagnosis of the invasion of measles from a study
of the exanthema as it appears on the buccal mucosa mem-
brane, Arch Pediatr 13:918-922, 1896.
Nozawa Y, Ono N, Abe M et al: An immunohistochemical study
of Warthin-Finkeldey cells in measles, Pathol Int 44:442-447,
1994.
Pomerance HH: The usual childhood diseases: forgotten but not
gone, Fetal Pediatr Pathol 24:169-189, 2005.
Roberts GBS, Bain AD: The pathology of measles, J Pathol Bacte-
riol 76:111-118, 1958.
Suringa DWR, Bank LJ, Ackerman AB: Role of measles virus in
skin lesions and Koplik’s spots, N Engl J Med 283:1139-1142,
1970.
Warthin AS: Occurrence of numerous large giant cells in the
tonsils and pharyngeal mucosa in the prodromal stage of
measles, Arch Pathol 11:864-874, 1931.
Rubella
Centers for Disease Control and Prevention: Elimination of
rubella and congenital rubella syndrome—United States,
1969-2004, MMWR Morb Mortal Wkly Rep 54:279-282,
2005.
Forchheimer F: German measles (Rubella). In Stedman TL:
Twentieth century practice, an international encyclopedia of modern
medical science by leading authorities of Europe and America, pp
175-188, New York, 1898, W Wood.
Pomerance HH: The usual childhood diseases: forgotten but not
gone, Fetal Pediatr Pathol 24:169-189, 2005.
Watson JC, Hadler SC, Dykewicz CA et al: Measles, mumps, and
rubella—vaccine use and strategies for elimination of measles,
rubella, and congenital rubella syndrome and control of
mumps: recommendations of the Advisory Committee on
Immunization Practices (ACIP), Morb Mortal Wkly Rep 47(RR-
8):1-57, 1998.
Mumps
Anonymous: Global status of mumps immunization and surveil-
lance, Wkly Epidemiol Rec 80:418-424, 2005.
Campos-Outcalt D: Mumps epidemic in 2006: are you prepared
to detect and prevent it? J Fam Pract 55:500-502, 2006.
Centers for Disease Control and Prevention: Update: mumps
activity—United States, January 1-October 7, 2006, MMWR
Morb Mortal Wkly Rep 55:1152-1153, 2006.
Centers for Disease Control and Prevention: Updated recom-
mendations of the Advisory Committee on Immunization
Practices (ACIP) for the control and elimination of mumps,
MMWR Morb Mortal Wkly Rep 55:629-630, 2006.
Linder TE, Brestel R, Schlegel C: Mumps virus infection: case
report of an unusual head and neck manifestation, Am J Oto-
laryngol 17:420-423, 1996.
van Loon FP, Holmes SJ, Sirotkin BI et al: Mumps surveillance—
United States 1988-1993, MMWR CDC Surveill Summ 44:1-
14, 1995.
Human Immunodeﬁciency Virus and Acquired
Immunodeﬁciency Syndrome
Baccaglini L, Atkinson JC, Patton LL et al: Management of oral
lesions in HIV-positive patients, Oral Surg Oral Med Oral Pathol
Oral Radiol 103(suppl 1):S50.e1-S50.e23, 2007.
Blignaut E, Patton LL, Nittayananta W et al: HIV phenotypes,
oral lesions, and management of HIV-related disease, Adv
Dent Res 19:122-129, 2006.
Campo J, Perea MA, del Romero J et al: Oral transmission of
HIV, reality or ﬁction? An update, Oral Dis 12:219-228,
2006.
Centers for Disease Control and Prevention: Twenty-ﬁve years
of HIV/AIDS—United States, 1981-2006, MMWR Morb
Mortal Wkly Rep 55:585-589, 2006.
Centers for Disease Control and Prevention: Revised recom-
mendations for HIV testing of adults, adolescents, and preg-
nant women, MMWR Recomm Rep 55:1-7, 2006.
Centers for Disease Control and Prevention: Updated U.S. public
health service guidelines for the management of occupational
exposures to HIV and recommendations for postexposure
prophylaxis, MMWR Recomm Rep 54:1-17, 2005.
Cherry-Peppers G, Daniels CO, Meeks V et al: Oral manifesta-
tions in the era of HAART, J Nat Med Assoc 95:21S-32S, 2003.
Cioc AM, Allen C, Kalmar JR et al: Oral plasmablastic lymphoma
in AIDS patients are associated with human herpesvirus 8,
Am J Surg Pathol 28:41046, 2004.
Cohen PT, Sande MA, Volberding PA: The AIDS knowledge base:
a textbook on HIV disease from the University of California, San
Francisco, and the San Francisco General Hospital, ed 3, Waltham,
Mass, 1999, Medical Publishing Group. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

284 ORAL AND MAXILLOFACIAL PATHOLOGY
Coogan MM, Greenspan J, Challacombe SJ: Oral lesions in infec-
tion with human immunodeﬁciency virus, Bull World Health
Organ 83:700-706, 2005.
EC-Clearinghouse on Oral Problems Related to HIV Infection
and WHO Collaborating Centre on Oral Manifestations of
the Immunodeﬁciency Virus: Classiﬁcation and diagnostic
criteria for oral lesions in HIV infection, J Oral Pathol Med
22:289-291, 1993.
Epstein JB, Cabay RJ, Glick M: Oral malignancies in HIV disease:
changes in disease presentation, increasing understanding of
molecular pathogenesis, and current management, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 100:571-578, 2005.
Fornatora ML, Reich RF, Gray RG et al: Intraoral molluscum
contagiosum: a report of a case and a review of the literature,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92:318-320,
2001.
Frezzini C, Leao JC, Porter S: Current trends in HIV disease of
the mouth, J Oral Pathol Med 34:513-531, 2005.
Gaitán-Cepeda LA, Martínez-González M, Ceballos-Salobreña A:
Oral candidosis as a clinical marker of immune failure in
patients with HIV/AIDS on HAART, AIDS Patient Care STDS
19:70-77, 2005.
Greenspan D, Greenspan JS: Signiﬁcance of oral hairy leukopla-
kia, Oral Surg Oral Med Oral Pathol 73:151-154, 1992.
Hernández SL, López de Blanc SA, Sambuelli RH et al: Oral his-
toplasmosis associated with HIV infection: a comparative
study, J Oral Pathol Med 33:445-450, 2004.
Hofer D, Hämmerle, Grassi M et al: Long-term results of sup-
portive periodontal therapy (SPT) in HIV-seropositive and
HIV-seronegative patients, J Clin Periodontol 29:630-637,
2002.
Holmstrup P, Westergaard J: HIV infection and periodontal dis-
eases, Periodontol 2000 18:37-46, 1998.
Jones AC, Gulley ML, Freedman PD: Necrotizing ulcerative
stomatitis in human immunodeﬁciency virus-seropositive
individuals: a review of the histopathologic, immunohisto-
chemical, and virologic characteristics of 18 cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 89:323-332, 2000.
Kerr AR, Ship JA: Management strategies for HIV-associated
aphthous stomatitis, Am J Clin Dermatol 4:669-680, 2003.
King MD, Reznik DA, O’Daniels CM et al: Human papillomavi-
rus-associated oral warts among human immunodeﬁciency
virus-positive patients in the era of highly active antiretroviral
therapy: an emerging pattern, Clin Inf Dis 34:641-648,
2002.
Lager I, Altini M, Coleman H: Oral Kaposi’s sarcoma: a clinico-
pathologic study from South Africa, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 96:701-710, 2003.
Lester R, Li CH, Phillips P et al: Improved outcome of human
immunodeﬁciency virus-associated plasmablastic lymphoma
of the oral cavity in the era of high active antiretroviral
therapy: a report of two cases, Leuk Lymphoma 45:1881-1885,
2004.
Mandel L, Kim D, Uy C: Parotid gland swellings in HIV diffuse
inﬁltrative CD8 lymphocytosis syndrome, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 85:565-568, 1998.
Mandel L, Surattanont F: Regression of HIV parotid swellings
after antiviral therapy: case reports with computed tomo-
graphic scan evidence, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 94:454-459, 2002.
Manders SM, Kostman JR, Mendez L et al: Thalidomide-resistant
HIV-associated aphthae successfully treated with granulo-
cyte colony-stimulating factor, J Am Acad Dermatol 33:380-
382, 1995.
Mercante DE, Leigh JE, Lilly EA et al: Assessment of the associa-
tion between HIV viral load and CD4 cell count on the occur-
rence of oropharyngeal candidiasis in HIV-infected patients,
J Acquir Immune Deﬁc Syndr 42:578-483, 2006.
Migliorati CA, Birman EG, Cury AE et al: Oropharyngeal candi-
diasis in HIV-infected patients under treatment with protease
inhibitors, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
98:301-310, 2004.
Miguez-Burbano MJ, Jackson Jr J, Hadrigan S: Thrombocytope-
nia in HIV disease: clinical relevance, physiopathology, and
management, Curr Med Chem Cardiovasc Hematol Agents 3:365-
376, 2005.
Miziara ID, Weber R: Oral candidosis and oral hairy leukoplakia
as predictors of HAART failure in Brazilian HIV-infected
patients, Oral Dis 12:402-407, 2006.
Pienaar ED, Young T, Holmes H: Interventions for the preven-
tion and management of oropharyngeal candidiasis associ-
ated with HIV infection in adults and children, Cochrane
Database Syst Rev 3:CD003940, 2006.
Piluso S, Ficarra G, Lucatorto FM et al: Cause of oral ulcers in
HIV-infected patients: a study of 19 cases, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 82:166-172, 1996.
Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J et al:
The changing clinical spectrum of human immunodeﬁciency
virus (HIV)-related oral lesions in 1,000 consecutive patients:
a 12-year study in a referral center in Mexico, Medicine 82:39-
50, 2003.
Reznik DA: Oral manifestations of HIV disease, Top HIV Med
13:143-148, 2006.
Rivera H, Nikitakis NG, Castillo S et al: Histopathological analy-
sis and demonstration of EBV and HIV p-24 antigen but not
CMV expression in labial minor salivary glands of HIV
patients affected by diffuse inﬁltrative lymphocytosis syn-
drome, J Oral Pathol Med 32:431-437, 2003.
Samaranayake LP: Re-emergence of tuberculosis and its
variants: implications for dentistry, Int Dent J 52:330-6,
2002.
Ship JA, Vissink A, Challacombe SJ: Use of prophylactic antifun-
gals in the immunocompromised host, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 103 (suppl 1):S6.e1-S6.e14,
2007.
Siwamogstham P, Kuansuwan C, Reichart P: Herpes zoster in
HIV infection with osteonecrosis of the jaw and tooth exfolia-
tion, Oral Dis 12:500-505, 2006.
Strauss RM, Doyle EL, Mohsen AH et al: Successful treatment of
molluscum contagiosum with topical imiquimod in a severely
immunocompromised HIV-positive patient, Int J STD AIDS
12:264-266, 2001.
Syrjänen S, Leimola-Virtanen R, Schmidt-Westhausen A et al:
Oral ulcers in AIDS patients frequently associated with cyto-
megalovirus (CMV) and Epstein-Barr virus (EBV) infections,
J Oral Pathol Med 28:204-209, 1999.
Triantos D, Porter SR, Scully C et al: Oral hairy leukoplakia:
clinicopathologic features, pathogenesis, diagnosis, and clini-
cal signiﬁcance, Clin Infect Dis 25:1392-1396, 1997.
Umadevi M, Adeyemi O, Patel M: Periodontal diseases and other
bacterial infections, Adv Dent Res 19:139-145, 2006.
Völter C, He Y, Delius H et al: Novel HPV types in oral papillo-
matous lesions from patients with HIV infection, Int J Cancer
66:453-456, 1996.
Walling DM, Flaitz CM, Nichols CM: Epstein-Barr virus replica-
tion in oral hairy leukoplakia: response, persistence, and
resistance to treatment with valacyclovir, J Inf Dis 188:883-
890, 2003.
Webster-Cyriaque J, Duus K, Cooper C et al: Oral EBV and
KSHV infection in HIV, Adv Dent Res 19:91-95, 2006.
Younai FS: Oral HIV transmission, J Can Dent Assoc 29:142-148,
2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

285
8
Physical and Chemical Injuries
CHAPTER OUTLINE
Linea Alba
Morsicatio Buccarum
Traumatic Ulcerations
Electrical and Thermal Burns
Chemical Injuries of the Oral Mucosa
Aspirin
Hydrogen Peroxide
Silver Nitrate
Phenol
Endodontic Materials
Noninfectious Oral Complications of Antineoplastic
Therapy
Bisphosphonate-Associated Osteonecrosis
Orofacial Complications of Methamphetamine
Abuse
Anesthetic Necrosis
Exfoliative Cheilitis
sal plane of the adjacent teeth (Fig. 8-1). The line varies
in prominence and usually is restricted to dentulous
areas. It often is more pronounced adjacent to the
posterior teeth.
HISTOPATHOLOGIC FEATURES
Biopsy is rarely indicated. If a biopsy is performed,
hyperorthokeratosis is seen overlying otherwise normal
oral mucosa. On occasion, intracellular edema of the
epithelium and mild chronic inﬂammation of the
underlying connective tissue may be noted.
TREATMENT AND PROGNOSIS
No treatment is required for patients with linea alba,
and no difﬁculties are documented as a result of its
development. Spontaneous regression may occur.
LINEA ALBA
Linea alba (“white line”) is a common alteration of the
buccal mucosa that most likely is associated with pres-
sure, frictional irritation, or sucking trauma from the
facial surfaces of the teeth. In one study of 256 young
men, the alteration was present in 13%; in another
study of 993 adolescents, linea alba was the second
most common oral mucosal pathosis and affected 5.3%.
No other associated problem, such as insufﬁcient hori-
zontal overlap or rough restorations of the teeth, is
necessary for the development of linea alba.
CLINICAL FEATURES
As the name implies, the alteration consists of a white
line that usually is bilateral. It may be scalloped and is
located on the buccal mucosa at the level of the occlu-
Submucosal Hemorrhage
Oral Trauma from Sexual Practices
Amalgam Tattoo and Other Localized Exogenous
Pigmentations
Oral Piercings and Other Body Modiﬁcations
Systemic Metallic Intoxication
Smoker’s Melanosis
Drug-Related Discolorations of the Oral Mucosa
Reactive Osseous and Chondromatous Metaplasia
Oral Ulceration with Bone Sequestration
Pseudocysts and Cysts of the Maxillary Sinus
Antral Pseudocyst
Sinus Mucoceles
Retention Cysts
Cervicofacial Emphysema
Myospherulosis `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

286 ORAL AND MAXILLOFACIAL PATHOLOGY
MORSICATIO BUCCARUM (CHRONIC
CHEEK CHEWING)
Morsicatio buccarum is a classic example of medical
terminology gone astray; it is the scientiﬁc term for
chronic cheek chewing. Morsicatio comes from the
Latin word morsus, or bite. Chronic nibbling produces
lesions that are located most frequently on the buccal
mucosa; however, the labial mucosa (morsicatio labi-
orum) and the lateral border of the tongue (morsica-
tio linguarum) also may be involved. Similar changes
have been seen as a result of suction and in glassblow-
ers whose technique produces chronic irritation of the
buccal mucosa.
A higher prevalence of classic morsicatio buccarum
has been found in people who are under stress or who
exhibit psychologic conditions. Most patients are aware
of their habit, although many deny the self-inﬂicted
injury or perform the act subconsciously. The occur-
rence is twice as prevalent in women and three times
more prevalent after age 35. At any given time, one in
every 800 adults has active lesions.
CLINICAL FEATURES
Most frequently, the lesions in patients with morsicatio
are found bilaterally on the anterior buccal mucosa.
They also may be unilateral, combined with lesions of
the lips or the tongue, or isolated to the lips or tongue.
Thickened, shredded, white areas may be combined
with intervening zones of erythema, erosion, or focal
traumatic ulceration (Figs. 8-2 and 8-3). The areas of
white mucosa demonstrate an irregular ragged surface,
and the patient may describe being able to remove
shreds of white material from the involved area.
The altered mucosa typically is located in the mid-
portion of the anterior buccal mucosa along the occlu-
sal plane. Large lesions may extend some distance
above or below the occlusal plane in patients whose
habit involves pushing the cheek between the teeth
with a ﬁnger.
HISTOPATHOLOGIC FEATURES
Biopsy reveals extensive hyperparakeratosis that often
results in an extremely ragged surface with numerous
projections of keratin. Surface bacterial colonization is
typical (Fig. 8-4). On occasion, clusters of vacuolated
cells are present in the superﬁcial portion of the prickle
cell layer. This histopathologic pattern is not pathog-
nomonic of morsicatio and may bear a striking resem-
blance to oral hairy leukoplakia (OHL), a lesion that
most often occurs in people who are infected with the
human immunodeﬁciency virus (HIV) (see page
268), or to uremic stomatitis (see page 851). A similar
histopathologic pattern is noted in patients who chron-
ically chew betel quid and has been termed betel
chewer’s mucosa (see page 402). Similarities with
linea alba and leukoedema also may be seen.
Fig. 8-1 Linea alba. White line of hyperkeratosis on the
right buccal mucosa at the level of the occlusal plane.
Fig. 8-2 Morsicatio buccarum. Thickened, shredded areas
of white hyperkeratosis of the left buccal mucosa.
Fig. 8-3 Morsicatio linguarum. Thickened, rough areas of
white hyperkeratosis of the lateral border of the tongue on
the left side. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 287
DIAGNOSIS
In most cases the clinical presentation of morsicatio
buccarum is sufﬁcient for a strong presumptive diag-
nosis, and clinicians familiar with these alterations
rarely perform biopsy. Some cases of morsicatio may
not be diagnostic from the clinical presentation, and
biopsy may be necessary. In patients at high risk for
HIV infection with isolated involvement of the lateral
border of the tongue, further investigation is desirable
to rule out HIV-associated OHL.
TREATMENT AND PROGNOSIS
No treatment of the oral lesions is required, and no
long-term difﬁculties arise from the presence of the
mucosal changes. For patients who desire treatment,
an oral acrylic shield that covers the facial surfaces of
the teeth may be constructed to eliminate the lesions
by restricting access to the buccal and labial mucosa.
For patients desiring either conﬁrmation of the cause
or preventive therapy, construction and use of two
lateral acrylic shields connected by a labial stainless
steel wire can provide quick resolution of the lesions
while being acceptable aesthetically and not interfer-
ing with speech. Several authors also have suggested
psychotherapy as the treatment of choice, but no exten-
sive well-controlled studies have indicated beneﬁts
from this approach.
TRAUMATIC ULCERATIONS
Acute and chronic injuries of the oral mucosa are fre-
quently observed. Injury can result from mechanical
damage, such as contact with sharp foodstuffs or
accidental biting during mastication, overzealous
toothbrushing, talking, or even sleeping. Some are self-
induced and clinically obvious, whereas others are
subtle and difﬁcult to diagnose. Damage also may
result from thermal, electrical, or chemical burns. (Oral
mucosal manifestations of such burns are discussed
later in the chapter.)
Acute or chronic trauma to the oral mucosa may
result in surface ulcerations. The ulcerations may
remain for extended periods of time, but most usually
heal within days. A histopathologically unique type of
chronic traumatic ulceration of the oral mucosa is the
eosinophilic ulceration (traumatic granuloma,
traumatic ulcerative granuloma with stromal
eosinophilia [TUGSE], eosinophilic granuloma
of the tongue), which exhibits a deep pseudoinva-
sive inﬂammatory reaction and is typically slow to
resolve. Interestingly, many of these traumatic granu-
lomas undergo resolution after incisional biopsy.
Lesions microscopically similar to eosinophilic ulcer-
ation have been reproduced in rat tongues after
repeated crushing trauma and in traumatic lesions
noted in patients with familial dysautonomia, a
disorder characterized by indifference to pain. In addi-
tion, similar sublingual ulcerations may occur in
infants as a result of chronic mucosal trauma from
adjacent anterior primary teeth, often associated with
nursing. These distinctive ulcerations of infancy have
been termed Riga-Fede disease and should be con-
sidered a variation of the traumatic eosinophilic
ulceration.
In rare subsets of TUGSE, the lesion does not
appear to be associated with trauma, and sheets of
large, atypical cells are seen histopathologically. The
nature of these atypical cells remains in dispute,
although it has been suggested that they may represent
reactive myoﬁbroblasts, histiocytes (atypical histio-
cytic granuloma), or T lymphocytes. Whether
these atypical eosinophilic ulcerations represent a
single pathosis or a variety of disorders that share
stromal eosinophilia is an area for future research. Of
these theories, several current investigations have
shown the atypical cells to be T lymphocytes with
strong immunoperoxidase reactivity for CD30. In
these cases, it is thought that this subset of TUGSE may
represent the oral counterpart of the primary cutane-
ous CD30+ lymphoproliferative disorder, which
also exhibits sequential ulceration, necrosis, and
self-regression.
In most cases of traumatic ulceration, there is an
adjacent source of irritation, although this is not present
invariably. The clinical presentation often suggests the
cause, but many cases resemble early ulcerative squa-
mous cell carcinoma; biopsy is performed to rule out
that possibility.
Fig. 8-4 Morsicatio buccarum. Oral mucosa exhibiting
greatly thickened layer of parakeratin with ragged surface
colonized by bacteria. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

288 ORAL AND MAXILLOFACIAL PATHOLOGY
CLINICAL FEATURES
Most injuries are unintentional and arise from a variety
of causes. As would be expected, simple chronic trau-
matic ulcerations occur most often on the tongue, lips,
and buccal mucosa—sites that may be injured by the
dentition (Fig. 8-5). Lesions of the gingiva, palate, and
mucobuccal fold may occur from other sources of
irritation. Overzealous toothbrushing can create linear
erosions along the free gingival margins. Although
these areas may superﬁcially resemble a number of the
chronic vesiculoerosive processes, thorough question-
ing of the patient often leads to the appropriate diag-
nosis. The individual lesions appear as areas of erythema
surrounding a central removable, yellow ﬁbrinopuru-
lent membrane. In many instances, the lesion develops
a rolled white border of hyperkeratosis immediately
adjacent to the area of ulceration (Fig. 8-6).
Eosinophilic ulcerations are not uncommon but fre-
quently are not reported. The lesions occur in people
of all ages, with a signiﬁcant male predominance. Most
have been reported on the tongue, although cases have
been seen on the gingiva, buccal mucosa, ﬂoor of
mouth, palate, and lip. The lesion may last from 1 week
to 8 months. The ulcerations appear very similar to the
simple traumatic ulcerations; however, on occasion,
underlying proliferative granulation tissue can result in
a raised lesion similar to a pyogenic granuloma (see
page 517) (Fig. 8-7).
Riga-Fede disease typically appears between 1 week
and 1 year of age. The condition often develops in
association with natal or neonatal teeth (see page 81).
The anterior ventral surface of the tongue is the most
common site of involvement, although the dorsal
surface also may be affected (Fig. 8-8). Ventral lesions
contact the adjacent mandibular anterior incisors;
lesions on the dorsal surface are associated with the
maxillary incisors. A presentation similar to Riga-Fede
disease can be the initial ﬁnding in a variety of neuro-
Fig. 8-5 Traumatic ulceration. Well-circumscribed
ulceration of the posterior buccal mucosa on the left side.
Fig. 8-6 Traumatic ulceration. Mucosal ulceration with a
hyperkeratotic collar located on the ventral surface of the
tongue.
Fig. 8-7 Traumatic granuloma. Exophytic ulcerated mass
on the ventrolateral tongue associated with multiple jagged
teeth.
Fig. 8-8 Riga-Fede disease. Newborn with traumatic
ulceration of anterior ventral surface of the tongue. Mucosal
damage occurred from contact of tongue with adjacent tooth
during breastfeeding. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 289
logic conditions related to self-mutilation, such as
familial dysautonomia (Riley-Day syndrome), con-
genital indifference to pain, Lesch-Nyhan syn-
drome, Gaucher disease, cerebral palsy, or Tourette
syndrome.
The atypical eosinophilic ulceration occurs in older
adults, with most cases developing in patients older
than age 40. Surface ulceration is present, and an
underlying tumefaction also is seen. The tongue is
the most common site, although the gingiva, alveolar
mucosa, mucobuccal fold, buccal mucosa, and lip may
be affected (Fig. 8-9).
HISTOPATHOLOGIC FEATURES
Simple traumatic ulcerations are covered by a ﬁbrino-
purulent membrane that consists of ﬁbrin intermixed
with neutrophils. The membrane is of variable thick-
ness, and the adjacent surface epithelium may be
normal or may demonstrate slight hyperplasia with or
without hyperkeratosis. The ulcer bed consists of gran-
ulation tissue that supports a mixed inﬂammatory
inﬁltrate of lymphocytes, histiocytes, neutrophils, and,
occasionally, plasma cells. In patients with eosinophilic
ulcerations, the pattern is very similar; however, the
inﬂammatory inﬁltrate extends into the deeper tissues
and exhibits sheets of lymphocytes and histiocytes
intermixed with eosinophils. In addition, the vascular
connective tissue deep to the ulceration may become
hyperplastic and cause surface elevation.
Atypical eosinophilic ulcerations exhibit numerous
features of the traumatic eosinophilic ulceration, but
the deeper tissues are replaced by a highly cellular
proliferation of large lymphoreticular cells. The inﬁl-
trate is pleomorphic, and mitotic features are some-
what common. Intermixed with the large atypical cells
are mature lymphocytes and numerous eosinophils.
Although an associated immunohistochemical proﬁle
rarely has been reported, several investigators have
shown the large cells to be T lymphocytes, the majority
of which react with CD30 (Ki-1). In many instances,
molecular studies for T-cell clonality by polymerase
chain reaction (PCR) have been performed on the
CD30+ cells and demonstrated monoclonal rearrange-
ment. Whether this monoclonal inﬁltrate represents a
true low-grade lymphoma or an unusual reactive lym-
phoproliferative process has not been determined.
TREATMENT AND PROGNOSIS
For traumatic ulcerations that have an obvious source
of injury, the irritating cause should be removed. Dyclo-
nine HCl or hydroxypropyl cellulose ﬁlms can be
applied for temporary pain relief. If the cause is not
obvious, or if a patient does not respond to therapy,
then biopsy is indicated. Rapid healing after a biopsy
is typical even with large eosinophilic ulcerations
(Fig. 8-10). Recurrence is not expected.
The use of corticosteroids in the management of
traumatic ulcerations is controversial. Some clinicians
have suggested that use of such medications may delay
healing. In spite of this, other investigators have
reported success using corticosteroids to treat chronic
traumatic ulcerations.
Although extraction of the anterior primary teeth is
not recommended, this procedure has resolved the
ulcerations in Riga-Fede disease. The teeth should be
retained if they are stable. Grinding the incisal mame-
lons, coverage of the teeth with a light-cured composite
or cellulose ﬁlm, construction of a protective shield,
or discontinuation of nursing have been tried with
variable success.
In patients demonstrating histopathologic similari-
ties to the cutaneous CD30+ lymphoproliferative dis-
order, a thorough evaluation for systemic lymphoma is
mandatory, along with lifelong follow-up. Although
recurrence frequently is seen, the ulcerations typically
heal spontaneously, and the vast majority of patients do
not demonstrate dissemination of the process. Further
documentation is critical to deﬁne more fully this
poorly understood process.
ELECTRICAL AND THERMAL BURNS
Electrical burns to the oral cavity are fairly common,
constituting approximately 5% of all burn admissions
to hospitals. Two types of electrical burns can be seen:
(1) contact and (2) arc.
Contact burns require a good ground and involve
electrical current passing through the body from the
point of contact to the ground site. The electric current
can cause cardiopulmonary arrest and may be fatal.
Fig. 8-9 Atypical histiocytic granuloma. Large ulceration
of the anterior dorsal surface of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

290 ORAL AND MAXILLOFACIAL PATHOLOGY
Most electrical burns affecting the oral cavity are the
arc type, in which the saliva acts as a conducting
medium and an electrical arc ﬂows between the elec-
trical source and the mouth. Extreme heat, up to
3000º C, is possible with resultant signiﬁcant tissue
destruction. Most cases result from chewing on the
female end of an extension cord or from biting through
a live wire.
Most thermal burns of the oral cavity arise from
ingestion of hot foods or beverages. Microwave ovens
have been associated with an increased frequency of
thermal burns because of their ability to cook food that
is cool on the exterior but extremely hot in the
interior.
CLINICAL FEATURES
Most electrical burns occur in children younger than
4 years of age. The lips are affected most frequently,
and the commissure commonly is involved. Initially,
the burn appears as a painless, charred, yellow area
that exhibits little to no bleeding (Fig. 8-11). Signiﬁcant
edema often develops within a few hours and may
persist up to 12 days. Beginning on the fourth day, the
affected area becomes necrotic and begins to slough.
Bleeding may develop during this period from expo-
sure of the underlying vital vasculature, and the pres-
ence of this complication should be monitored closely.
The adjacent mucobuccal fold, the tongue, or both also
may be involved. On occasion, adjacent teeth may
become nonvital, with or without necrosis of the sur-
rounding alveolar bone. Malformation of developing
teeth also has been documented. In patients receiving
high-voltage electrical injury, resultant facial nerve
paralysis is infrequently reported and typically resolves
over several weeks to months.
The injuries related to thermal food burns usually
appear on the palate or posterior buccal mucosa (Fig.
8-12). The lesions appear as zones of erythema and
ulceration that often exhibit remnants of necrotic epi-
thelium at the periphery. If hot beverages are swal-
lowed, swelling of the upper airway can occur and lead
to dyspnea, which may develop several hours after the
injury.
TREATMENT AND PROGNOSIS
For patients with electrical burns of the oral cavity,
tetanus immunization, if not current, is required. Most
clinicians prescribe a prophylactic antibiotic, usually
penicillin, to prevent secondary infection in severe
cases. The primary problem with oral burns is contrac-
ture of the mouth opening during healing. Without
A
B
C
Fig. 8-10 Eosinophilic ulceration. A, Initial presentation
of a large ulceration of the dorsal surface of the tongue.
B, Signiﬁcant resolution noted 2 weeks after incisional
biopsy. C, Subsequent healing noted 4 weeks after biopsy.
Fig. 8-11 Electrical burn. Yellow charred area of necrosis
along the left oral commissure. (Courtesy of Dr. Patricia Hagen.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 291
intervention, signiﬁcant microstomia can develop and
may produce such restricted access to the mouth that
hygiene and eating become impossible in severe cases.
Extensive scarring and disﬁgurement are typical in
untreated patients.
To prevent the disﬁgurement, a variety of microsto-
mia prevention appliances can be used to eliminate or
reduce the need for subsequent surgical reconstruc-
tion. Compliance is the most important consideration
when choosing the most appropriate device. Tissue-
supported appliances appear most effective for infants
and young children; older, more cooperative patients
usually beneﬁt from tooth-supported devices. In most
cases, splinting is maintained for 6 to 8 months to
ensure proper scar maturation. Evaluation for possible
surgical reconstruction is usually performed after a
1-year follow-up.
Most thermal burns are of little clinical consequence
and resolve without treatment. When the upper airway
is involved and associated with breathing difﬁculties,
antibiotics and corticosteroids often are administered.
In rare cases, swelling of the airway mandates intuba-
tion or tracheotomy to resolve the associated dyspnea.
In these severe cases, oral intake of food often is dis-
continued temporarily with nutrition provided by a
nasogastric tube.
CHEMICAL INJURIES OF THE
ORAL MUCOSA
A large number of chemicals and drugs come into
contact with the oral tissues. A percentage of these
agents are caustic and can cause clinically signiﬁcant
damage.
Patients often can be their own worst enemies. The
array of chemicals that have been placed within the
mouth in an attempt to resolve oral problems is
amazing. Aspirin, sodium perborate, hydrogen perox-
ide, gasoline, turpentine, rubbing alcohol, and battery
acid are just a few of the more interesting examples.
Certain patients, typically children or those under
psychiatric care, may hold medications within their
mouths rather than swallow them. A surprising number
of medications are potentially caustic when held in the
mouth long enough. Aspirin, bisphosphonates, and two
psychoactive drugs, chlorpromazine and promazine,
are well-documented examples.
Topical medications for mouth pain can compound
the problem. Mucosal damage has been documented
from many of the topical medicaments sold as treat-
ments for toothache or mouth sores. Products contain-
ing isopropyl alcohol, phenol, hydrogen peroxide, or
eugenol have produced adverse reactions in patients.
Over-the-counter tooth-whitening products also
contain hydrogen peroxide or one of its precursors,
carbamide peroxidase, which has been shown to create
mucosal necrosis (Fig. 8-13).
Health care practitioners are responsible for the use
of many caustic materials. Silver nitrate, formocresol,
sodium hypochlorite, paraformaldehyde, chromic acid,
trichloroacetic acid, dental cavity varnishes, and acid-
etch materials all can cause patient injury. Education
and use of the rubber dam have reduced the frequency
of such injuries.
The improper use of aspirin, hydrogen peroxide,
silver nitrate, phenol, and certain endodontic materials
deserves further discussion because of their frequency
of misuse, the severity of related damage, and the lack
of adequate documentation of these materials as
harmful agents.
Fig. 8-12 Thermal food burn. Area of yellow-white
epithelial necrosis of the left posterior hard palate. Damage
was the result of attempted ingestion of a hot pizza roll.
Fig. 8-13 Mucosal burn from tooth-whitening strips.
Sharply demarcated zone of epithelial necrosis on the
maxillary facial gingiva, which developed from the use of
tooth-whitening strips. Less severe involvement also is
present on the mandibular gingiva. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

292 ORAL AND MAXILLOFACIAL PATHOLOGY
ASPIRIN
Mucosal necrosis from aspirin being held in the mouth
is not rare (Fig. 8-14). Aspirin is available not only in
the well-known tablets but also as powder.
HYDROGEN PEROXIDE
Hydrogen peroxide became a popular intraoral medi-
cation for prevention of periodontitis in the late 1970s.
Since that time, mucosal damage has been seen more
frequently as a result of this application. Concentrations
at 3% or greater are associated most often with adverse
reactions. Epithelial necrosis has been noted with dilu-
tions as low as 1%, and many over-the-counter oral
medications exceed this concentration (Fig. 8-15).
SILVER NITRATE
Silver nitrate remains a popular treatment for aphthous
ulcerations, because the chemical cautery brings about
rapid pain relief by destroying nerve endings. In spite
of this, its use should be strongly discouraged. In all
cases the extent of mucosal damage is increased by its
use. In some patients an abnormal reaction is seen,
with resultant signiﬁcant damage and enhanced pain.
In one report, an application of a silver nitrate stick to
a small aphthous ulceration led to a necrotic defect that
exceeded 2 × 2 cm and had to be débrided surgically.
In addition, rare reports have documented irreversible
systemic argyria secondary to habitual intraoral use of
topical silver nitrate after recommendation by a dentist
(see page 315).
PHENOL
Phenol has occasionally been used in dentistry as a
cavity-sterilizing agent and cauterizing material. It is
extremely caustic, and judicious use is required. Over-
the-counter agents advertised as “canker sore”
treatments may contain low concentrations of phenol,
often combined with high levels of alcohol. Extensive
mucosal necrosis and (rarely) underlying bone loss
have been seen in patients who placed this material
(phenol concentration 0.5%) in attempts to resolve
minor mucosal sore spots (Fig. 8-16).
A prescription therapy containing 50% sulfuric acid,
4% sulfonated phenol, and 24% sulfonated phenolic
agents is being marketed heavily to dentists for treat-
ment of aphthous ulcerations. Because extensive necro-
sis has been seen from use of medicaments containing
0.5% phenol, this product must be closely monitored
and used with great care.
ENDODONTIC MATERIALS
Some endodontic materials are dangerous because of
the possibility of soft tissue damage (Fig. 8-17) or their
injection into hard tissue with resultant deep spread
Fig. 8-14 Aspirin burn. Extensive area of white epithelial
necrosis of the left buccal mucosa caused by aspirin
placement in an attempt to alleviate dental pain.
Fig. 8-15 Hydrogen peroxide burn. Extensive epithelial
necrosis of the anterior maxillary gingiva secondary to
interproximal placement of hydrogen peroxide with cotton
swabs.
Fig. 8-16 Phenol burn. Extensive epithelial necrosis of
the mandibular alveolar mucosa on the left side. Damage
resulted from placement of an over-the-counter, phenol-
containing, antiseptic and anesthetic gel under a denture.
(Courtesy of Dr. Dean K. White.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 293
and necrosis. Because of the past difﬁculty of obtaining
profound anesthesia in some patients undergoing root
canal therapy, some clinicians have used arsenical
paste or paraformaldehyde formulations to devitalize
the inﬂamed pulp. Gingival and bone necrosis have
been documented as a consequence of leakage of this
material from the pulp chamber into the surrounding
tissues. In addition, extrusion of ﬁlling material con-
taining paraformaldehyde into the periapical tissues
has led to signiﬁcant difﬁculties, and its use should be
discouraged. Sodium hypochlorite produces similar
results when it leaks into the surrounding supporting
tissues or is injected past the apex, leading some to
suggest chlorhexidine as a safer irrigant. The following
can reduce the chances of tissue damage:
●Using a rubber dam
●Avoiding excessive pressure during application
●Keeping the syringe needle away from the apex
CLINICAL FEATURES
The previously discussed caustic agents produce similar
damage. With short exposure, the affected mucosa
exhibits a superﬁcial white, wrinkled appearance. As
the duration of exposure increases, the necrosis pro-
ceeds and the affected epithelium becomes separated
from the underlying tissue and can be desquamated
easily. Removal of the necrotic epithelium reveals red,
bleeding connective tissue that subsequently will be
covered by a yellowish, ﬁbrinopurulent membrane.
Mucosa bound to bone is keratinized and more resis-
tant to damage, whereas the nonkeratinized movable
mucosa is destroyed more quickly. In addition to
mucosal necrosis, signiﬁcant tooth erosion has been
seen in patients who chronically chew aspirin or hold
the medication in their teeth as it dissolves.
The use of the rubber dam can dramatically reduce
iatrogenic mucosal burns. When cotton rolls are used
for moisture control during dental procedures, two
problems may occur. On occasion, caustic materials
can leak into the cotton roll and be held in place against
the mucosa for an extended period, with mucosal injury
resulting from the chemical absorbed by the cotton. In
addition, oral mucosa can adhere to dry cotton rolls,
and rapid removal of the rolls from the mouth often can
cause stripping of the epithelium in the area. The latter
pattern of mucosal injury has been termed cotton roll
burn (cotton roll stomatitis) (Fig. 8-18).
Caustic materials injected into bone during end-
odontic procedures can result in signiﬁcant bone
necrosis, pain, and perforation into soft tissue. Necrotic
surface ulceration and edema with underlying areas of
soft tissue necrosis may occur adjacent to the site of
perforation.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the white slough removed
from areas of mucosal chemical burns reveals coagula-
tive necrosis of the epithelium, with only the outline of
the individual epithelial cells and nuclei remaining
(Fig. 8-19). The necrosis begins on the surface and
moves basally. The amount of epithelium affected
depends on the duration of contact and the concentra-
tion of the offending agent. The underlying connective
tissue contains a mixture of acute and chronic inﬂam-
matory cells.
TREATMENT AND PROGNOSIS
The best treatment of chemical injuries is prevention
of exposure of the oral mucosa to caustic materials.
When using potentially caustic drugs (e.g., aspirin,
Fig. 8-17 Formocresol burn. Tissue necrosis secondary to
leakage of endodontic material between a rubber dam clamp
and the tooth.
Fig. 8-18 Cotton roll burn. Zone of white epithelial
necrosis and erythema of the maxillary alveolar mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

294 ORAL AND MAXILLOFACIAL PATHOLOGY
chlorpromazine), the clinician must instruct the patient
to swallow the medication and not allow it to remain
in the oral cavity for any signiﬁcant length of time.
Children should not use chewable aspirin immediately
before bedtime, and they should rinse after use.
Superﬁcial areas of necrosis typically resolve com-
pletely without scarring within 10 to 14 days after dis-
continuation of the offending agent. For temporary
protection, some clinicians have recommended cover-
age with a protective emollient paste or a hydroxypro-
pyl cellulose ﬁlm. Topical dyclonine HCl provides
excellent but temporary pain relief. When large areas
of necrosis are present, such as that related to the use
of silver nitrate or accidental intrabony injection of
offending materials, surgical débridement and antibi-
otic coverage often are required to promote healing
and prevent spread of the necrosis.
NONINFECTIOUS ORAL
COMPLICATIONS OF
ANTINEOPLASTIC THERAPY
No systemic anticancer therapy currently available is
able to destroy tumor cells without causing the death
of at least some normal cells, and tissues with rapid
turnover (e.g., oral epithelium) are especially suscepti-
ble. The mouth is a common site (and one of the most
visible areas) for complications related to cancer
therapy. Both radiation therapy and systemic chemo-
therapy may cause signiﬁcant oral problems. The more
potent the treatment, the greater the risk of complica-
tions. Each year almost 400,000 patients in the United
States suffer acute or chronic oral side effects from
anticancer treatments. With the advancement of
medical practice, these complications are becoming
more common as more patients have longer survival
times and as intense therapies, such as bone marrow
transplantation, become more commonplace. Oral
complications are noted almost uniformly in patients
receiving head and neck radiation, and close to 75% of
bone marrow transplant patients are affected. The
prevalence of chemotherapy-associated oral complica-
tions varies from 10% to 75%, depending on the type
of associated cancer and the form of chemotherapy
used.
CLINICAL FEATURES
A variety of noninfectious oral complications are seen
regularly as a result of both radiation and chemother-
apy. Two acute changes, mucositis and hemorrhage,
are the predominant problems associated with chemo-
therapy, especially in cancers, such as leukemia, that
involve high treatment doses.
Painful acute mucositis and dermatitis are the most
frequently encountered side effects of radiation, but
several chronic alterations continue to plague patients
long after their courses of therapy are completed.
Depending on the ﬁelds of radiation, the radiation
dose, and the age of the patient, the following outcomes
are possible:
● Xerostomia
●Loss of taste (hypogeusia)
● Osteoradionecrosis
● Trismus
● Chronic dermatitis
● Developmental abnormalities
HEMORRHAGE
Intraoral hemorrhage is typically secondary to throm-
bocytopenia, which develops from bone marrow sup-
pression. Intestinal or hepatic damage, however, may
cause lower vitamin K–dependent clotting factors, with
resultant increased coagulation times. Conversely,
tissue damage related to therapy may cause release of
tissue thromboplastin at levels capable of producing
potentially devastating disseminated intravascular
coagulation (DIC). Oral petechiae and ecchymosis sec-
ondary to minor trauma are the most common presen-
tations. Any mucosal site may be affected, but the
labial mucosa, tongue, and gingiva are involved most
frequently.
MUCOSITIS
Recent research suggests that mucosal damage second-
ary to cancer therapy is much more complex than pre-
viously thought and appears to arise from an extended
series of molecular and cellular events that take place
not only in the epithelium but also in the underlying
stroma. Genetic differences in the rate of tissue apop-
Fig. 8-19 Chemical-related epithelial necrosis. Oral
mucosa exhibiting superﬁcial coagulative necrosis of the
epithelial cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 295
tosis, microvascular injury from endothelial apoptosis,
and increased peripheral blood levels of tumor necro-
sis factor α and interleukin-6 appear to be involved.
Beyond the direct effects of the antineoplastic agent,
additional risk factors include young age, female sex,
poor oral hygiene, oral foci of infection, poor nutrition,
impaired salivary function, tobacco use, and alcohol
consumption.
Cases of oral mucositis related to radiation or che-
motherapy are similar in their clinical presentations.
The manifestations of chemotherapy develop after a
few days of treatment; radiation mucositis may begin
to appear during the second week of therapy. Both
chemotherapy and radiation-induced mucositis will
resolve slowly 2 to 3 weeks after cessation of treatment.
Oral mucositis associated with chemotherapy typically
involves the nonkeratinized surfaces (i.e., buccal
mucosa, ventrolateral tongue, soft palate, ﬂoor of the
mouth), whereas radiation therapy primarily affects
the mucosal surfaces within the direct portals of
radiation.
The earliest manifestation is development of a
whitish discoloration from a lack of sufﬁcient desqua-
mation of keratin. This is soon followed by loss of this
layer with replacement by atrophic mucosa, which is
edematous, erythematous, and friable. Subsequently,
areas of ulceration develop with formation of a remov-
able yellowish, ﬁbrinopurulent surface membrane
(Figs. 8-20 to 8-22). Pain, burning, and discomfort are
signiﬁcant and can be worsened by eating and oral
hygiene procedures.
DERMATITIS
Acute dermatitis of the skin in the ﬁelds of radiation
is common and varies according to the intensity of the
therapy. Patients with mild radiation dermatitis experi-
ence erythema, edema, burning, and pruritus. This
condition resolves in 2 to 3 weeks after therapy and is
replaced by hyperpigmentation and variable hair loss.
Moderate radiation causes erythema and edema in
combination with erosions and ulcerations. Within 3
months these alterations resolve, and permanent hair
loss, hyperpigmentation, and scarring may ensue.
Necrosis and deep ulcerations can occur in severe
acute reactions. Radiation dermatitis also may become
chronic and be characterized by dry, smooth, shiny,
atrophic, necrotic, telangiectatic, depilated, or ulcer-
ated areas.
XEROSTOMIA
Salivary glands are very sensitive to radiation, and
xerostomia is a common complication. When a portion
of the salivary glands is included in the ﬁelds of radia-
tion, the remaining glands undergo compensatory
hyperplasia in an attempt to maintain function. The
changes begin within 1 week of initiation of radiation
therapy, with a dramatic decrease in salivary ﬂow
noted during the ﬁrst 6 weeks of treatment. Even
further decreases may be noted for up to 3 years.
Serous glands exhibit an increased radiosensitivity
when compared with the mucous glands. On signiﬁ-
cant exposure, the parotid glands are affected dramati-
cally and irreversibly. In contrast, the mucous glands
partially recover and, over several months, may achieve
ﬂow that approaches 50% of preradiation levels. Symp-
tomatic dry mouth appears most strongly associated
with a decrease in palatal mucous secretions, with the
loss of parotid serous secretion exerting a less notice-
able effect. In addition to the discomfort of a mouth
that lacks proper lubrication, diminished ﬂow of saliva
leads to a signiﬁcant decrease of the bactericidal action
and self-cleansing properties of saliva.
Fig. 8-20 Chemotherapy-related epithelial necrosis.
Vermilion border of the lower lip exhibiting epithelial
necrosis and ulceration in a patient receiving systemic
chemotherapy.
Fig. 8-21 Chemotherapy-related epithelial necrosis.
Large, irregular area of epithelial necrosis and ulceration of
the anterior ventral surface of the tongue in a patient
receiving systemic chemotherapy. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

296 ORAL AND MAXILLOFACIAL PATHOLOGY
Without intervention, patients often develop symp-
tomatic dry mouth that affects their ability to eat com-
fortably, wear dentures, speak, and sleep. In addition,
there often is an increase in the caries index (xerosto-
mia-related caries), regardless of the patient’s past
caries history (Fig. 8-23). The decay is predominantly
cervical in location and secondary to xerostomia (not a
direct effect of the radiation).
LOSS OF TASTE
In patients who receive signiﬁcant radiation to the oral
cavity, a substantial loss of all four tastes (hypogeusia)
often develops within several weeks. Although these
tastes return within 4 months for most patients, some
patients are left with permanent hypogeusia; others
may have persistent dysgeusia (altered sense of taste)
(see page 875).
OSTEORADIONECROSIS
Osteoradionecrosis is one of the most serious compli-
cations of radiation to the head and neck; however, it
is seen less frequently today because of better treat-
ment modalities and prevention. The current preva-
lence rate is approximately 5%, whereas the frequency
approached 15% less than 20 years ago. Although the
risk is low, it increases dramatically if a local surgical
procedure is performed within 21 days of therapy
initiation or within 12 months after therapy.
In the past, many researchers believed that radia-
tion induced an osseous endarteritis that led to tissue
hypoxia, hypocellularity, and hypovascularity and
created a predisposition to necrosis if a minor injury
occurred. This theory led to widespread use of hyper-
baric oxygen in the prevention and treatment of this
pathosis. However, many now believe the process is
more complex and may involve radiation damage to
osseous cells; when these cells lose normal function,
bone turnover is suppressed in a manner similar to
the effect on osteoclasts associated with use of
bisphosphonates (see page 299). Researchers believe
that damage to these cells not only disrupts their
primary function but also affects bone vascularity
A
B
C
Fig. 8-22 Radiation mucositis. A, Squamous cell
carcinoma before radiation therapy. Granular erythroplakia of
the ﬂoor of the mouth on the patient’s right side. B, Same
lesion after initiation of radiation therapy. Note the large,
irregular area of epithelial necrosis and ulceration of the
anterior ﬂoor of the mouth on the patient’s right side.
C, Normal oral mucosa after radiation therapy. Note
resolution of the tumor and the radiation mucositis.
Fig. 8-23 Xerostomia-related caries. Extensive cervical
caries of mandibular dentition secondary to radiation-related
xerostomia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 297
through a complex interaction of cytokines and growth
factors.
Previously, investigators suggested that radiation-
associated reduction in healing capacity might be per-
manent, with the risk for osteonecrosis remaining high
for many years. Currently, others have proposed that
repair of damaged osseous cells occurs as they are
replaced by future cellular generations. Investigations
have suggested that signiﬁcant recovery does occur,
and the prevalence of osteonecrosis is reduced signiﬁ-
cantly after a 1-year recovery period, with or without
use of hyperbaric oxygen. More recent clinical trials of
irradiated patients have shown a low prevalence of
osteonecrosis if a period of postradiation healing (1
year or longer) is combined with atraumatic surgical
technique.
Although most instances of osteoradionecrosis arise
secondary to local trauma, a minority appear sponta-
neous. The mandible is involved most frequently,
although a few cases have involved the maxilla (Fig.
8-24). Affected areas of bone reveal ill-deﬁned areas of
radiolucency that may develop zones of relative radi-
opacity as the dead bone separates from the residual
vital areas (Fig. 8-25). Intractable pain, cortical perfora-
tion, ﬁstula formation, surface ulceration, and patho-
logic fracture may be present (Fig. 8-26).
The radiation dose is the main factor associated with
bone necrosis, although the proximity of the tumor to
bone, the presence of remaining dentition, and the
type of treatment also exert an effect. Additional factors
associated with an increased prevalence include older
age, male sex, poor health or nutritional status, and
continued use of tobacco or alcohol.
Prevention of bone necrosis is the best course of
action. Before therapy, all questionable teeth should be
extracted or restored, and oral foci of infection should
be eliminated; excellent oral hygiene should be initi-
ated and maintained. A healing time of at least 3 weeks
between extensive dental procedures and the initiation
of radiotherapy signiﬁcantly decreases the chance of
bone necrosis. Extraction of teeth or any bone trauma
is strongly contraindicated during radiation therapy.
TRISMUS
Trismus may develop and can produce extensive dif-
ﬁculties concerning access for hygiene and dental
treatment. Tonic muscle spasms with or without ﬁbro-
sis of the muscles of mastication and the temporoman-
dibular joint (TMJ) capsule can cause difﬁculties in jaw
opening. When these structures are radiated heavily,
jaw-opening exercises may help to decrease or prevent
problems.
Fig. 8-24 Osteoradionecrosis. Ulceration overlying left
body of the mandible with exposure and sequestration of
superﬁcial alveolar bone.
Fig. 8-25 Osteoradionecrosis. Multiple ill-deﬁned areas of
radiolucency and radiopacity of the mandibular body.
Fig. 8-26 Osteoradionecrosis. Same patient as depicted in
Fig. 8-24. Note ﬁstula formation of the left submandibular
area resulting from osteoradionecrosis of the mandibular
body. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

298 ORAL AND MAXILLOFACIAL PATHOLOGY
DEVELOPMENTAL ABNORMALITIES
Antineoplastic therapy during childhood can affect
growth and development. The changes vary according
to the age at treatment and the type and severity of
therapy. Radiation can alter the facial bones and result
in micrognathia, retrognathia, or malocclusion. Devel-
oping teeth are very sensitive and can exhibit a number
of changes, such as root dwarﬁsm, blunting of roots,
dilaceration of roots, incomplete calciﬁcation, prema-
ture closure of pulp canals in deciduous teeth, enlarged
canals in permanent teeth, microdontia, and hypodon-
tia (see page 58).
TREATMENT AND PROGNOSIS
Optimal treatment planning involves the oral health
practitioner before initiation of antineoplastic therapy.
Elimination of all current or potential oral foci of infec-
tion is paramount, along with patient education about
maintaining ultimate oral hygiene. Proper nutrition,
cessation of tobacco use, and alcohol abstinence will
minimize oral complications. Once cancer therapy is
initiated, efforts must be directed toward relieving
pain, preventing dehydration, maintaining adequate
nutrition, eliminating foci of infection, and ensuring
continued appropriate oral hygiene.
MUCOSITIS
In an attempt to decrease the severity, duration, and
symptoms associated with oral mucositis, a large
number of treatments such as anesthetic, analgesic,
antimicrobial, and coating agents have been tried with
mixed reviews. Few have been proven to be consis-
tently beneﬁcial in well-designed placebo-controlled
trials. A low-cost salt and soda rinse often has demon-
strated similar effectiveness and a lower adverse
reaction proﬁle when compared with many other
interventions. When all treatments fail, the degree of
mucositis and associated pain may mandate systemic
morphine therapy.
Cryotherapy (placement of ice chips in the mouth 5
minutes before chemotherapy and continued for 30
minutes) has been shown to reduce signiﬁcantly the
prevalence and severity of oral mucositis secondary to
bolus injection of chemotherapeutic drugs with a short
half-life, such as 5-ﬂuorouracil or edatrexate. Although
limited by the hardware expense and necessity for spe-
cialized training, low-level helium-neon laser therapy
also appears to reduce the frequency and severity of
chemotherapy-associated mucositis.
A new avenue of research is concentrating on growth
factors that may affect the prevalence of oral mucositis.
Recently, intravenous (IV) recombinant human ker-
atinocyte growth factor (palifermin) became the
ﬁrst compound approved by the U.S. Food and Drug
Administration (FDA) for reduction of oral mucositis
related to myelotoxic chemotherapy. In clinical studies,
this expensive biologic response modiﬁer provided a
modest, but statistically signiﬁcant, reduction in the
severity of mucositis, severity of oral pain, use of nar-
cotic analgesia, and need for total parenteral
nutrition.
One of the more effective mechanisms to reduce
radiation-associated mucositis has been placement of
midline radiation blocks or use of three-dimensional
radiation treatment to limit the volume of irradiated
mucosa. Although not approved in the United States
but available in Canada and Europe, topical benzyda-
mine reduces the frequency, severity, and pain of radi-
ation-associated oral mucositis. This unique nonsteroidal
antiinﬂammatory drug (NSAID) also exhibits analge-
sic, anesthetic, and antimicrobial properties.
XEROSTOMIA
Xerostomic patients should be counseled to avoid all
agents that may decrease salivation, especially the use
of tobacco products and alcohol. To combat xerosto-
mia-related caries, a regimen of daily topical ﬂuoride
application should be instituted.
The problem of chronic xerostomia has been
approached through the use of salivary substitutes and
sialagogues. Because the mucous glands often demon-
strate signiﬁcant recovery after radiation, the siala-
gogues show promise because they stimulate the
residual functional glands. Moisturizing gels, sugarless
candies, and chewing gum are used, but the most efﬁ-
cacious product in controlled clinical studies has been
systemic use of one of the cholinergic drugs, pilocar-
pine or cevimeline. Although these drugs may be ben-
eﬁcial for many patients, they are contraindicated in
patients with asthma, gastrointestinal ulcerations, labile
hypertension, glaucoma, chronic obstructive pulmo-
nary disease, and signiﬁcant cardiovascular disease.
Adverse reactions are uncommon but include excess
sweating, rhinitis, headache, nausea, uropoiesis, ﬂatu-
lence, and circulatory disorders.
Other systemic salivary stimulants that are associ-
ated with a less dramatic inﬂuence on ﬂow include
bethanechol and anetholetrithione. Anetholetrithione
appears to act by increasing the number of salivary
gland receptors. Although somewhat effective when
used alone, this medication has been combined with
one of the cholinergic medications and achieved
improvement in patients who failed to respond to the
use of a single agent.
LOSS OF TASTE
Although the taste buds often regenerate within 4
months after radiation therapy, the degree of long-term
impairment is highly variable. In those with continu- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 299
ing symptoms, zinc sulfate supplements greater than
the usual recommended daily doses appear to be
beneﬁcial.
OSTEORADIONECROSIS
Although prevention must be stressed, cases of osteo-
radionecrosis do occur. Use of hyperbaric oxygen has
numerous contraindications and possible adverse reac-
tions. Because of the newer theories of pathogenesis
for osteoradionecrosis, many clinicians are less inclined
to use hyperbaric oxygen except in selected cases.
Therapy consists of antibiotics, débridement, irriga-
tion, and removal of diseased bone. The amount of
bone removed is determined by clinical judgment,
with the surgery extended until brightly bleeding edges
are seen.
BISPHOSPHONATE-ASSOCIATED
OSTEONECROSIS
The initial association between use of bisphosphonates
and subsequent development of gnathic osteonecrosis
was documented in 2003. Bisphosphonates comprise
a unique class of medications that has been shown to
inhibit osteoclasts and possibly interfere with angio-
genesis through actions such as inhibition of vascular
endothelial growth factor. These medications can be
delivered by mouth (PO) or intravenously (IV) and are
used primarily to slow osseous involvement of a number
of cancers (multiple myeloma and metastatic breast or
prostate carcinoma), to treat Paget’s disease (see page
623), and to reverse osteoporosis.
The ﬁrst-generation bisphosphonates have a rela-
tively low potency and are readily metabolized by
osteoclasts. Addition of a nitrogen side chain was added
subsequently, creating a more potent second genera-
tion of these drugs, designated aminobisphospho-
nates (Box 8-1). In contrast to the ﬁrst generation,
these formulations are incorporated into the skeleton
and demonstrate an extended half-life (e.g., estimated
to be 12 years for alendronate). Currently, strong asso-
ciation with gnathic osteonecrosis has been limited to
the aminobisphosphonates.
Although bone may seem to be a stable tissue, it
constantly is undergoing a process of resorption and
reapposition throughout life. The typical lifespan of an
osteoblast/osteocyte is approximately 150 days. Osteo-
clasts also play a critical role in the maintenance of
normal bone by repairing microfractures and resorb-
ing areas of bone that contain foci of older nonvital
osteocytes. On resorption of bone, cytokines and growth
factors such as bone morphogenetic protein are
released and induce formation of active bone-forming
osteoblasts. If osteoclastic function declines, then
microfractures accumulate and the lifespan of the
entrapped osteocytes is exceeded, creating areas of
vulnerable bone. When osteoclasts ingest bispho s-
phonate-treated bone, the medication is cytotoxic and
induces osteoclastic apoptosis, a reduction in recruit-
ment of additional osteoclasts, and a stimulation of
osteoblasts to release an osteoclast-inhibiting factor.
The incorporation of the medication is highest in areas
of active remodeling, such as the jaws. Although the
vast majority of osteonecrosis cases have occurred in
the jaws, extragnathic involvement has been docu-
mented (e.g., osteonecrosis of ear after removal of
exostosis of the external ear canal).
CLINICAL AND RADIOGRAPHIC
FEATURES
In an excellent systematic review of 368 reported cases
of bisphosphonate-associated osteonecrosis (BON),
94% were discovered in patients who were treated with
Box 8-1
Bisphosphonate Medications
FIRST-GENERATION DRUGS
●Bonefos (clodronate)
Relative potency of 10
PO and IV formulations
●Didronel (etidronate disodium)
Relative potency of 1
PO
●Skelid (tiludronic disodium)
Relative potency of 10
PO
AMINOBISPHOSPHONATE DRUGS
●Actonel (risedronate sodium)
Relative potency of 5000
PO
●Aredia (pamidronate disodium)
Relative potency 100
IV
●Boniva (ibandronate sodium)
Relative potency 10,000
PO and IV formulations
●Fosamax (alendronate sodium)
Relative potency 1000
PO
●Reclast (zoledronic acid)
Relative potency 100,000
IV formulation
Infused annually for osteoporosis
FDA approval pending
●Zometa (zoledronic acid)
Relative potency 100,000
IV
PO, By mouth; IV, intravenous; FDA, U.S. Food and Drug Administration. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

300 ORAL AND MAXILLOFACIAL PATHOLOGY
the IV formulations (primarily pamidronate and zole-
dronic acid) for cancer, with 85% being reported in
patients with multiple myeloma. Current estimates
indicate that the prevalence of osteonecrosis in patients
taking aminobisphosphonates for cancer is 6% to 10%.
Prospective trials will be necessary to conﬁrm these
ﬁgures.
Osteonecrosis related to use of oral aminobisphos-
phonates is most uncommon (conservative estimate by
drug industry: annual incidence is 0.7 per 100,000);
however, prospective trials for the true incidence of
this complication have yet to be performed. Risk factors
for BON associated with the PO formulations include
advanced patient age (older than 65 years), corticoste-
roid use, use of chemotherapy drugs, diabetes, smoking
or alcohol use, poor oral hygiene, and duration of drug
use exceeding 3 years. A predictive test for those at risk
for bisphosphonate osteonecrosis has not been con-
ﬁrmed. Some investigators recently have suggested
use of a serum marker for bone turnover, serum C-
telopeptide (CTX), but additional prospective studies
are needed to conﬁrm the utility of this test.
Although a mandibular predominance has been
noted, involvement of the maxilla or both jaws is not
uncommon (Fig. 8-27). In 60% of these patients, the
necrosis has followed an invasive dental procedure,
with the remainder occurring spontaneously (Fig.
8-28). On occasion, the necrosis can occur after minor
trauma to bony prominences, such as tori or other
exostoses (Fig. 8-29). Affected patients have areas of
exposed, necrotic bone that is asymptomatic in approx-
imately one third.
Investigators have suggested that bone at imminent
risk for osteonecrosis often will demonstrate increased
radiopacity before clinical evidence of frank necrosis.
These changes typically occur predominantly in areas
of high bone remodeling, such as the alveolar ridges.
Panoramic radiographs often will reveal a marked
radiodensity of the crestal portions of each jaw, with a
more normal appearance of the bone away from tooth-
bearing portions. Periosteal hyperplasia also is not rare.
In more severe cases, the osteonecrosis creates a moth-
eaten and ill-deﬁned radiolucency with or without
central radiopaque sequestra (Fig. 8-30). In some cases
the necrosis can lead to development of a cutaneous
sinus or pathologic fracture (Fig. 8-31).
Fig. 8-27 Bisphosphonate-associated osteonecrosis.
Bilateral necrotic exposed bone of the mandible in a patient
receiving zoledronic acid for metastatic breast cancer. (Courtesy
of Dr. Brent Mortenson.)
Fig. 8-28 Bisphosphonate-associated osteonecrosis.
Extensive necrosis of the mandible, which followed extraction
of multiple teeth. The patient was receiving zoledronic acid
for metastatic breast cancer. (Courtesy of Dr. Benny Bell.)
Fig. 8-29 Bisphosphonate-associated osteonecrosis.
Lobulated palatal torus with an area of exposed necrotic
bone in a patient taking alendronate for osteoporosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 301
drug use. All patients who take these medications
should be warned of the risks and instructed to obtain
and maintain ultimate oral hygiene. The oral medica-
tions are extremely caustic; patients should be warned
to minimize oral mucosal contact and ensure the medi-
cation is swallowed completely.
Routine dental therapy, in most cases, should not be
modiﬁed solely on the basis of oral aminobisphospho-
nate use. All restorative, prosthodontic, conventional
endodontic, and routine periodontic procedures can
be implemented as needed. Although orthodontic
treatment is not contraindicated, progress should be
evaluated after 2 to 3 months of active therapy. At that
point, therapy can proceed if the tooth movement is
Fig. 8-30 Bisphosphonate-associated osteonecrosis.
Panoramic radiograph of patient depicted in Fig. 8-27. Note
sclerosis of tooth-bearing areas along with multiple
radiolucencies and periosteal hyperplasia of the lower border
of the mandible. (Courtesy of Dr. Brent Mortenson.)
Fig. 8-32 Bisphosphonate-associated osseous changes.
Pagetoid bone exhibiting enlarged, irregular osteoclasts that
contain numerous intracytoplasmic vacuoles. (Courtesy of Dr.
Don Cohen.)
Fig. 8-31 Bisphosphonate-associated osteonecrosis.
Patient with multiple cutaneous sinuses associated with
extensive necrosis of the left side of the mandible. The
patient was taking zoledronic acid for multiple myeloma.
(Courtesy of Dr. Molly Rosebush.)
HISTOPATHOLOGIC FEATURES
Biopsy of vital bone altered by aminobisphosphonates
is not common. In such cases the specimen often
reveals irregular trabeculae of pagetoid bone, with
adjacent enlarged and irregular osteoclasts that often
demonstrate numerous intracytoplasmic vacuoles (Fig.
8-32). Specimens of active areas of BON reveal tra-
beculae of sclerotic lamellar bone, which demonstrate
loss of the osteocytes from their lacunae and frequent
peripheral resorption with bacterial colonization (Fig.
8-33). Although the peripheral bacterial colonies often
resemble actinomycetes, the infestation is not consis-
tent with cervicofacial actinomycosis.
TREATMENT AND PROGNOSIS
The clinical approach to patients treated with amino-
bisphosphonates varies according to the formulation of
the drug, the disease being treated, and the duration of
Fig. 8-33 Bisphosphonate-associated osteonecrosis.
Sclerotic lamellar bone exhibiting loss of the osteocytes from
their lacunae and peripheral resorption with bacterial
colonization. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

302 ORAL AND MAXILLOFACIAL PATHOLOGY
occurring predictably with normal forces. Invasive
orthodontic techniques such as orthognathic surgery,
four-tooth extraction cases, and miniscrew anchorage
should be avoided, if possible. Because the medica-
tion is drawn to sites of active bone remodeling, a
drug holiday (or switching to a nonaminobisphosph-
onate agent) during active orthodontics may be
advantageous.
When manipulation of bone is considered (e.g., sur-
gical endodontics, periodontal bone recontouring, oral
surgery, implant placement), the patient should be
advised of the potential complications of aminobisphos-
phonate use and the risk of BON. Written informed
consent and documentation of a discussion of the ben-
eﬁts, risks, and alternative therapies are highly advised.
For elective surgical procedures in patients with a
duration of drug use exceeding 3 years, discontinua-
tion of the medication 3 months before and 3 months
after surgery has been suggested. Because of the
reduced angiogenesis, osseous grafts should be used
judiciously. If multiple sites require surgery, then one
sextant should be treated with a 2-month disease-free
follow-up before completion of the remaining sextants.
During this interval, use of chlorhexidine twice daily
is recommended. The sextant-by-sextant approach is
not necessary for periapical inﬂammatory disease or
abscesses, both of which can lead directly to osteone-
crosis and demand immediate resolution.
Dental therapy in patients taking an IV formulation
for cancer is much more problematic. Prevention is
paramount. In patients evaluated before initiation of
an IV aminobisphosphonate, the goal is to eliminate
all dental infections and improve dental health
to prevent future invasive therapy; this includes
removal of large tori or partially impacted teeth. If only
noninvasive therapy is necessary, then the initiation of
the medication need not be delayed. If surgical proce-
dures are performed, then a month-long delay in
initiation of the medication is recommended, along
with prophylactic antibiotic therapy (i.e., penicillin;
quinolone and metronidazole, or erythromycin and
metronidazole for those allergic to penicillin).
For patients presenting in the midst of active IV
therapy, a number of clinicians have suggested that
manipulation of bone should be avoided. Conventional
endodontics is a better option than extraction. If a non-
vital tooth is not restorable, then endodontics should
be performed and followed by crown amputation.
Teeth with 1+ or 2+ mobility should be splinted; those
with 3+ mobility can be extracted.
For patients with BON, the goal of therapy is to stop
pain. A number of clinicians believe that removal of
bone typically results in further bone necrosis, and
hyperbaric oxygen has not been beneﬁcial. Asymptom-
atic patients should rinse daily with chlorhexidine and
be monitored closely. Any rough edges of exposed
bone should be smoothed. If the exposed bone irritates
adjacent tissues, then coverage with a soft splint may
prove beneﬁcial. In symptomatic patients, systemic
antibiotic therapy (i.e., penicillin with or without
metronidazole, ciproﬂoxacin or erythromycin and
metronidazole for those allergic to penicillin) and
chlorhexidine usually lead to pain relief. If the antibiot-
ics fail to stop the pain, then hospitalization with IV
therapy is indicated. In recalcitrant cases the bulk of
the dead bone is reduced surgically, followed by admin-
istration of systemic antibiotics. Because of the long
half-life of bisphosphonates, discontinuation of the
drug offers no short-term beneﬁt. In isolated anecdotal
reports of recalcitrant cases, discontinuation of the
medication for 6 to 12 months occasionally has
been associated with spontaneous sequestration and
resolution.
As mentioned in the discussion of the radiographic
features, the alveolar ridges of patients affected with
osteonecrosis exhibit signiﬁcant sclerosis because of
increased drug deposition in areas of high remodeling.
Some investigators have successfully treated patients
with BON by resection of all of the osteosclerotic areas
with extension to the underlying more lucent and nor-
mally bleeding bone. As adjunctive therapy to enhance
healing, the osseous defect can be covered with a
resorbable collagen membrane impregnated with
platelet-rich plasma.
Overall, the beneﬁts of aminobisphosphonate
therapy for osteoporosis and metastatic cancer appear
to greatly outweigh the risk of developing BON.
However, the oral medications should be prescribed
only for those individuals with inadequate bone density
and should be discontinued or switched to a nonami-
nobisphosphonate once the bone density returns to an
acceptable level.
Increased bone density does not correlate necessar-
ily to good bone quality. The negative effects of over-
suppression of bone metabolism must be considered
in all patients prescribed oral aminobisphosphonates.
Several reports have documented spontaneous non-
traumatic stress fractures with associated delayed
healing in patients on long-term aminobisphosphonate
therapy. Many physicians now believe that amino-
bisphosphonate therapy should be stopped after 5
years and not reinitiated until bone density studies
conﬁrm redevelopment of signiﬁcant osteoporosis.
Dentists should be proactive and strongly encour-
age patients to speak to their attending physicians
for consideration of these factors during planning
and execution of long-term care. For individuals sched-
uled to receive IV aminobisphosphonate therapy as
part of their cancer management, the involved oncolo-
gist should recommend pretreatment dental evalua- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 303
tion and preventive care, with long-term, close
follow-up.
OROFACIAL COMPLICATIONS OF
METHAMPHETAMINE ABUSE
Methamphetamine (“meth”) is a drug with stimulant
effects on the central nervous system (CNS). In 1937
the drug was approved in the United States for the treat-
ment of narcolepsy and attention deﬁcit hyperactivity
disorder. Within a few years, many began to use the
drug to increase alertness, control weight, and combat
depression. Because methamphetamine users perceive
increased physical ability, greater energy, and eupho-
ria, illegal use and manufacture of the drug began to
develop. Because of greater control over the main
ingredient, pseudoephedrine, production of home-
made methamphetamine is decreasing but often being
replaced by illegal importation of the ﬁnished product.
The drug is a powdered crystal that dissolves easily in
liquid and can be smoked, snorted, injected, or taken
orally. The drug is known by nicknames that include
chalk, crank, crystal, ﬁre, glass, ice, meth, and speed.
CLINICAL FEATURES
Although methamphetamine abuse may occur through-
out society, most users are men between the ages of 19
and 40 years. The effects of the medication last up to
12 hours, and the typical abuser reports use that
exceeds 20 days per month, creating an almost con-
tinuous effect of the drug. The short-term effects of
methamphetamine include insomnia, aggressiveness,
agitation, hyperactivity, decreased appetite, tachycar-
dia, tachypnea, hypertension, hyperthermia, vomiting,
tremors, and xerostomia. Long-term effects addition-
ally include strong psychologic addiction, violent
behavior, anxiety, confusion, depression, paranoia,
auditory hallucinations, delusions, mood changes, skin
lesions, and a number of cardiovascular, CNS, hepatic,
gastrointestinal, renal, and pulmonary disorders.
Many addicts develop delusions of parasitosis (for-
mication, from the Latin word formica, which trans-
lates to ant), a neurosis that produces the sensation of
snakes or insects crawling on or under the skin. This
sensation causes the patient to attempt to remove the
perceived parasites, usually by picking at the skin with
ﬁngernails, resulting in widespread traumatic injury.
The factitial damage can alter dramatically the facial
appearance in a short period of time, and these lesions
have been nicknamed speed bumps, meth sores, or crank
bugs.
Rampant dental caries is another common manifes-
tation and exhibits numerous similarities with milk-
bottle caries. The carious destruction initially affects
the facial smooth and interproximal surfaces, but
without intervention, the coronal structure of the entire
dentition can be destroyed (Fig. 8-34). The carious
destruction appears to be caused by poor oral hygiene
combined with extreme drug-related xerostomia,
which leads to heavy consumption of acidic and sugar-
ﬁlled soft drinks or other reﬁned carbohydrates.
TREATMENT AND PROGNOSIS
The oral health practitioner should be alerted when an
emaciated, agitated, and nervous young adult presents
with tachycardia, tachypnea, hypertension, hyperther-
mia, and rampant smooth surface and interproximal
caries. Failure to recognize these signs can be serious.
For up to 6 hours after ingestion, methamphetamine
potentiates the effects of sympathomimetic amines.
Use of local anesthetics with epinephrine or levonor-
defrin can lead to a hypertensive crisis, cerebral vascu-
lar accident, or myocardial infarction. Caution also
should be exercised when administering sedatives,
general anesthesia, nitrous oxide, or prescriptions for
narcotics. Although cessation of the illicit drug use is
paramount, patients should be encouraged during
periods of xerostomia to discontinue use of highly
acidic and sugar-ﬁlled soft drinks and to avoid diuretics
such as caffeine, tobacco, and alcohol. In addition, the
importance of personal and oral hygiene should be
stressed. Preventive measures such as topical ﬂuorides
may assist in protecting the remaining dentition. A
medical consultation with referral to a substance abuse
center should be encouraged.
ANESTHETIC NECROSIS
Administration of a local anesthetic agent can, on rare
occasions, be followed by ulceration and necrosis at the
site of injection. Researchers believe that this
Fig. 8-34 Methamphetamine-related dental caries.
Extensive smooth-surface decay of the anterior dentition. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

304 ORAL AND MAXILLOFACIAL PATHOLOGY
necrosis results from localized ischemia, although the
exact cause is unknown and may vary from case to
case. Faulty technique, such as subperiosteal injection
or administration of excess solution in tissue ﬁrmly
bound to bone, has been blamed. The epinephrine con-
tained in many local anesthetics also has received
attention as a possible cause of ischemia and secondary
necrosis.
CLINICAL FEATURES
Anesthetic necrosis usually develops several days after
the procedure and most commonly appears on the
hard palate (Fig. 8-35). A well-circumscribed area of
ulceration develops at the site of injection. The ulcer-
ation often is deep, and, on occasion, healing may be
delayed. One report has documented sequestration of
bone at the site of tissue necrosis.
TREATMENT AND PROGNOSIS
Treatment of anesthetic necrosis usually is not required
unless the ulceration fails to heal. Minor trauma, such
as that caused by performing a cytologic smear, has
been reported to induce resolution in these chronic
cases. Recurrence is unusual but has been reported in
some patients in association with use of epinephrine-
containing anesthetics. In these cases the use of a local
anesthetic without epinephrine is recommended.
EXFOLIATIVE CHEILITIS
Exfoliative cheilitis is a persistent scaling and ﬂaking
of the vermilion border, usually involving both lips.
The process arises from excessive production and
subsequent desquamation of superﬁcial keratin. A
signiﬁcant percentage of cases appears related to
chronic injury secondary to habits such as lip licking,
biting, picking, or sucking. Those cases proven to
arise from chronic injury are termed factitious
cheilitis.
Many patients deny chronic self-irritation of the
area. The patient may be experiencing associated per-
sonality disturbances, psychologic difﬁculties, or stress.
In a review of 48 patients with exfoliative cheilitis, 87%
exhibited psychiatric conditions and 47% also demon-
strated abnormal thyroid function. Evidence suggests
that there may be a link between thyroid dysfunction
and some psychiatric disturbances.
In other cases, no evidence of chronic injury is
evident. In these patients other causes should be ruled
out (e.g., atopy, chronic candidal infection, actinic chei-
litis, cheilitis glandularis, hypervitaminosis A, photo-
sensitivity). In a review of 165 patients with acquired
immunodeﬁciency syndrome (AIDS), more than one
quarter had alterations that resembled exfoliative chei-
litis. In this group the lip alterations appeared second-
ary to chronic candidal infestation. The most common
presentation of bacterial or fungal infections of the lips
is angular cheilitis (see page 216). Diffuse primary
infection of the entire lip is very unusual; most diffuse
cases represent a secondary candidal infection in areas
of low-grade trauma of the vermilion border of the lip
(cheilocandidiasis).
In one review of 75 patients with chronic cheilitis,
a thorough evaluation revealed that more than one
third represented irritant contact dermatitis (often sec-
ondary to chronic lip licking). In 25% of the patients,
the cheilitis was discovered to be an allergic contact
mucositis (see page 350). Atopic eczema was thought
to be the cause in 19% of cases; the remaining portion
was related to a wide variety of pathoses.
In spite of a thorough investigation, there often
remain a number of patients with classic exfoliative
cheilitis for which no underlying cause can be found.
These idiopathic cases are most troublesome and often
resistant to a wide variety of interventions.
CLINICAL FEATURES
A marked female predominance is seen in cases of
factitious origin, with most cases affecting those
younger than 30 years of age. Mild cases feature chronic
dryness, scaling, or cracking of the vermilion border of
the lip (Fig. 8-36). With progression, the vermilion can
become covered with a thickened, yellowish hyper-
keratotic crust that can be hemorrhagic or that may
exhibit extensive ﬁssuring. The perioral skin may
become involved and exhibit areas of crusted erythema
(Fig. 8-37). Although this pattern may be confused with
perioral dermatitis (see page 352), the most appropri-
Fig. 8-35 Anesthetic necrosis. Mucosal necrosis of the
hard palate secondary to palatal injection with a local
anesthetic agent containing epinephrine. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 305
ate name for this process is circumoral dermatitis. Both
lips or just the lower lip may be involved.
In patients with chronic cheilitis, development of
ﬁssures on the vermilion border is not rare. In a preva-
lence study of more than 20,000 patients, these ﬁs-
sures involved either lip and were slightly more
common in the upper lip. In contrast to typical exfolia-
tive cheilitis, these ﬁssures demonstrate a signiﬁcant
male predilection and a prevalence rate of approxi-
mately 0.6%. The majority arise in young adults, with
rare occurrence noted in children and older adults.
Although the cause is unknown, proposed contribut-
ing factors include overexposure to sun, wind, and cold
weather; mouth breathing; bacterial or fungal infec-
tions; and smoking. An increased prevalence of lip ﬁs-
sures has been noted in patients with Down syndrome
and may be the result of the high frequency of mouth
breathing or the tendency to develop orofacial candi-
diasis. Application of lipstick or lip balm appears to be
protective. Fissure occurrence also may be related to a
physiologic weakness of the tissues. Those affecting the
lower lip typically occur in the midline, whereas ﬁs-
sures on the upper vermilion most frequently involve
a lateral position. These are the sites of prenatal merging
of the mandibular and maxillary processes.
TREATMENT AND PROGNOSIS
In those cases associated with an obvious cause, elimi-
nation of the trigger typically results in resolution of the
changes. In those cases with no underlying physical,
infectious, or allergic cause, psychotherapy (often com-
bined with mild tranquilization or stress reduction)
may achieve resolution. In cases for which no cause
can be found, therapeutic interventions often are not
successful.
Cases that result from candidal infections often do
not resolve until the chronic trauma also is eliminated.
Initial topical antifungal agents, antibiotics, or both
can be administered to patients in whom chronic
trauma is not obvious or is denied. If the condition
does not resolve, then further investigation is war-
ranted in an attempt to discover the true source of the
lip alterations.
Hydrocortisone and iodoquinol (antibacterial and
antimycotic) cream has been used to resolve chronic
lip ﬁssures in some patients (Fig. 8-38). Other reported
therapies include various corticosteroid preparations,
topical tacrolimus, sunscreens, and moisturizing prep-
arations. In many cases, resistance to topical therapy or
frequent recurrence is noted. In these cases, cryother-
apy or excision with or without Z-plasty has been used
successfully.
SUBMUCOSAL HEMORRHAGE
Everyone has experienced a bruise from minor trauma.
This occurs when a traumatic event results in hemor-
rhage and entrapment of blood within tissues. Differ-
ent terms are used, depending on the size of the
hemorrhage:
●Minute hemorrhages into skin, mucosa, or serosa
are termed petechiae.
●If a slightly larger area is affected, the hemorrhage
is termed a purpura.
●Any accumulation greater than 2 cm is termed an
ecchymosis.
●If the accumulation of blood within tissue pro-
duces a mass, this is termed a hematoma.
Blunt trauma to the oral mucosa often results in
hematoma formation. Less well known are petechiae
and purpura, which can arise from repeated or pro-
longed increased intrathoracic pressure (Valsalva
maneuver) associated with such activities as repeated
Fig. 8-36 Exfoliative cheilitis. Scaling and erythema of the
vermilion border of the lower lip.
Fig. 8-37 Circumoral dermatitis. Crusting and erythema of
the skin surface adjacent to the vermilion border in a child
who chronically sucked on both lips. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

306 ORAL AND MAXILLOFACIAL PATHOLOGY
coughing, vomiting, convulsions, or giving birth (Fig.
8-39). When considering a diagnosis of traumatic hem-
orrhage, the clinician should keep in mind that hemor-
rhages can result from nontraumatic causes, such as
anticoagulant therapy, thrombocytopenia, dissemi-
nated intravascular coagulation (DIC), and a number
of viral infections, especially infectious mononucleosis
and measles.
With the increased frequency of dental implant
placement, a number of reports have surfaced related
to potentially life-threatening ﬂoor of mouth hemor-
rhage secondary to a tear in the lingual periosteum or
perforation of the cortical plate during implant site
preparation. Similar spontaneous sublingual hemor-
rhage has been documented in patients with severe
hypertension or a systemic coagulopathy. Another
unusual hemorrhagic event involves the development
of an organized hematoma within the maxillary sinus.
The blood originates from a variety sources, the most
common of which is intranasal hemorrhage that drains
through the ostia and collects in the antrum.
CLINICAL FEATURES
Submucosal hemorrhage appears as a nonblanching
ﬂat or elevated zone with a color that varies from red
or purple to blue or blue-black (Fig. 8-40). As would be
expected, traumatic lesions are located most frequently
on the labial or buccal mucosa. Blunt facial trauma
often is responsible, but injuries such as minor as cheek
biting may produce a hematoma or areas of purpura
(Fig. 8-41). Mild pain may be present.
The hemorrhage associated with increased intratho-
racic pressure usually is located on the skin of the
face and neck and appears as widespread petechiae
that clear within 24 to 72 hours. Although it has not
been as well documented as the cutaneous lesions,
mucosal hemorrhage can be seen in the same setting
A B
Fig. 8-38 Lip ﬁssure. A, Chronic ﬁssure of the vermilion border of the upper lip. B, Same
site 2 weeks later, after use of hydrocortisone and iodoquinol cream.
Fig. 8-39 Petechiae. Submucosal hemorrhage of the soft
palate caused by violent coughing.
Fig. 8-40 Purpura. Submucosal hemorrhage of the lower
labial mucosa on the left side secondary to blunt trauma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 307
and most often appears as soft palatal petechiae or
purpura.
Hematoma formation associated with surgical
implant preparation usually is associated with damage
of the soft tissues adjacent to the lingual surface of the
mandible and produces swelling and elevation of the
ﬂoor of the mouth. Although the hemorrhage is notice-
able immediately in most patients, the problem may
not become evident clinically for 4 to 6 hours. Disten-
sion, elevation, and protrusion of the tongue may occur
and be associated with inability to swallow or signiﬁ-
cant dyspnea.
Patients with antral hematomas typically complain
of frequent nasal bleeding but also may experience
unilateral nasal obstruction, hyposmia, headache, and
malar swelling. Facial paresthesia and vision problems
occur less frequently. Computed tomography (CT)
typically demonstrates a soft tissue mass ﬁlling and
expanding the antrum, often associated with proptosis
and partial destruction or displacement of the sinus
walls. In many instances, the radiographic appearance
is worrisome for a malignant neoplasm.
TREATMENT AND PROGNOSIS
Often, no treatment is required if the hemorrhage is
not associated with signiﬁcant morbidity or related to
systemic disease. The areas should resolve spontane-
ously. Large hematomas may require several weeks to
resolve. If the hemorrhage occurs secondary to an
underlying disorder, then treatment is directed toward
control of the associated disease.
In cases of emergent hemorrhage associated with
surgical implant placement, the ﬁrst priority is to secure
the airway. Although the hemorrhage can be controlled
with conservative measures in some cases, the majority
require surgical exploration with isolation and repair
of the damaged vessel. Antral hematomas usually are
removed via a Caldwell-Luc procedure for both thera-
peutic and diagnostic purposes. After successful
removal, a search for the bleeding source or any under-
lying coagulopathy is recommended to prevent
recurrence.
ORAL TRAUMA FROM
SEXUAL PRACTICES
Although orogenital sexual practices are illegal in many
jurisdictions, they are extremely common. Among
homosexual men and women, orogenital sexual activ-
ity almost is universal. For married heterosexual
couples younger than age 25, the frequency has been
reported to be as high as 90%. Considering the preva-
lence of these practices, the frequency of associated
traumatic oral lesions is surprisingly low.
CLINICAL FEATURES
The most commonly reported lesion related to orogeni-
tal sex is submucosal palatal hemorrhage secondary to
fellatio. The lesions appear as erythema, petechiae,
purpura, or ecchymosis of the soft palate. The areas
often are asymptomatic and resolve without treatment
in 7 to 10 days (Fig. 8-42). Recurrences are possible
with repetition of the inciting (exciting?) event. The
erythrocytic extravasation is thought to result from the
musculature of the soft palate elevating and tensing
against an environment of negative pressure. Similar
lesions have been induced from coughing, vomiting,
or forceful sucking on drinking straws and glasses.
A B
Fig. 8-41 Hematoma. A, Dark-purple nodular mass of the buccal mucosa in a patient on
coumadin therapy. B, Near resolution of the lesion 8 days later after discontinuation of the
medication. (Courtesy of Dr. Charles Ferguson.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

308 ORAL AND MAXILLOFACIAL PATHOLOGY
Forceful thrusting against the vascular soft palate has
been suggested as another possible cause.
Oral lesions also can occur from performing cunni-
lingus, resulting in horizontal ulcerations of the lingual
frenum. As the tongue is thrust forward, the taut frenum
rubs or rakes across the incisal edges of the mandibular
central incisors. The ulceration created coincides with
sharp tooth edges when the tongue is in its most forward
position. The lesions resolve in 7 to 10 days but may
recur with repeated performances. Linear ﬁbrous
hyperplasia has been discovered in the same pattern
in individuals who chronically perform the act (Fig.
8-43).
HISTOPATHOLOGIC FEATURES
With an appropriate index of suspicion, biopsy usually
is not required; however, a biopsy has been performed
in some cases of palatal lesions secondary to fellatio.
These suction-related lesions reveal subepithelial accu-
mulations of red blood cells that may be extensive
enough to separate the surface epithelium from under-
lying connective tissue. Patchy degeneration of the
epithelial basal cell layer can occur. The epithelium
classically demonstrates migration of erythrocytes and
leukocytes from the underlying lamina propria.
TREATMENT AND PROGNOSIS
No treatment is required, and the prognosis is good. In
patients who request assistance, palatal petechiae can
be prevented through the use of less negative pressure
and avoidance of forceful thrusting. Smoothing and
polishing the rough incisal edges of the adjacent man-
dibular teeth can minimize the chance of lingual
frenum ulceration.
AMALGAM TATTOO AND OTHER
LOCALIZED EXOGENOUS
PIGMENTATIONS
A number of pigmented materials can be implanted
within the oral mucosa, resulting in clinically evident
pigmentations. Implantation of dental amalgam
(amalgam tattoo) occurs most often, with a frequency
that far outdistances that for all other materials. Local-
ized argyrosis has been used as another name for
amalgam tattoo, but this nomenclature is inappropriate
because amalgam contains not only silver but also
mercury, tin, copper, zinc, and other metals.
Amalgam can be incorporated into the oral mucosa
in several ways. Previous areas of mucosal abrasion can
be contaminated by amalgam dust within the oral
ﬂuids. Broken amalgam pieces can fall into extraction
sites. If dental ﬂoss becomes contaminated with
amalgam particles of a recently placed restoration,
then linear areas of pigmentation can be created in the
gingival tissues as a result of hygiene procedures (Fig.
8-44). Amalgam from endodontic retroﬁll procedures
can be left within the soft tissue at the surgical site (Fig.
8-45). Finally, ﬁne metallic particles can be driven
through the oral mucosa from the pressure of high-
speed air turbine drills.
Theoretically, the use of the rubber dam should
decrease the risk; however, immediately after removal
of the dam, the occlusion often is adjusted with the
potential for amalgam contamination of any areas of
mucosal damage. Submucosal implantation of pencil
graphite, coal and metal dust, fragments of broken car-
borundum disks, dental burs, and, in the past, charcoal
dentifrices, have resulted in similar-appearing areas of
discoloration.
Intentional tattooing, which can be found in approx-
imately 25% of the world’s population, also may be
Fig. 8-42 Palatal petechiae from fellatio. Submucosal
hemorrhage of the soft palate resulting from the effects of
negative pressure.
Fig. 8-43 Fibrous hyperplasia from repeated cunnilingus.
Linear ﬁbrous hyperplasia of the lingual frenum caused by
repeated irritation from lower incisors. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 309
performed in the oral cavity. Although some cases are
culturally related, health professionals also are respon-
sible for a number of intentional oral and facial tattoos
for the purpose of demonstrating landmarks, judging
tumor response to antineoplastic therapies, repigment-
ing areas of vitiligo, cosmetically disguising disﬁgured
areas, and applying permanent cosmetic makeup. Inju-
dicious intraoral use of these marking agents can cause
diffusion of the pigment with discoloration of the adja-
cent skin surface.
CLINICAL AND RADIOGRAPHIC
FEATURES
Amalgam tattoos appear as macules or, rarely, as
slightly raised lesions. They may be black, blue, or gray.
The borders can be well deﬁned, irregular, or diffuse
(Fig. 8-46). Lateral spread may occur for several months
after the implantation. In most cases, only one site is
affected, although multiple tattoos in a single patient
may be present. Any mucosal surface can be involved,
but the most common sites are the gingiva, alveolar
mucosa, and buccal mucosa (Fig. 8-47).
Periapical radiographs, when taken, are negative in
many cases. When metallic fragments are visible radio-
graphically, the clinical area of discoloration typically
extends beyond the size of the fragment. The fragments
are densely radiopaque, varying from several millime-
ters to pinpoint in size (see Fig. 8-47). On occasion, the
pattern of the amalgam dispersal has been sufﬁciently
unique to be used as a distinctive characteristic in the
identiﬁcation of unknown deceased individuals.
The pattern of accidental localized foreign body
tattoo other than amalgam is diverse and depends on
the associated trauma that impacted the material.
Mucosal graphite implantation is rarely documented,
but it most likely occurs with a higher frequency than
indicated by the number of cases reported. Examples
in the literature have been presented as grayish areas
of mucosal discoloration of the hard palate, the most
likely site for pencil-related trauma.
Cosmetic tattooing is gaining in popularity and may
include injection of permanent cosmetic inks into the
eyelids and vermilion border of the upper and lower
lips. On occasion, patients may react to the material
and experience swelling, burning, and itching at the
site, followed by enlargement and induration. In such
cases, biopsy often reveals a granulomatous reaction to
the foreign material.
Fig. 8-44 Floss-related amalgam implantation. Linear
strips of mucosal pigmentation that align with the interdental
papillae. The patient used dental ﬂoss on the mandibular ﬁrst
molar immediately after the placement of the amalgam
restoration. Because the area was still anesthetized, the
patient impaled the ﬂoss on the gingiva, then continued
forward using the amalgam-impregnated ﬂoss in the bicuspid
area to create additional amalgam tattoos.
Fig. 8-45 Endodontic-related amalgam implantation.
Multifocal areas of mucosal discoloration overlying the
maxillary anterior incisors, which have been treated with
apical retroﬁll procedures.
Fig. 8-46 Amalgam tattoo. Area of mucosal discoloration
of the ﬂoor of the mouth on the patient’s left side. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

310 ORAL AND MAXILLOFACIAL PATHOLOGY
The intentional intraoral tattoos that are not placed
by health professionals occur most frequently on the
anterior maxillary facial gingiva of individuals from a
number of African countries and have been docu-
mented at institutions in the United States (Fig. 8-48).
In these cases the anterior maxillary facial gingiva is
given a heavy blue-black discoloration. Occasionally,
tattoos (usually blue or black) are placed on the labial
mucosa of adults in the United States to convey a per-
sonal, often vulgar, message (Fig. 8-49).
HISTOPATHOLOGIC FEATURES
Microscopic examination of amalgam tattoos reveals
pigmented fragments of the metal within the connec-
tive tissue. Scattered, large, dark, solid fragments or
numerous ﬁne, black, or dark-brown granules may be
seen (Fig. 8-50). The silver salts of the dental amalgam
preferentially stain the reticulin ﬁbers, especially those
encircling nerves and vascular channels (Fig. 8-51).
The biologic response to amalgam appears related
to particle size and the elemental composition of the
A
B
Fig. 8-47 Amalgam tattoo. A, Area of mucosal
discoloration of the mandibular alveolar ridge immediately
below the bridge pontic. B, Radiograph of the same patient
showing radiopaque metallic fragment present at the site of
mucosal discoloration.
Fig. 8-48 Intentional intraoral tattoo. Cultural tattoo of
the maxillary facial gingiva in a patient from Senegal. (Courtesy
of Dr. Kristin McNamara.)
Fig. 8-49 Intentional intraoral tattoo. Amateur tattoo of
the lower labial mucosa. (Courtesy of Dr. Edward Herschaft.)
amalgam. Large fragments often become surrounded
by dense ﬁbrous connective tissue with mild inﬂamma-
tion. Smaller particles typically are associated with a
more signiﬁcant inﬂammatory response that may be
granulomatous or a mixture of lymphocytes and plasma
cells. Graphite implantation appears similar micro-
scopically to amalgam but can be differentiated by its
pattern of birefringence after treatment with ammo-
nium sulﬁde and by the lack of staining of the reticulin
ﬁbers. In addition, energy dispersive x-ray microanaly-
sis can be used to identify the type of material present
within areas of foreign body tattoos.
TREATMENT AND PROGNOSIS
To conﬁrm the diagnosis of amalgam tattoo, the clini-
cian can obtain radiographs of the areas of mucosal
discoloration in an attempt to demonstrate the metallic `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 311
fragments. The ﬁlms should be capable of high detail,
because many of the fragments are no larger than the
point of a pin.
No treatment is required if the fragments can be
detected radiographically. If no metallic fragments are
found and the lesion cannot be diagnosed clinically,
then biopsy may be needed to rule out the possibility
of melanocytic neoplasia. On occasion, the amalgam
implantation may create pigmentation in a cosmeti-
cally objectionable location such as the anterior maxil-
lary facial gingiva. In such cases, conservative surgical
excision can be performed; alternatively amalgam
tattoos have been removed successfully with Q-
switched ruby or alexandrite lasers. With respect to
cosmetic tattoos, a variety of treatments such as corti-
costeroids and lasers have been used with variable
results.
ORAL PIERCINGS AND OTHER
BODY MODIFICATIONS
Historical evidence from almost every continent shows
that body piercing is an ancient practice with a strong
association with religious, cultural, or superstitious
beliefs. In the Western world, body piercing beyond
the earlobes has become increasingly popular as a
method of self-expression during the past decade. In a
2001 survey of 481 college students in the United
States, 51% admitted body piercing, and the prevalence
still appears to be rising. Usually, the piercing is per-
formed to place jewelry in sites such as the eyebrows,
helix of the ears, nose, navel, nipples, genitals, and a
number of intraoral sites.
Forked tongue (split tongue, biﬁd tongue) is a
rather recent addition to the art of body modiﬁcation,
with few associated publications. In this practice the
anterior one third of the tongue is split down the
middle. This has been performed slowly by pulling
ﬁshing line through a pierced hole and tightening the
loop over a period of 3 weeks or using a surgical instru-
ment or laser to quickly separate the two halves. Some
form of cautery is necessary to prevent the halves from
reuniting. Forked tongue also has been reported as a
complication of tongue piercing.
Another practice with unique orofacial manifesta-
tions is implantation of a form of talisman (magical
charm) called susuk (charm needles, charm pins).
This practice is common in southeast Asia, especially
Malaysia, Thailand, Singapore, Indonesia, and Brunei.
The susuk is placed by a native magician or medicine
man termed bomoh and is thought to enhance or pre-
serve beauty, relieve pain, bring success in business, or
provide protection against harm. The majority of the
individuals with susuk are Muslims, although Islam
strictly prohibits black magic. Therefore, many affected
individuals will deny placement of susuk, even when
confronted directly with hard evidence.
CLINICAL AND RADIOGRAPHIC
FEATURES
Intraoral piercings are noted most frequently in ado-
lescents and young adults, with a female predomi-
nance. The most commonly affected sites are the
tongue, lips, buccal mucosa, and, rarely, the uvula.
The selected site typically is pierced with a 14- to 16-
gauge sheeted needle, then the jewelry of choice is
threaded through the wound. The jewelry most often
is gold, silver, or stainless steel; in the tongue, the
most frequent adornment is a barbell (dumbbell
might be a better name!) consisting of a metal rod with
a ball that screws onto each end (Fig. 8-52). The lip
jewelry is termed a labret and most often consists
of a ring or a rod with a ﬂat end attached to the
Fig. 8-50 Amalgam tattoo. Numerous dark, solid
fragments of amalgam are surrounded by a lymphohistiocytic
inﬂammatory inﬁltrate.
Fig. 8-51 Amalgam tattoo. Dark amalgam stain encircling
numerous vascular channels. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

312 ORAL AND MAXILLOFACIAL PATHOLOGY
mucosal side and a round ball for the cutaneous sur-
face (Fig. 8-53).
If no complications occur, healing of the piercing
site takes place within 4 to 6 weeks. Potential acute
complications include pain, prolonged or profuse
bleeding, swelling (to the point of airway obstruction
in rare cases), infection including Ludwig’s angina and
cerebellar brain abscess, lingual nerve damage, speech
impediment, and allergy to the jewelry. Chronic com-
plications include mucosal or gingival trauma, chipped
or fractured teeth, hypersalivation, aspiration or swal-
lowing of jewelry, tissue hyperplasia around the posts,
and embedded jewelry. Gingival recession (labrets,
barbells) and tooth fracture (barbells) are extremely
common, with the prevalence closely related to the
duration of use. Molars and premolars are fractured
most frequently, with the damage associated more
often with a short-stem barbell, whereas greater sever-
ity of gingival recession is associated with long-stem
barbells and labrets.
In individuals with forked tongues, the anterior
half of the tongue is split down the middle (Fig. 8-54).
Risks of the procedure include inﬂammation, infec-
tion, profuse or prolonged hemorrhage, and perma-
nent neurovascular damage. After healing, some
individuals have developed the ability to control each
half independently.
Susuk usually is shaped like a needle that is pointed
on one end and blunt on the other. Most are made from
silver or gold, measure 0.5 mm in diameter, and vary
from 0.5 to 1.0 cm in length. Rarely, they are made
from diamonds. The pins vary in number from one to
many and are inserted subcutaneously, often in a sym-
metrical fashion. The orofacial region is the most
common location, but some choose the chest, arms,
breasts, and pubic region. In most instances, the indi-
viduals are middle-aged adults. Normally, no clinical
evidence exists, either visually or by palpation, and the
pins are discovered during routine radiography for
unrelated medical or dental problems (Fig. 8-55).
TREATMENT AND PROGNOSIS
As mentioned, intraoral barbells and labrets are associ-
ated with an increasing prevalence of oral complica-
tions that relate closely with duration of use. The patient
should be strongly encouraged to remove the jewelry.
On removal, if the site demonstrates signiﬁcant inﬂam-
mation, local débridement, antibiotic therapy, and
chlorhexidine mouthwash may be appropriate.
Except for slight sibilant distortions and shortening
of the protrusive length of the tongue, few long-term
adverse events have been noted in patients with forked
tongues.
Susuk have not been associated with harmful effects,
and no treatment is required. If the needles have a
Fig. 8-52 Lingual piercing. Tongue pierced with a jewelry
item known as a barbell.
Fig. 8-53 Labial piercing. Lower lip pierced bilaterally with
labrets consisting of a circular rod with terminating balls. The
patient also has a lingual barbell.
Fig. 8-54 Forked tongue. Anterior portion of the tongue
divided into two separate lobes, each of which can be
controlled independently. (Courtesy Dr. Fleming Chisholm.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 313
ferrous content, then magnetic resonance imaging
(MRI) would be contraindicated. On occasion, affected
individuals request removal of the susuk before they
die because they believe their death will be excruciat-
ingly painful.
SYSTEMIC METALLIC INTOXICATION
Ingestion or exposure to any one of several heavy
metals can cause signiﬁcant systemic and oral abnor-
malities. Exposure to heavy metals may be massive,
resulting in acute reactions, or it may be minimal over
a longer period, producing chronic changes. Oral alter-
ations from ingestion of lead, mercury, silver, bismuth,
arsenic, and gold are rare but may occur and warrant
discussion. Oral complications from excessive zinc,
iron, tin, and manganese are extremely rare.
LEAD
Little is known about the prevalence of lead poisoning
(plumbism), but lead is one of the most widespread
environmental toxins affecting children in the United
States. Lead solder for plumbing was not banned until
1986. Homes built before then have the potential for
signiﬁcant water contamination, and one of the primary
causes of lead intoxication in infants is formula prepa-
ration using tap water tainted by the metal.
Another signiﬁcant source of lead poisoning in chil-
dren is lead-based paint; children may ingest chips of
the paint in older homes or be exposed to the fumes or
dust during sanding and renovation. Paint with a high
lead content was not restricted until 1977 and still
remains in many homes. Removal of lead from gaso-
line began in 1972 but was not completed until 1995.
These sources of lead combined with previous indus-
trial emissions have resulted in sites with highly con-
taminated soil, especially in urban areas. Despite the
widespread publicity and signiﬁcant efforts to restrict
exposure to lead during childhood, signiﬁcant risk
remains.
Adult exposure also occurs and often is related to
industry. The potential for exposure exists during han-
dling of lead oxide batteries, in lead-processing indus-
tries, and from the welding of lead-covered surfaces.
Some food and drink containers or vegetables grown
in lead-contaminated soil also may contain inappropri-
ate levels of the metal. Lead contamination in illicit
alcohol has made the distinction between symptoms of
lead intoxiﬁcation and chronic alcohol abuse very dif-
ﬁcult in certain sections of the American Deep South.
Lead also can be found in brass ﬁxtures, ceramics,
crystal, electrical cable, radiation shielding, folk reme-
dies, and cosmetics. Rarely, plumbism arises from
retained lead bullet fragments in gunshot victims.
MERCURY
The danger of mercury exposure is well known. Ele-
mental mercury is poorly absorbed, and its ingestion is
relatively harmless. In contrast, inhalation of mercury
vapor is very hazardous, with a high rate of absorption
and systemic retention. Ingestion of mercury salts (e.g.,
mercurous chloride) also is associated with signiﬁcant
adverse reactions. Exposure has occurred in associa-
tion with the use of mercury in teething powders,
cathartic agents, and anthelmintic preparations.
A great deal of attention has been directed toward
the mercury released from dental amalgams, but no
well-documented adverse health effects have been
identiﬁed (except for relatively rare contact hypersen-
sitivity to mercury, see page 354). The level of mercury
Fig. 8-55 Susuk (charm needles). Panoramic radiograph showing multiple radiopaque
needles superimposed on the jaws. (Courtesy of Dr. Jeff Bayme.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

314 ORAL AND MAXILLOFACIAL PATHOLOGY
that is released from amalgams does not appear sufﬁ-
ciently high to cause disease and has been shown not
to exceed the range expected from background expo-
sure to environmental mercury. In an attempt to shed
light on this controversy, the National Institutes of
Health (NIH) funded two large randomized clinical
trials that compared the neurologic and renal effects of
dental amalgam in a 7-year study of a large cohort of
children. In these pivotal investigations, no adverse
effects from dental amalgam were seen. Interestingly,
the control group that received only composite restora-
tions demonstrated a 50% higher need for additional
restorative treatment because of the failure of their
restorations during the long-term study.
SILVER
Silver has known antibacterial properties and has been
associated with a number of additional health beneﬁts.
In the past, silver compounds were used topically in
nose drops and systemically for a variety of disorders
including mental illness, epilepsy, nicotine addition,
common colds, sinusitis, gastrointestinal ulcerations,
syphilis, and gonorrhea. Because of the numerous com-
plications, including silver intoxiﬁcation, the FDA con-
cluded that the risk of systemic silver products exceeded
their beneﬁts. In 1999 the use of colloidal silver or
silver salts was banned in over-the-counter products.
Several silver nitrate and silver sulfadiazine formula-
tions remain available by prescription. These products
should be used only under strict supervision. Well-
documented examples of generalized argyria have
been seen secondary to long-term treatment of aph-
thous ulcerations, denture sores, and minor gingival
hemorrhage with topical silver nitrate.
Devices for production of homemade colloidal silver
suspension and a number of colloidal silver proteins
continue to be marketed over the Internet and in health
food stores as essential mineral supplements for dis-
eases such as arthritis, cancer, diabetes, AIDS, and
herpes. These unregulated silver products have no
known physiologic function, and their continued use
cannot be supported.
BISMUTH AND ARSENIC
In the United States, exposure to bismuth and arsenic
currently is rare. The medical use of these metals has
diminished dramatically; most current cases arise from
occupational exposure. Bismuth was used in the past
for treatment of venereal diseases and various derma-
toses, whereas arsenic compounds were prescribed for
asthma and skin disorders such as psoriasis. Bismuth
iodoform parafﬁn paste continues to be used by otolar-
yngologists and oral surgeons as a surgical pack, with
rare reports of associated toxicity. In addition, bismuth
subsalicylate tablets (Pepto-Bismol) have been reported
to produce localized mucosal discoloration. Chronic
exposure to arsenic continues in some lesser developed
areas of the world from drinking contaminated water.
GOLD
Gold has been used in medical treatment in the past
and continues to be used today in selected cases of
active rheumatoid arthritis and other immunologically
mediated diseases. In these cases the side effects are
well known, and physicians observe the patients closely.
In reviews of large-scale skin testing, gold has been
found to be among the top 10 most frequent allergens,
with positive reactions seen in about 10% of the popula-
tion, including increased prevalence in patients who
have gold dental restorations.
CLINICAL FEATURES
LEAD
Lead poisoning results in nonspeciﬁc systemic signs
and symptoms, thereby making the ultimate diagnosis
very difﬁcult. The presentation is extremely variable
and determined by the type of lead (organic or inor-
ganic) and the age of the patient. Patients with acute
cases most often have abdominal colic, which may
occur along with anemia, fatigue, irritability, and weak-
ness. Encephalopathy and renal dysfunction also may
occur. Chronic exposure causes dysfunction of the
nervous system, kidneys, marrow, bone, and joints.
Symptoms generally include fatigue, musculoskeletal
pain, and headache. Bones and teeth represent a major
reservoir in patients with chronic plumbism, with 90%
of the body’s deposition being within bone. In radio-
graphs of the long bones in infants, a radiopaque lead
line often is noted along the epiphyseal plates. In addi-
tion, abdominal radiographs often will reveal small
radiopaque paint chips in the gastrointestinal tract.
Oral manifestations include ulcerative stomatitis
and a gingival lead line (Burton’s line). The lead line
appears as a bluish line along the marginal gingiva
resulting from the action of bacterial hydrogen sulﬁde
on lead in the gingival sulcus to produce a precipitate
of lead sulﬁde. Gray areas also may be noted on the
buccal mucosa and tongue. Additional manifestations
include the following:
●Tremor of the tongue on thrusting
●Advanced periodontal disease
● Excessive salivation
● Metallic taste
MERCURY
Mercury poisoning also may be acute or chronic. With
acute cases, abdominal pain, vomiting, diarrhea, thirst,
pharyngitis, and gingivitis typically are present. With
chronic cases, gastrointestinal upset and numerous `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 315
neurologic symptoms occur. Oral changes include a
metallic taste and ulcerative stomatitis combined with
inﬂammation and enlargement of the salivary glands,
gingiva, and tongue. The gingiva may become blue-gray
to black. Mercuric sulﬁde can be generated by the bac-
terial action on the metal and can cause signiﬁcant
destruction of the alveolar bone with resultant exfolia-
tion of teeth.
Chronic mercury exposure in infants and children
is termed acrodynia (pink disease, Swift disease).
The children have cold, clammy skin, especially on the
hands, feet, nose, ears, and cheeks. An erythematous
and pruritic rash is present. Severe sweating, increased
lacrimation, irritability, insomnia, photophobia, hyper-
tension, weakness, tachycardia, and gastrointestinal
upset also may be present. On occasion, these highly
irritable children have torn out patches of their hair.
Oral signs include excessive salivation, ulcerative gin-
givitis, bruxism, and premature loss of teeth. Because
mercury salts were formerly used in the processing of
felt, hat makers in past centuries were exposed to the
metal and experienced similar symptoms, giving rise
to the phrase “mad as a hatter.”
SILVER
Acute silver intoxication can produce coma, pleural
edema, hemolysis, and bone marrow failure. Chronic
systemic silver intoxication is known as argyria. Silver
is disseminated throughout the body with substantial
amounts accumulating as subepithelial deposits in the
skin. These deposits result in a diffuse grayish discolor-
ation that develops primarily in the sun-exposed areas
(Fig. 8-56). The sclerae and nails also may be pig-
mented. One of the ﬁrst signs of argyria occurs in the
oral cavity and appears as a slate-blue silver line along
the gingival margins. This discoloration is secondary to
deposition of metallic silver and silver sulﬁde pigments.
In addition, the oral mucosa often exhibits a diffuse
blue-black discoloration.
BISMUTH
Chronic bismuth exposure can result in a diffuse blue-
gray discoloration of the skin. The conjunctiva and oral
cavity also may be involved. A blue-gray line along the
gingival margin similar to that seen from lead intoxica-
tion is the most common intraoral presentation.
Bismuth combines with bacterial hydrogen sulﬁde to
form bismuth sulﬁde, which is irritating locally but not
as destructive as mercuric sulﬁde. Associated ptyalism,
burning, stomatitis, and ulceration may be seen. Intoxi-
cation from bismuth-containing surgical packs has
been associated with CNS symptoms such as delirium.
Chronic use of bismuth subsalicylate tablets can create
a removable black discoloration of the otherwise
normal ﬁliform papillae. Although the lingual altera-
tion may resemble black hairy tongue, the papillae are
not elongated.
ARSENIC
In addition to widespread effects on numerous organ
systems, signiﬁcant dermatologic alterations frequently
occur. Prolonged ingestion of arsenic often results in a
diffuse macular hyperpigmentation. The discoloration
is due to both the presence of the metal and an
increased melanin production. In addition, palmar and
plantar hyperkeratosis often is noted, as well as numer-
ous premalignant skin lesions called arsenical kerato-
ses. Development of basal cell carcinoma and cutaneous
squamous cell carcinoma has been seen after years of
exposure. Oral manifestations are rare and typically
appear as excessive salivation and painful areas of nec-
rotizing ulcerative stomatitis. In the past, extensive
dorsal hyperkeratosis of the tongue was seen in patients
with syphilis and may be related to arsenic therapy
used before the advent of antibiotic therapy.
GOLD
The most common complication of gold therapy is der-
matitis, which often is preceded by a warning signal:
pruritus. Although a generalized exfoliative dermatitis
with resultant alopecia and loss of nails can be seen,
dermatitis about the face, eyelids, and at direct sites of
skin contact is the most common presentation. Because
of the high frequency of allergy to gold, skin testing
often is performed before administration of gold drug
therapy.
The second most common adverse reaction to gold
is severe oral mucositis, which most frequently involves
Fig. 8-56 Argyria. Grayish discoloration of the face
compared with a more normal facial complexion in an
individual who used a silver-containing nutritional
supplement. Before development of silver intoxication, this
blue-eyed, red-haired individual had a very light complexion.
(Courtesy of Bradford R. Williams.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

316 ORAL AND MAXILLOFACIAL PATHOLOGY
the buccal mucosa, lateral border of the tongue, palate,
and pharynx. These mucosal changes represent a sys-
temic allergic reaction and are different from intraoral
contact gold hypersensitivity (see page 347). A metallic
taste often precedes development of the oral lesions
and should be considered another warning signal.
Therapy with gold rarely can bring about a slate-blue
discoloration of sun-exposed skin (chrysiasis).
TREATMENT AND PROGNOSIS
The management of heavy metal intoxication involves
removal from further exposure to the agent, supportive
care, decontamination, and use of chelating agents. In
some cases a medication may be responsible and can
be discontinued; however, sometimes the source of the
metal may be difﬁcult to determine. In infants with
radiographic evidence of gastrointestinal lead-contain-
ing paint chips, bowel irrigation with a polyethylene
glycol electrolyte lavage solution may be warranted. In
the past, two chelators, ethylenediaminetetraacetic
acid (EDTA) (calcium disodium ethylenediaminetet-
raacetate) and BAL (2,3-dimercaptopropanol), were
ﬁrst-line therapy in the treatment of lead poisoning,
whereas arsenic and mercury intoxication were treated
with BAL. These medications may have signiﬁcant side
effects, and less toxic alternatives such as DMSA (2,3-
dimercaptosuccinic acid) and DMPS (2,3-dimercapto-
propane-1-sulfonate) now are available. No antidote
exists for silver intoxication, and treatment is limited to
supportive measures. Attempts to remove the bluish
discoloration of facial argyria with dermabrasion have
been unsuccessful. Encephalopathy associated with
use of bismuth-containing surgical packs clears on
removal of the material.
SMOKER’S MELANOSIS
Oral pigmentations are increased signiﬁcantly in heavy
smokers. In one investigation of more than 31,000
whites, 21.5% of tobacco smokers exhibited areas of
melanin pigmentation compared with 3% among those
not using tobacco. In another study of an ethnically
pigmented population, smokers had more oral surfaces
exhibiting melanin pigmentation.
Melanin pigmentation in the skin exerts a well-
known protective effect against ultraviolet (UV)
damage. Investigations of melanocytes located away
from sun-exposed areas have shown the ability of
melanin to bind to noxious substances. Exposure to
polycyclic amines (e.g., nicotine and benzpyrene) has
been shown to stimulate melanin production by mela-
nocytes that also are known to bind strongly to nico-
tine. Research has suggested that melanin production
in the oral mucosa of smokers serves as a protective
response against some of the harmful substances in
tobacco smoke. This concept is supported by the ﬁnd-
ings in “reverse” smokers, who smoke with the lit end
of the cigarette inside the mouth and demonstrate
heavy melanin pigmentation of the palate. In some
reverse smokers, areas of melanocytes are lost and
zones of depigmented red mucosa can develop. Cancer
is found in 12% of patients with these red zones, further
delineating the probable protective effects of melano-
cytes against toxic substances.
CLINICAL FEATURES
Although any mucosal surface may be affected, smok-
er’s melanosis most commonly affects the anterior
facial gingiva (Fig. 8-57). Most people affected by this
condition are cigarette users. In contrast, pipe smokers
frequently exhibit pigmentations located on the com-
missural and buccal mucosae. Reverse smokers show
alterations of the hard palate.
The areas of pigmentation signiﬁcantly increase
during the ﬁrst year of smoking and appear correlated
to the number of cigarettes smoked each day. A higher
frequency is seen in females, and researchers have
suggested that female sex hormones exert a synergistic
effect when combined with smoking. Reports from
Sweden, Germany, and Japan have shown tobacco
smoking to be the most common cause for mucosal
pigmentation in light-skinned adult populations.
HISTOPATHOLOGIC FEATURES
Biopsy specimens of affected areas in people with
smoker’s melanosis reveal increased melanin pigmen-
tation of the basal cell layer of the surface epithelium,
similar to a melanotic macule (see page 379). In addi-
tion, collections of incontinent melanin pigmentation
Fig. 8-57 Smoker’s melanosis. Light, diffuse melanin
pigmentation in a white female who is a heavy smoker.
Pigmentary changes are limited to the anterior facial gingiva. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 317
are seen free within the superﬁcial connective tissue
and in scattered melanophages.
DIAGNOSIS
The clinician can make the diagnosis by correlating the
smoking history with the clinical presentation and
medical history. Other causes of melanin pigmenta-
tion, such as trauma, neuroﬁbromatosis, Peutz-Jeghers
syndrome, drug-related pigmentation, endocrine dis-
turbances, hemochromatosis, chronic pulmonary
disease, and racial pigmentation should be excluded.
TREATMENT AND PROGNOSIS
Cessation of smoking results in gradual disappearance
of the areas of related pigmentation over a 3-year period.
Biopsy should be considered when the pigmentation is
in unexpected locations, such as the hard palate, or
when there are unusual clinical changes, such as
increased melanin density or surface elevation.
DRUG-RELATED DISCOLORATIONS
OF THE ORAL MUCOSA
An expanding number of medications have been impli-
cated as a cause of oral mucosal discolorations.
Although many medications stimulate melanin pro-
duction by melanocytes, deposition of drug metabolites
is responsible for the color change in others. These
pigmentary alterations have been associated with use
of phenolphthalein, minocycline, tranquilizers, anti-
malarial medications, estrogen, chemotherapeutic
agents, and some medications used in the treatment of
patients with AIDS.
The antimalarial agents that are most frequently
implicated are chloroquine, hydrochloroquine, quini-
dine, and quinacrine; chlorpromazine represents the
most frequently implicated tranquilizer. Besides treat-
ing malaria, antimalarial agents are used for many
other disorders, including lupus erythematosus and
rheumatoid arthritis.
Oral mucosal pigmentation associated with chemo-
therapeutic medications is most commonly reported
with use of doxorubicin, busulfan, cyclophosphamide,
or 5-ﬂuorouracil. Although idiopathic hyperpigmenta-
tion also may occur, AIDS patients receiving zidovu-
dine (AZT), clofazimine, or ketoconazole have
demonstrated increased melanin pigmentation.
CLINICAL FEATURES
The clinical presentations of pigmentations related to
drug use vary. Most agents produce a diffuse melanosis
of the skin and mucosal surfaces, but others may cause
a unique pattern. As in many cases of increased melanin
pigmentation, females are more sensitive, most likely
as a result of an interaction with sex hormones.
Use of phenolphthalein as a laxative has been associ-
ated with numerous small, well-circumscribed areas of
hyperpigmentation on the skin. Similar areas of oral
mucosal melanosis also can occur.
Long-term use of minocycline, a semisynthetic
derivative of tetracycline, results in discoloration of the
bone and developing teeth. The affected bone is dark
green but creates a blue-gray discoloration as seen
through the translucent oral mucosa. The most com-
mon presentations include a linear band above the
facial attached gingiva near the mucogingival junction
and a broad zone of discoloration on the hard palate
(Fig. 8-58).
Rare soft tissue pigmentation of the lips, tongue,
eyes, and skin also has been reported with use of mino-
cycline. The cutaneous pigmentation appears to be
dose-dependent and is seen in up to 15% of patients
being treated for acne and as many as 70% of those
treated for rheumatoid arthritis. The pigmentation
presents in three patterns, two of which are thought to
be caused by deposition of drug metabolites that
become chelated with iron. In the third pattern, the
medication triggers a diffuse muddy-brown or gray
cutaneous pigmentation resulting from increased mel-
anosis of the epithelial basal cell layer and superﬁcial
connective tissue. This latter pattern is accentuated in
sun-exposed areas, and the diagnosis can be made only
when there is a direct association between initiation
and cessation of the medication and the appearance
and fading of the pigmentation. Minocycline-related
pigmentation of the oral mucosa unrelated to discolor-
ation of the underlying bone also has been reported,
Fig. 8-58 Minocycline-related discoloration. Blue-gray
discoloration of the facial surface of the anterior mandibular
alveolus because stained alveolar bone is visible through the
thin mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

318 ORAL AND MAXILLOFACIAL PATHOLOGY
with patients exhibiting either widespread increased
melanosis or focal accumulations of iron-containing
particles (Figs. 8-59 and 8-60). Although the cutaneous
and oral mucosal staining fade after discontinuation of
the medication, the dental discoloration remains.
The classic presentation of intraoral pigmentation
from use of antimalarial medications or tranquilizers
is a blue-black discoloration limited to the hard palate
(Fig. 8-61). In addition, the intake of antimalarial medi-
cations may occasionally lead to a more diffuse brown
melanosis of the oral mucosa and skin.
Estrogen, chemotherapeutic agents, and medica-
tions used in the treatment of AIDS patients may result
in a diffuse brown melanosis of the skin and mucosal
surfaces. Any mucosal surface may be involved, but the
attached gingiva and buccal mucosa are most fre-
quently affected. The pattern and appearance of the
oral mucosal involvement are similar to those seen in
racial pigmentation.
TREATMENT AND PROGNOSIS
Although the discolorations of the oral mucosa may
be aesthetically displeasing, they cause no long-term
problems. In most instances, discontinuing the
medication results in gradual fading of the areas of
hyperpigmentation.
REACTIVE OSSEOUS AND
CHONDROMATOUS METAPLASIA
(CUTRIGHT LESION)
On occasion, cartilage or bone may be discovered
within soft tissue specimens removed from the oral
cavity. Cartilaginous rests are known to exist in the area
of the nasopalatine duct. In the past, several investiga-
tors have reported the presence of cartilage within
ﬂabby soft tissue removed from maxillary edentulous
alveolar ridges of long-term denture wearers. This
ﬁnding was thought to represent cartilaginous meta-
plasia secondary to chronic denture trauma. In retro-
spect, the islands of cartilage within these cases most
likely represent embryologic remnants, not traumatic
metaplasia. These rests are also occasionally discov-
ered during histopathologic examination of naso-
palatine duct cysts and maxillary gingivectomy
specimens.
Fig. 8-59 Minocycline-associated pigmentation. Sharply
demarcated brown pigmentation on the vermilion border
of the lips, which arose in association with long-term
minocycline use and is the result of increased melanin
deposition.
Fig. 8-60 Minocycline-associated pigmentation. Multifocal
areas of palatal pigmentation secondary to deposition of drug
metabolites chelated to iron in association with long-term
minocycline use. (From Treister NS, Magalnick D, Woo S-B: Oral
mucosal pigmentation secondary to minocycline therapy: report of two cases
and a review of the literature, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 97:718-725, 2004.)
Fig. 8-61 Chlorpromazine pigmentation. Diffuse grayish
pigmentation of the hard palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 319
Despite the suggestion that the anterior maxillary
lesions are embryologic and not traumatic, develop-
ment of osseous and chondromatous metaplasia
from mechanical denture irritation does occur.
Although such metaplasia is probably uncommon in
the anterior maxilla, its development is not rare along
the crest of the posterior mandibular alveolar ridge in
long-term denture wearers with atrophic ridges.
CLINICAL AND RADIOGRAPHIC
FEATURES
In patients with reactive osseous and chondromatous
metaplasia, an extremely tender and localized area of
the alveolar ridge is typically noted that may be associ-
ated with local enlargement (Fig. 8-62). These changes
almost always arise in patients with extensive atrophy
of the mandibular alveolar ridge leading to a knife
edge–like crest. Although most examples involve the
posterior mandible, similar areas may rarely be seen
overlying the maxillary alveolar ridge or associated
with anterior portions of the mandible. Because of sig-
niﬁcant associated symptoms and occasional enlarge-
ment, biopsy is frequently performed.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of reactive osseous and
chondromatous metaplasia typically demonstrates a
mass of hypercellular periosteum that blends into
areas of osseous and chondromatous tissue. The bone
and cartilage frequently exhibit atypical features, such
as hypercellularity, pleomorphism, nuclear hyperchro-
matism, and occasional binucleated or multinucleated
cells (Fig. 8-63). These alterations are worrisome for
sarcoma, but the appropriate diagnosis can be made
when an appropriate clinicopathologic correlation is
made. In contrast, the cartilaginous rest discovered
incidentally in maxillary specimens is usually very
bland without any atypical features that would suggest
malignancy.
TREATMENT AND PROGNOSIS
The thin mandibular ridges may be recontoured or
supplemented with graft material to improve shape
and to alleviate the symptoms associated with the local-
ized periosteal hyperplasia. Implants also may reduce
the traumatic injury to the ridge and lessen the chance
of recurrence. If the ridge modiﬁcation is not made,
then the continued injury to the site occasionally results
in recurrence of the lesion.
ORAL ULCERATION WITH
BONE SEQUESTRATION
(SPONTANEOUS SEQUESTRATION;
TRAUMATIC SEQUESTRATION)
Focal superﬁcial sequestration of a fragment of cortical
bone not related to systemic disease, infection, or a
major traumatic event is uncommon. In such instances
the cause of the focal osteonecrosis is not known,
although many believe the primary event is a traumatic
or aphthous ulceration that leads to osteitis and
necrosis of a small focus of adjacent cortical bone.
Others have suggested the blood supply of the periph-
eral cortical plate may be delivered by the periosteal
microvasculature, and loss of this supply leads to
focal bone necrosis and sequestration. Such lesions
tend to occur in anatomically unique sites in which
a bony prominence is covered by a thin mucosal
surface.
Fig. 8-62 Periosteal hyperplasia with osseous and
chondromatous metaplasia. Tender, elevated nodule along
the thin crest of the mandibular alveolar ridge. (Courtesy of Dr.
Steven Tucker.)
Fig. 8-63 Osseous and chondromatous metaplasia. High-
power photomicrograph demonstrating cellular woven bone
and metaplastic cartilage. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

320 ORAL AND MAXILLOFACIAL PATHOLOGY
CLINICAL AND RADIOGRAPHIC FEATURES
In most instances, the sequestration arises without the
patient’s awareness of any preceding trauma. The most
frequent site of sequestrum development is the lingual
surface of the posterior mandible along the mylohyoid
ridge (Fig. 8-64). Focal involvement of exostoses also
may occur. Although any exostosis may be involved,
mandibular tori are affected most frequently.
The overlying mucosa typically demonstrates a focal
area of ulceration that has been present for a period of
time that varies from a few days to several months. The
presence and intensity of associated pain are variable.
Although most cases are unilateral, bilateral involve-
ment may occur. On occasion an occlusal radiograph
will reveal a faint radiopaque mass superimposed and
partially lingual to the intact cortical plate.
The mylohyoid ridge often is prominent but typi-
cally protected from trauma by the lingual inclination
of the adjacent molars. Absence of the adjacent molars
or restorations that do not replace the normal inclina-
tion could predispose the area to repeated trauma;
such alterations have been noted in the majority of
affected patients.
HISTOPATHOLOGIC FEATURES
The sequestra consist of well-organized lamellar bone
that exhibits loss of the osteocytes from their lacunae,
along with peripheral resorption and bacterial
colonization.
TREATMENT AND PROGNOSIS
Spontaneous loss of the dead bone or surgical removal
of the sequestrum results in rapid healing. Recurrence
is uncommon. In some instances, the dead bone is
freely movable and easily removed. In other cases, the
fragment is adherent to the underlying vital bone and
must be surgically excised. In an attempt to avoid
surgery, some clinicians use a tetracycline rinse in
addition to topical corticosteroids. Alternatively, these
patients can be recalled weekly for 2 to 4 weeks, during
which time the dead bone may exfoliate spontaneously
without the need for invasive therapy.
PSEUDOCYSTS AND CYSTS OF THE
MAXILLARY SINUS
Antral pseudocysts are common ﬁndings on pan-
oramic radiographs. They appear as dome-shaped,
faintly radiopaque lesions arising from the ﬂoor of the
maxillary sinus. In the past these sinus changes were
incorrectly termed sinus mucoceles, because previ-
ous investigators thought the lesions resulted from
mucus extravasation similar to that seen in salivary
glands of soft tissue. In fact, it appears that no compa-
rable mucus extravasation occurs in the maxillary
sinus.
ANTRAL PSEUDOCYST
Antral pseudocyst is the best term for the dome-shaped
lesion of the sinus ﬂoor. The process usually consists of
an inﬂammatory exudate (serum, not mucin) that has
accumulated under the maxillary sinus mucosa and
caused a sessile elevation (Fig. 8-65). The exudate is
surrounded by connective tissue, and the epithelial
lining of the sinus is superior to the ﬂuid. Reviews of
large numbers of radiographs have determined the
prevalence, which varies from 1.5% to 14% of the popu-
lation. The cause of the inﬂammatory inﬁltrate has not
been deﬁnitively determined, but in a radiographic
review, most cases showed a possible source from an
adjacent odontogenic infection. Primary irritation of
the sinus lining, such as that seen from a sinus infection
or allergies, also can theoretically result in the subperi-
osteal inﬂammatory inﬁltrate.
An increased prevalence of pseudocysts has been
noted during the cold winter months, leading some
investigators to associate these lesions with an increased
frequency of upper respiratory tract infections or irrita-
tion from dry, forced-air heating. Although allergies
have been proposed as a cause, no increased preva-
lence has been noted during the time of peak pollen
exposure.
SINUS MUCOCELES
True sinus mucoceles are accumulations of mucin that
are completely encased by epithelium. They occur in
two situations. One type of sinus mucocele occurs after
trauma or surgery to the sinus; this type is best known
as a surgical ciliated cyst, traumatic ciliated cyst, or
Fig. 8-64 Spontaneous sequestration. Mucosal ulceration
with exposed bone of the posterior lingual surface of the
mandible. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 321
postoperative maxillary cyst. A portion of the sinus
lining becomes separated from the main body of the
sinus and forms an epithelium-lined cavity into which
mucin is secreted (see Fig. 8-65). The cyst most fre-
quently originates after a Caldwell-Luc operation but
may arise from difﬁcult extraction of a maxillary tooth
in which the ﬂoor of the maxillary sinus is damaged.
Authors have suggested that sinus or nasal epithelium
rarely can be transplanted accidentally to the mandible
during genioplasty or chin augmentation procedures
and lead to formation of ciliated cysts in ectopic
locations.
The second type of sinus mucocele arises from an
obstruction of the sinus ostium, thereby blocking
normal drainage. This blocked sinus then acts like a
separate cystlike structure lined by epithelium and
ﬁlled with mucin. Sinus mucoceles enlarge in size as
the intraluminal pressure increases and can distend
the walls of the sinus and erode through bone, often
clinically mimicking malignancy of antral origin.
Postoperative maxillary cysts appear to be uncom-
mon in the United States and Europe but are reported
more frequently in Japan. Mucoceles arising from ostial
obstruction are much more numerous and most fre-
quently involve the frontal sinus, with the ethmoid and
sphenoid sinuses being affected less often. Maxillary
sinus mucoceles are relatively rare and account for less
than 10% of paranasal sinus mucoceles.
RETENTION CYSTS
Retention cysts of the maxillary sinus arise from the
partial blockage of a duct of the seromucous glands or
from an invagination of the respiratory epithelium. The
mucin is surrounded by epithelium, and no extravasa-
tion occurs. Most retention cysts are located around the
ostium or within antral polyps. The majority of cysts are
small, not evident clinically, and discovered during his-
topathologic examination of antral polyps.
CLINICAL AND RADIOGRAPHIC
FEATURES
Many symptoms have been attributed to sinus muco-
celes; however, because of the confusion between
pseudocysts and true mucoceles, it is unclear which
symptoms are associated with pseudocysts and which
are related to true sinus mucoceles. Most pseudocysts
are asymptomatic; although it is rare, affected patients
may exhibit facial fullness or report paresthesia, pain,
or soreness on palpation. As true sinus mucoceles
enlarge and expand bone, symptoms may develop and
vary according to the location and the degree of expan-
sion and destruction.
Radiographically, the pseudocyst classically appears
as a dome-shaped and slightly radiopaque lesion over-
lying the intact ﬂoor of the maxillary sinus (Figs. 8-66
and 8-67). Maxillary cysts and neoplasms can simulate
the dome-shaped pattern of an antral pseudocyst, but
close examination of these pathoses typically reveals
the ﬂoor of the sinus covering the superior aspect of
the lesion. When the maxillary sinus is involved by a
true sinus mucocele, the entire sinus will be cloudy. As
the lesion enlarges, the walls of the sinus may become
F F
M M
Antral pseudocyst True mucocele
FluidFluid
Fig. 8-65 Antral pseudocyst and true sinus mucocele. An
antral pseudocyst is an accumulation of serum beneath the
sinus lining. A sinus mucocele is an epithelium-lined cystic
structure separate from the sinus.
Fig. 8-66 Antral pseudocyst. Three-dimensional cone-
beam radiograph showing dome-shaped radiopacity within
the maxillary sinus. (Courtesy of Dr. Scott Jenkins and Dr. Nick Morrow.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

322 ORAL AND MAXILLOFACIAL PATHOLOGY
thinned and eventually eroded. Surgical ciliated cysts
are spherical lesions that are separate from the sinus
and lack the dome-shaped appearance of pseudocysts
(Fig. 8-68). As these postoperative cysts enlarge, they
too can lead to perforation of the sinus walls. Retention
cysts rarely reach a size that would produce detectable
radiographic changes.
HISTOPATHOLOGIC FEATURES
Antral pseudocysts are covered by sinus epithelium
and demonstrate a subepithelial inﬂammatory exudate
that consists of serum occasionally intermixed with
inﬂammatory cells (Fig. 8-69). Collections of choles-
terol clefts and scattered small dystrophic calciﬁcations
may be seen. True sinus mucoceles and surgical cili-
ated cysts are true cystic structures lined by ciliated
pseudostratiﬁed columnar epithelium, squamous epi-
thelium with mucous cells, or metaplastic squamous
epithelium (Fig. 8-70). A sinus retention cyst shows
focal dilatation of a duct associated with the seromu-
cous glands of the sinus lining. The lumen of the dilated
duct is ﬁlled with thick mucus, often intermixed with
chronic inﬂammatory cells.
TREATMENT AND PROGNOSIS
Typically, pseudocysts of the maxillary sinus are harm-
less, and no treatment is necessary. The adjacent teeth
should be evaluated thoroughly, and any foci of infec-
Fig. 8-67 Antral pseudocyst. Three-dimensional cone-
beam sagittal section of same patient depicted in Fig. 8-66.
Note that the ﬂoor of the sinus remains intact below the
lesion. (Courtesy of Dr. Scott Jenkins and Dr. Nick Morrow.)
Fig. 8-68 Surgical ciliated cyst. Well-deﬁned radiolucency
between vital maxillary bicuspids. (Courtesy of Dr. Patrick
Coleman.)
Fig. 8-69 Antral pseudocyst. Medium-power
photomicrograph demonstrating sinus lining overlying
edematous connective tissue.
Fig. 8-70 Surgical ciliated cyst. True cyst lined by
respiratory epithelium. Inset provides high-power view of
the ciliated pseudostratiﬁed columnar epithelium that lines
the cyst. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 323
tion should be eliminated. A few clinicians prefer to
conﬁrm their radiographic impression and rule out a
tumor through drainage of the inﬂammatory exudate.
Removal by means of a Caldwell-Luc operation should
be performed on any radiographically diagnosed lesion
that produces signiﬁcant expansion or is associated
deﬁnitively with symptoms such as headache.
Because sinus mucoceles and surgical ciliated cysts
are expansile and destructive lesions, the traditional
therapy for these pathoses is assured surgical removal.
Numerous investigators also have shown that sinus
mucoceles arising from ostial obstruction often do not
require surgical excision and respond well to endo-
scopic middle meatal antrostomy and marsupialization
of the mucocele.
CERVICOFACIAL EMPHYSEMA
Cervicofacial emphysema arises from the introduc-
tion of air into subcutaneous or fascial spaces of the
face and neck. The forced air may spread through the
spaces to the retropharyngeal and mediastinal areas.
The ﬁrst case was reported almost 100 years ago and
occurred as a result of blowing into a bugle a short time
after tooth extraction.
Cervicofacial emphysema of dental origin may arise
in several ways:
●After the use of compressed air by the clinician
● After difﬁcult or prolonged extractions
●As a result of increased intraoral pressure (e.g.,
sneezing, blowing) after an oral surgical
procedure
●From no obvious cause
Introduction of air within tissue has been seen after
a large number of dental procedures, but most instances
involve either surgical extraction of teeth, osteotomies,
signiﬁcant trauma, or the use of air or water syringes.
In addition, the prevalence has increased as a result of
the use of air-driven handpieces during oral surgery.
On occasion, cervicofacial emphysema has resulted
from compressed air being accidentally forced into
small intraoral lacerations located away from the ﬁeld
of operation. Conservative surgical ﬂap design without
extension into fascial planes and limited use of air-
driven handpieces during surgical procedures may
minimize the chance of occurrence. Rare reports of
cervicofacial emphysema after self-induced oral injury
have been reported in prisoners attempting to escape
by simulation of a medical emergency and a drug
abuser with Munchausen syndrome who was trying to
access unnecessary medical intervention.
An analogous problem termed pneumoparotid
can arise when air enters the parotid duct, leading to
enlargement of the parotid gland caused by air insuf-
ﬂation. This can be accidental, self-induced, or occupa-
tional (e.g., glassblowers, wind instrument players).
Stensen’s duct has numerous redundant mucosal
folds that seal as intraoral pressure is increased; in
addition, contraction of the buccinator muscle further
prevents entrance of air by compressing the duct. In
spite of this protection, dramatic increases in intraoral
pressures can result in air ﬁlling the parotid ductal
system.
CLINICAL AND RADIOGRAPHIC
FEATURES
More than 90% of cases of cervicofacial emphysema
develop during surgery or within the ﬁrst postoperative
hour. Cases with delayed onset are associated with
increased postoperative pressure created by the patient.
The initial change is one of soft tissue enlargement
from the presence of the air in deeper tissues (Fig.
8-71). Pain is usually minimal, and crepitus is detected
easily with gentle palpation. Subsequently, the enlarge-
ment increases and spreads because of secondary
inﬂammation and edema. Variable pain, facial ery-
thema, dysphagia, dysphonia, vision difﬁculties, and
mild fever may occur. The facial enlargement often is
confused with an angioedema, but the diagnosis can be
made by identifying crepitus within the swelling.
Fig. 8-71 Cervicofacial emphysema. Periorbital and facial
enlargement caused by use of an air-driven handpiece during
third molar removal. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

324 ORAL AND MAXILLOFACIAL PATHOLOGY
Signiﬁcant spread into the mediastinum can result
in dysphonia, dysphagia, or dyspnea. Cardiac ausculta-
tion often reveals crepitus synchronous with the heart
beat (Hamman’s crunch) in cases with mediastinal
involvement. Pneumomediastinum can be conﬁrmed
on chest radiographs by observing displacement of the
mediastinal pleura.
Pneumoparotid typically appears as a unilateral
enlargement of the parotid that demonstrates crepitus
on gentle palpation. Milking the parotid duct produces
a frothy, air-ﬁlled saliva, rather than the typical clear,
waterlike secretion.
TREATMENT AND PROGNOSIS
Broad-spectrum antibiotic coverage is recommended
in all dental-related cases of cervicofacial emphysema.
The body gradually removes the entrapped air during
a 2- to 5-day period. Most cases spontaneously resolve
without signiﬁcant difﬁculty. Rare cases of respiratory
distress have been noted, and assisted ventilation was
required.
The ﬁrst goal of therapy for pneumoparotid is dis-
covery of the inciting event. In occupation-related
cases, such as those seen in trumpet players, the indi-
vidual should be coached to compress the cheeks
during playing. This procedure contracts the buccina-
tor muscle and compresses the parotid duct. Acute
symptoms are treated with antibiotics, massage, hydra-
tion, sialogogues, and warm compresses.
MYOSPHERULOSIS
Placement of topical antibiotic in a petrolatum base
into a surgical site may occasionally result in a unique
foreign body reaction, known as myospherulosis. The
resultant histopathologic pattern is most unusual and
was thought initially to represent a previously unde-
scribed endosporulating fungus.
CLINICAL AND RADIOGRAPHIC
FEATURES
Myospherulosis may occur at any site within soft tissue
or bone where the antibiotic has been placed. The
initial report described involvement of the arms, legs,
and gluteal and scapular regions. Most cases in the
dental literature have occurred within bone at previous
extraction sites where an antibiotic had been placed in
an attempt to prevent alveolar osteitis. Although maxil-
lary and oral soft tissue examples have been docu-
mented, most cases have occurred within mandibular
surgical sites. In addition, myospherulosis is reported
occasionally in a paranasal sinus after a surgical proce-
dure in which a gauze packing coated with an antibi-
otic ointment was used.
The involved area may exhibit swelling or be discov-
ered as an asymptomatic and circumscribed radiolu-
cency in a previous extraction site (Fig. 8-72). In some
cases pain and purulent drainage have resulted. On
exploration of the lesion, a black, greasy, tarlike mate-
rial is found.
HISTOPATHOLOGIC FEATURES
The histopathologic pattern is unique; it is the result of
a tissue interaction with both the petroleum base and
the antibiotic, typically tetracycline. Dense collagenous
tissue is intermixed with a granulomatous inﬂamma-
tory response showing macrophages and multinucle-
ated giant cells. Within the connective tissue are
multiple cystlike spaces that contain numerous brown-
to black-staining spherules (Fig. 8-73). The collections
Fig. 8-72 Myospherulosis. Radiolucency has persisted after
extraction of the mandibular third molar. An antibiotic
ointment was placed at the time of initial surgery.
Fig. 8-73 Myospherulosis. High-power photomicrograph
exhibiting multiple cystlike spaces containing numerous
brown-stained spherules. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 325
of spherules sometimes are surrounded by an outer
membrane known as a parent body, forming structures
that resemble a “bag of marbles.” The spherules
re present red blood cells that have been altered by the
medication. The unusual dark coloration is due to the
degradation of hemoglobin. To complicate matters,
myospherulosis arising in a paranasal sinus occasion-
ally is contaminated with respiratory fungal organisms,
such as the zygomycetes or aspergillus.
TREATMENT AND PROGNOSIS
Myospherulosis is treated by surgical removal of the
foreign material and associated tissue. Histopathologic
examination of the altered tissue provides the deﬁni-
tive diagnosis. Recurrence is not expected. Those
arising in a paranasal sinus and exhibiting fungal infes-
tation respond well to local measures and do not
require systemic antimicrobial therapy. Some investi-
gators have recommended discontinuation of nasal
packing with antibiotic ointment, because patients
with antral myospherulosis have been found to be
almost three times more likely than controls to
develop adhesions and require revision of their sinus
surgery.
A similar clinical and radiographic pattern has
been seen in association with the use of powdered tet-
racycline in a polymer dressing. Although somewhat
different histopathologically, this formulation also
leads to a granulomatous foreign body reaction.
Because of complications associated with both formu-
lations, the practice of applying topical antibiotics to
oral wounds should be approached with caution, and
other methods of delivery should be considered. If
topical antibiotics are used, then they should be accom-
panied by close follow-up to ensure appropriate clini-
cal and radiographic evidence of healing of the surgical
site.
BIBLIOGRAPHY
Linea Alba
Kashani HG, Mackenzie IC, Kerber PE: Cytology of linea alba
using a ﬁlter imprint technique, Clin Prev Dent 2:21-24,
1980.
Parlak AH, Koybasi S, Yavuz et al: Prevalence of oral lesions in
13- to 16-year old students in Duzce, Turkey, Oral Dis 12:553-
558, 2006.
Wood NK, Goaz PW: Differential diagnosis of oral and maxillofacial
lesions, ed 5, pp 98-99, St Louis, 1997, Mosby.
Morsicatio Buccarum
Bouquot JE: Common oral lesions found during a mass screening
examination, J Am Dent Assoc 112:50-57, 1986.
Hjørting-Hansen E, Holst E: Morsicatio mucosae oris and suctio
mucosae oris: an analysis of oral mucosal changes due to
biting and sucking habits, Scand J Dent Res 78:492-499,
1970.
Kocsard E, Schwarz L, Stephen BS et al: Morsicatio buccarum,
Br J Dermatol 74:454-457, 1962.
Reichart PA, Philipsen HP: Betel chewer’s mucosa—a review,
J Oral Pathol Med 27:239-242, 1998.
Romero M, Vicente A, Bravo LA: Prevention of habitual
cheek biting: a case report, Spec Care Dentist 25:214-216,
2005.
Schiödt M, Larsen V, Bessermann M: Oral ﬁndings in glassblow-
ers, Community Dent Oral Epidemiol 8:195-200, 1980.
Sewerin I: A clinical and epidemiologic study of morsicatio buc-
carum/labiorum, Scand J Dent Res 79:73-80, 1971.
Van Wyk CW, Staz J, Farman AG: The chewing lesion of the
cheeks and lips: its features and the prevalence among a
selected group of adolescents, J Dent 5:193-199, 1977.
Eosinophilic Ulcerations
Aloebeid B, Pan L-X, Milligan L et al: Eosinophil-rich CD30+
lymphoproliferative disorder of the oral mucosa, Am J Clin
Pathol 121:43-50, 2004.
Baghdadi ZD: Riga-Fede disease: report of a case and review,
J Clin Pediatr Dent 25:209-213, 2001.
Bhaskar SN, Lilly GE: Traumatic granuloma of the tongue (human
and experimental), Oral Surg Oral Med Oral Pathol 18:206-
218, 1964.
El-Mofty SK, Swanson PE, Wick MR et al: Eosinophilic ulcer of
the oral mucosa: report of 38 new cases with immunohisto-
chemical observations, Oral Surg Oral Med Oral Pathol 75:716-
722, 1993.
Eversole LR, Leider AS, Jacobsen PL et al: Atypical histiocytic
granuloma: light microscopic, ultrastructural, and histochem-
ical ﬁndings in an unusual pseudomalignant reactive lesion
of the oral cavity, Cancer 55:1722-1729, 1985.
Ficarra G, Prignano F, Romagnoli P: Traumatic eosinophilic
granuloma of the oral mucosa: a CD30+ (Ki-1) lymphoprolif-
erative disorder, Oral Oncol 33:375-379, 1997.
Hirshberg A, Amariglio N, Akrish S et al: Traumatic ulcerative
granuloma with stromal eosinophilia, Am J Clin Pathol
126:522-529, 2006.
Kabani S, Cataldo E, Folkerth R et al: Atypical lymphohistiocytic
inﬁltrate (pseudolymphoma) of the oral cavity, Oral Surg Oral
Med Oral Pathol 66:587-592, 1988.
Regezi JA, Zarbo RJ, Daniels TE et al: Oral traumatic granuloma:
characterization of the cellular inﬁltrate, Oral Surg Oral Med
Oral Pathol 75:723-727 1993.
Throndson RR, Wright JM, Watkins D: Atypical histiocytic gran-
uloma of the oral mucosa: an unusual clinicopathologic entity
simulating malignancy, J Oral Maxillofac Surg 59:822-826,
2001.
Zaenglein AL, Chang MU, Meehan SA et al: Extensive Riga-Fede
disease of the lip and tongue, J Am Acad Dermatol 47:445-447,
2002.
Electrical Burns
Czerepak CS: Oral splint therapy to manage electrical burns of
the mouths in children, Clin Plast Surg 11:685-692, 1984.
Goto R, Miyabe K, Mori N: Thermal burn of the pharynx and
larynx after swallowing hot milk, Auris Nasus Larynx 29:301-
303, 2002.
Gormley MB, Marshall J, Jarrett W et al: Thermal trauma: a
review of 22 electrical burns of the lip, J Oral Surg 30:531-
533, 1972.
Leake JE, Curtin JW: Electrical burns of the mouth in children,
Clin Plast Surg 11:669-683, 1986.
Taylor LB, Walker J: A review of selected microstomia preven-
tion appliances, Pediatr Dent 19:413-418, 1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

326 ORAL AND MAXILLOFACIAL PATHOLOGY
Oral Adverse Reactions to Chemicals
Baruchin AM, Lustig JP, Nahlieli O et al: Burns of the oral
mucosa: report of 6 cases, J Craniomaxillofac Surg 19:94-96,
1991.
Buck IF, Zeff S, Kalnins L et al: The treatment of intraoral chemi-
cal burns, J Oral Ther 2:101-106, 1965.
Frost DE, Barkmeier WW, Abrams H: Aphthous ulcer—a treat-
ment complication, Oral Surg Oral Med Oral Pathol 45:863-
869, 1978.
Gernhardt CR, Eppendorf K, Kozlowski A et al: Toxicity of con-
centrated sodium hypochlorite used as an endodontic ir-
rigant, Int Endod J 37:272-280, 2004.
Grace EG, Sarlani E, Kaplan S: Tooth erosion caused by chewing
aspirin, J Am Dent Assoc 135:911-914, 2004.
Kawakami J, Muto T, Shigeo K et al: Tooth exfoliation and necro-
sis of the crestal bone caused by use of formocresol, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 95:736-738, 2003.
Özgöz, M, Yagˇiz H, Çiçek Y et al: Gingival necrosis following the
use of a paraformaldehyde-containing paste: a case report, Int
Endod J 37:157-161, 2004.
Rawal SY, Claman LJ, Kalmar JR et al: Traumatic lesions of the
gingiva: a case series, J Periodontol 75:762-769, 2004.
Rees TD, Orth CF: Oral ulcerations with use of hydrogen perox-
ide, J Periodontol 57:689-692, 1986.
Noninfectious Complications of Antineoplastic Therapy
Annane D, Depondt J, Aubert P et al: Hyperbaric oxygen therapy
for radionecrosis of the jaw: a randomized, placebo-con-
trolled, double-blind trial from the ORN96 study group, J Clin
Oncol 22:4893-4900, 2004.
Dreizen S: Description and incidence of oral complications.
Consensus Development Conference on Oral Complications
of Cancer Therapies: Diagnosis, Prevention, and Treatment,
NCI Monogr 9:11-15, 1990.
Epstein JB, Klasser GD: Emerging approaches for prophylaxis
and management of oropharyngeal mucositis in cancer
therapy, Expert Opin Emerging Drugs 11:353-373, 2006.
Keller EE: Placement of dental implants in the irradiated man-
dible: a protocol without adjunctive hyperbaric oxygen, J Oral
Maxillofac Surg 55:972-980, 1997.
Marx RE, Johnson RP, Kline SN: Prevention of osteoradionecro-
sis: a randomized prospective clinical trial of hyperbaric
oxygen versus penicillin, J Am Dent Assoc 111:49-54. 1985.
Rubenstein EB, Peterson DE, Schubert M et al: Clinical practice
guidelines for the prevention and treatment of cancer therapy-
induced oral and gastrointestinal mucositis, Cancer 100(suppl
9):2026-2046, 2004.
Scully C, Sonis S, Diz PD: Oral mucositis, Oral Dis 12:229-241,
2006.
Sulaiman F, Huryn JM, Zlotolow IM: Dental extraction in the
irradiated head and neck patient: a retrospective analysis of
Memorial Sloan-Kettering Cancer Center protocols, criteria,
and end results, J Oral Maxillofac Surg 61:1123-1131, 2003.
Teng MS, Futran ND: Osteonecrosis of the mandible, Curr Opin
Otolaryngol Head Neck Surg 13:217-221, 2005.
Bisphosphonate-Related Osteonecrosis
Adornato MC, Morcos I, Rozanski J: The treatment of bisphos-
phonate-associated osteonecrosis of the jaws with bone resec-
tion and autologous platelet-derived growth factors, J Am Dent
Assoc 138:971-977, 2007.
American Dental Association Council on Scientiﬁc Affairs:
Dental management of patients receiving oral bisphospho-
nate therapy. Expert panel recommendations, J Am Dent Assoc
137:1144-1150, 2006.
Cohen D, Bhattacharyya N, Islam J et al: Case based evidence for
expanding the criteria for the diagnosis of bisphosphonate induced
osteochemonecrosis, Abstract 31, American Academy of Oral
and Maxillofacial Pathology, Kansas City, Mo, May 8, 2007.
Odvina CV, Zerwekh JE, Rao DS et al: Severely suppressed bone
turnover: a potential complication of alendronate therapy,
J Clin Endocrinol Metab 90:1294-1301, 2005.
Ott SM: Long-term safety of bisphosphonates, J Clin Endocrinol
Metab 90:1897-1899, 2005.
Marx RE: Pamidronate (Aredia) and zoledronate (Zometa)
induced avascular necrosis of the jaws: a growing epidemic
(letter to the editor), J Oral Maxillofac Surg 61:1115-1117,
2003.
Marx RE, Cillo JE Jr, Ulloa JJ: Oral bisphosphonate-induced
osteonecrosis: risk factors, prediction of risk using serum CTX
testing, prevention, and treatment, J Oral Maxillofac Surg
65:2397-2410, 2007.
Marx RE, Sawatari Y, Fortin M et al: Bisphosphonate-induced
exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk
factors, recognition, prevention, and treatment, J Oral Maxil-
lofac Surg 63:1567-1575, 2005.
Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related
osteonecrosis of the jaw: background and guidelines for diag-
nosis, staging and management, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 102:433-441, 2006.
Ruggiero SL, Mehrotra B, Rosenberg TJ et al: Osteonecrosis of
the jaws associated with the use of bisphosphonates: a review
of 63 cases, J Oral Maxillofac Surg 62:527-534, 2004.
Schneider JP: Should bisphosphonates be continued indeﬁ-
nitely? An unusual fracture in a healthy woman on long-term
alendronate, Geriatrics 61:31-33, 2006.
Woo S-B, Hellstein JW, Kalmar JR: Systematic review: bisphos-
phonates and osteonecrosis of the jaws, Ann Intern Med
144:753-761, 2006.
Orofacial Complications of Methamphetamine Abuse
Curtis EK: Meth mouth: a review of methamphetamine abuse
and its oral manifestations, Gen Dent 54:125-129, 2006.
Goodchild JH, Donaldson M, Mangini DJ: Methamphetamine
abuse and the impact on dental health, Dent Today 26:124-
131, 2007.
Rhodus NL, Little JW: Methamphetamine abuse and “meth
mouth,” Northwest Dent 84:29, 31, 33-37, 2005.
Richards JR, Brofeldt BT: Patterns of tooth wear associated
with methamphetamine use, J Periodontol 71:1371-1374,
2000.
Shaner JW, Kimmes N, Saini T et al: “Meth mouth”: rampant
caries in methamphetamine abusers, AIDS Patient Care STDs
20:146-150, 2006.
Anesthetic Necrosis
Carroll MJ: Tissue necrosis following a buccal inﬁltration, Br
Dent J 149:209-210, 1980.
Giunta J, Tsamsouris A, Cataldo E et al: Postanesthetic
necrotic defect, Oral Surg Oral Med Oral Pathol 40:590-593,
1975.
Schaffer J, Calman HI, Levy B: Changes in the palate color and
form (case 9), Dent Radiogr Photogr 39:3-6, 19-22, 1966.
Exfoliative Cheilitis
Axéll T, Skoglund A: Chronic lip ﬁssures. Prevalence, pathology
and treatment, Int J Oral Surg 10:354-358, 1981.
Connolly M, Kennedy C: Exfoliative cheilitis successfully treated
with topical tacrolimus, Br J Dermatol 151:241-242, 2004.
Daley TD, Gupta AK: Exfoliative cheilitis, J Oral Pathol Med
24:177-179, 1995.
Freeman S, Stephens R: Cheilitis: analysis of 75 cases referred
to a contact dermatitis clinic, Am J Contact Dermat 7:146-151,
1996. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 327
Leyland L, Field EA: Case report: exfoliative cheilitis managed
with antidepressant medication, Dent Update 31:524-526,
2004.
Reade PC, Sim R: Exfoliative cheilitis—a factitious disorder? Int J
Oral Maxillofac Surg 15:313-317, 1986.
Rosenquist B: Median lip ﬁssure: etiology and suggested treat-
ment, Oral Surg Oral Med Oral Pathol 72:10-14, 1991.
Scully C, van-Bruggen W, Diz-Dios P et al: Down syndrome: lip
lesions (angular stomatitis and ﬁssures) and Candida albicans,
Br J Dermatol 147:37-40, 2002.
Taniguchi S, Kono T: Exfoliative cheilitis: a case report and
review of the literature, Dermatology 196:253-255, 1998.
Submucosal Hemorrhage
Kalpidis CDR, Setayesh RM: Hemorrhaging associated with
endosseous implant placement in the anterior mandible: a
review of the literature, J Periodontol 75:631-645, 2004.
Kravitz P: The clinical picture of “cough purpura,” benign and
nonthrombocytopenic eruption, Va Med 106:373-374,
1979.
Lee B-J, Park H-J, Heo S-C: Organized hematoma of the maxil-
lary sinus, Acta Otolaryngol 123:869-872, 2003.
Tabaee A, Kacker A: Hematoma of the maxillary sinus presenting
as a mass—a case report and review of the literature, Int J
Pediatr Otorhinolaryngol 65:153-157, 2002.
Woo BM, Al-Bustani S, Ueeck BA: Floor of mouth haemorrhage
and life-threatening airway obstruction during immediate
implant placement in the anterior mandible, Int J Oral Maxil-
lofac Surg 35:961-964, 2006.
Oral Trauma from Sexual Practices
Damm DD, White DK, Brinker CM: Variations of palatal ery-
thema secondary to fellatio, Oral Surg Oral Med Oral Pathol
52:417-421, 1981.
Elam AL: Sexually related trauma: a review, Ann Emerg Med
15:576-584, 1986.
Farman AG, Van Wyk CW: The features of non-infectious
oral lesions caused by fellatio, J Dent Assoc S Afr 32:53-55,
1977.
Leider AS: Intraoral ulcers of questionable origin, J Am Dent Assoc
92:1177-1178, 1976.
Mader CL: Lingual frenum ulcer resulting from orogenital sex,
J Am Dent Assoc 103:888-890, 1981.
Terezhalmy GT: Oral manifestations of sexually related diseases,
Ear Nose Throat J 62:287-296, 1983.
Van Wyk CW: Oral lesions caused by habits, Forensic Sci 7:41-49,
1976.
Localized Exogenous Pigmentations
Buchner A, Hansen LS: Amalgam pigmentation (amalgam tattoo)
of the oral mucosa: a clinicopathologic study of 268 cases,
Oral Surg Oral Med Oral Pathol 49:139-147, 1980.
Daley TD, Gibson D: Practical applications of energy dispersive
x-ray microanalysis in diagnostic oral pathology, Oral Surg
Oral Med Oral Pathol 69:339-344, 1990.
Kaufman T, Bloch C, Schmidt W et al: Chronic inﬂammation
and pain inside the mandibular jaw and a 10-year forgotten
amalgam ﬁlling in an alveolar cavity of an extracted molar
tooth, Ultrastruct Pathol 29:405-413, 2005.
Klontz KC, Lambert LA, Jewell RE et al: Adverse effects of cos-
metic tattooing: an illustrative case of granulomatous derma-
titis following the application of permanent makeup, Arch
Dermatol 141:918-919, 2005.
Mani NJ: Gingival tattoo: a hitherto undescribed mucosal pig-
mentation, Quintessence Int 16:157-159, 1985.
Muller H, van der Velden, Samderubun EM: Tattooing in maxil-
lofacial surgery, J Craniomaxillofac Surg 16:382-384, 1988.
Peters E, Gardner DG: A method of distinguishing between
amalgam and graphite in tissue, Oral Surg Oral Med Oral
Pathol 62:73-76, 1986.
Shah G, Alster TS: Treatment of an amalgam tattoo with a Q-
switched alexandrite (755 nm) laser, Dermatol Surg 28:1180-
1181, 2002.
Slabbert H, Ackermann GL, Altini M: Amalgam tattoo as a means
for person identiﬁcation, J Forensic Odontostomatol 9:17-23,
1991.
Weaver T, Auclair PL, Taybos GM: An amalgam tattoo causing
local and systemic disease? Oral Surg Oral Med Oral Pathol
63:137-140, 1987.
Oral Piercings and Forked Tongue
Benecke M: First report of nonpsychotic self-cannibalism
(autophagy), tongue splitting, and scar patterns (scariﬁcation)
as an extreme form of cultural body modiﬁcation in a western
civilization, Am J Forensic Med 20:281-285, 1999.
Brennan M, O’Connell B, O’Sullivan M: Multiple dental fractures
following tongue barbell placement: a case report, Dent Trau-
matol 22:41-43, 2006.
Bressmann T: Self-inﬂicted cosmetic tongue split: a case report,
J Can Dent Assoc 70:156-157, 2004.
Campbell A, Moore A, Williams E et al: Tongue piercing: impact
of time and barbell stem length on lingual gingival recession
and tooth chipping, J Periodontol 73:289-297, 2002.
Fleming PS, Flood TR: Biﬁd tongue—a complication of tongue
piercing, Br Dent J 198:265-266, 2005.
Kapferer I, Benesch T, Gregoric N et al: Lip piercing: prevalence
of associated gingival recession and contributing factors. A
cross-sectional study, J Periodontol Res 42:177-183, 2007.
Loh FC, Yeo JF: Talisman in the orofacial region, Oral Surg Oral
Med Oral Pathol 68:252-255, 1989.
Nor MM, Yushar A, Razali M et al: Incidental radiologic ﬁndings
of susuk in the orofacial region, Dentomaxillofac Radiol 35:473-
474, 2006.
Systemic Metal Intoxication
Ahnlide I, Ahlgren C, Björkner B et al: Gold concentration in
blood in relation to the number of gold restorations and
contact allergy to gold, Acta Odontol Scand 60:301-305,
2002.
Bellinger DC, Trachtenberg F, Barregard L et al: Neuropsycho-
logical and renal effects of dental amalgam in children. A
randomized trial, J Am Med Assoc 295:1775-1783, 2006.
DeRouen TA, Martin MD, Leroux BG et al: Neurobehavioral
effects of dental amalgam in children. A randomized trial,
J Am Med Assoc 295:1784-1792, 2006.
Dodes JE: The amalgam controversy. An evidence-based analy-
sis, J Am Dent Assoc 132:348-356, 2001.
Drake PL, Hazelwood KJ: Exposure-repeated health effects of
silver and silver compounds: a review, Ann Occup Hyg 49:575-
585, 2005.
Dummet CO: Systemic signiﬁcance of oral pigmentation and
discoloration, Postgrad Med J 49(1):78-82, 1971.
Eisler R: Mammalian sensitivity to elemental gold (Au degrees),
Biol Trace Elem Res 100:1-18, 2004.
Fowler J Jr, Taylor J, Storrs F et al: Gold allergy in North America,
Am J Contact Dermat 12:3-5, 2001.
Gordon NC, Brown S, Khosla VM et al: Lead poisoning: a com-
prehensive review and report of a case, Oral Surg Oral Med
Oral Pathol 47:500-512, 1979.
Harris RA, Poole A: Beware of bismuth: post maxillectomy delir-
ium, ANZ J Surg 72:846-847, 2002.
Ioffreda MD, Gordon CA, Adams DR et al: Black tongue, Arch
Dermatol 137:968-969, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

328 ORAL AND MAXILLOFACIAL PATHOLOGY
Jacobs R: Argyria: my life story, Clin Dermatol 24:66-69, 2006.
Langworth S, Björkman L, Elinder C-G et al: Multidisciplinary
examination of patients with illness attributed to dental ﬁll-
ings, J Oral Rehabil 29:705-713, 2002.
Lee SM, Lee SH: Generalized argyria after habitual use of AgNO
3,
J Dermatol 21:50-53, 1994.
Marshall JP, Schneider RP: Systemic argyria secondary to topical
silver nitrate, Arch Dermatol 113:1077-1179, 1977.
Martin MD, Williams BJ, Charleston JD et al: Spontaneous exfo-
liation of teeth following severe elemental mercury poison-
ing: case report and histological investigation for mechanism,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:495-501,
1997.
Mirsattari SM, Hammond RR, Sharpe MD et al: Myoclonic status
epilepticus following repeated oral ingestion of colloidal
silver, Neurology 62:1408-1410, 2004.
Su M, Barrueto F Jr, Hoffman RS: Childhood lead poisoning from
paint chips: a continuing problem, J Urban Health 79:491-
501, 2002.
Wadhera A, Fung M: Systemic argyria associated with ingestion
of colloidal silver, Dermatol Online J 11(1):12, 2005.
Smoker’s Melanosis
Axéll T, Hedin CA: Epidemiologic study of excessive oral melanin
pigmentation with special reference to the inﬂuence of
tobacco habits, Scand J Dent Res 90:434-442, 1982.
Hedin CA: Smokers’ melanosis, Arch Dermatol 113:1533-1538,
1977.
Hedin CA, Axéll T: Oral melanin pigmentation in 467 Thai and
Malaysian people with special emphasis on smoker’s melano-
sis, J Oral Pathol Med 20:8-12, 1991.
Hedin CA, Larsson Å: The ultrastructure of the gingival epithe-
lium in smokers’ melanosis, J Periodontal Res 19:177-190,
1984.
Hedin CA, Pindborg JJ, Daftary DK et al: Melanin depigmenta-
tion of the palatal mucosa in reverse smokers: a preliminary
study, J Oral Pathol Med 21:440-444, 1992.
Ramer M, Burakoff RP: Smoker’s melanosis, N Y State Dent J
63:20-21, 1997.
Drug-Related Discolorations of the Oral Mucosa
Birek C, Main JHP: Two cases of oral pigmentation associated
with quinidine therapy, Oral Surg Oral Med Oral Pathol 66:59-
61, 1988.
Cale AE, Freedman PD, Lumerman H: Pigmentation of the jaw-
bones and teeth secondary to minocycline hydrochloride
therapy, J Periodontol 59:112-114, 1988.
Cockings JM, Savage NW: Minocycline and oral pigmentation,
Aust Dent J 43:14-16, 1998.
Dummet CO: Oral mucosal discolorations related to pharmaco-
therapeutics, J Oral Ther Pharmacol 1:106-110, 1964.
Granstein RD, Sober AJ: Drug- and heavy metal-induced hyper-
pigmentation, J Am Acad Dermatol 5:1-18, 1981.
Hood AF: Cutaneous side effects of cancer chemotherapy, Med
Clin North Am 70:187-209, 1986.
Langford A, Pohle H-D, Gelderblom H et al: Oral hyperpigmen-
tation in HIV-infected patients, Oral Surg Oral Med Oral Pathol
67:301-307, 1989.
LaPorta VN, Nikitakis NG, Sindler AJ et al: Minocycline-associ-
ated intra-oral soft-tissue pigmentation: clinicopathologic cor-
relations and review, J Clin Periodontol 32:119-122, 2005.
Pérusse R, Morency R: Oral pigmentation induced by Premarin,
Cutis 48:61-64, 1991.
Treister NS, Magalnick D, Woo S-B: Oral mucosal pigmentation
secondary to minocycline therapy: report of two cases and a
review of the literature, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 97:718-725, 2004.
Traumatic Osseous and Chondromatous Metaplasia
Cutright DE: Osseous and chondromatous metaplasia caused
by dentures, Oral Surg Oral Med Oral Pathol 34:625-633,
1972.
Daley TD, Damm DD, Wysocki GP et al: Atypical cartilage in
reactive osteocartilagenous metaplasia of the traumatized
edentulous mandibular ridge, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 83:26-29, 1997.
Lello GE, Makek M: Submucosal nodular chondrometaplasia in
denture wearers, J Prosthet Dent 54:237-240, 1985.
Magnusson BC, Engström H, Kahnberg K-E: Metaplastic forma-
tion of bone and chondroid in ﬂabby ridges, Br J Oral Maxil-
lofac Surg 24:300-305, 1986.
Oral Ulceration with Bone Sequestration
Farah CS, Savage NW: Oral ulceration with bone sequestration,
Aust Dent J 48:61-64, 2003.
Kessler HP: Lingual mandibular sequestration with ulceration,
Tex Dent J 122:198-199, 206-207, 2005.
Peters E, Lovas GL, Wysocki GP: Lingual mandibular sequestra-
tion and ulceration, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 75:739-743, 1993.
Scully C: Oral ulceration: a new and unusual complication, Br
Dent J 192:139-140, 2002.
Sonnier KE, Horning GM: Spontaneous bony exposure: a report
of 4 cases of idiopathic exposure and sequestration of alveolar
bone, J Periodontol 68:758-762, 1997.
Pseudocysts and Cysts of the Maxillary Sinus
Allard RHB, van der Kwast WAM, van der Waal I: Mucosal
antral cysts: review of the literature and report of a
radiographic survey, Oral Surg Oral Med Oral Pathol 51:2-9,
1981.
Bockmühl U, Kratzsch B, Benda K et al: Surgery for paranasal
sinus mucoceles: efﬁcacy of endonasal micro-endoscopic
management and long-term results of 185 patients, Rhinology
44:62-67, 2006.
Bourgeois SL, Nelson BL: Surgical ciliated cyst of the mandible
secondary to simultaneous LeFort I osteotomy and genio-
plasty: report of case and review of the literature, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 100:36-39, 2005.
Carter LC, Calamel A, Haller A et al: Seasonal variation in maxil-
lary antral pseudocyst in a general clinical population, Dento-
maxillofac Radiol 27:22-24, 1998.
Gardner DG: Pseudocysts and retention cysts of the maxillary
sinus, Oral Surg Oral Med Oral Pathol 58:561-567, 1984.
Gardner DG, Gullane PJ: Mucoceles of the maxillary sinus, Oral
Surg Oral Med Oral Pathol 62:538-543, 1986.
Kaneshiro S, Nakajima T, Yoshikawa Y et al: The postoperative
maxillary cyst: report of 71 cases, J Oral Surg 39:191-198,
1981.
Cervicofacial Emphysema
Horowitz I, Hirshberg A, Freedman A: Pneumomediastinum
and subcutaneous emphysema following surgical extraction
of mandibular third molars: three case reports, Oral Surg Oral
Med Oral Pathol 63:25-28, 1987.
Karras SC, Sexton JJ: Cervicofacial and mediastinal emphysema
as the result of a dental procedure, J Emerg Med 14:9-13,
1996.
López-Peláez MF, Roldán J, Mateo S: Cervical emphysema,
pneumomediastinum, and pneumothorax following self-
induced oral injury: report of four cases and review of the
literature, Chest 120:306-309, 2001.
Martìn-Granizo R, Herrera M, Garcìa-Gonzàlez D et al: Pneu-
moparotid in childhood: report of two cases, J Oral Maxillofac
Surg 57:1468-1471, 1999. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 8 PHYSICAL AND CHEMICAL INJURIES 329
Stanton DC, Balasanian E, Yepes JF: Subcutaneous cervicofacial
emphysema and pneumo-mediastinum: a rare complication
after a crown preparation, Gen Dent 53:122-124, 2005.
Tosun F, Ozer C, Akcam T et al: A patient with severe cervicofa-
cial subcutaneous emphysema associated with Munchausen’s
syndrome, J Craniofac Surg 16:661-664, 2005.
Myospherulosis
Dunlap CL, Barker BF: Myospherulosis of the jaws, Oral Surg Oral
Med Oral Pathol 50:238-243, 1980.
Lynch DP, Newland JR, McClendon JL: Myospherulosis of the
oral hard and soft tissues, J Oral Maxillofac Surg 42:349-355,
1984.
Moore JW, Brekke JH: Foreign body giant cell reaction related
to placement of tetracycline-treated polylactic acid: report of
18 cases, J Oral Maxillofac Surg 48:808-812, 1990.
Sarkar S, Gangane N, Sharma S: Myospherulosis of maxillary
sinus—a case report with review of literature, Indian J Pathol
Microbiol 41:491-493, 1998.
Sindwani R, Cohen JT, Pilch BZ et al: Myospherulosis following
sinus surgery: pathological curiosity or important clinical
entity, Laryngoscope 113:1123-1127, 2003.
Wallace ML, Neville BW: Myospherulosis: report of a case,
J Periodontol 61:55-57, 1990. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

330
9
Allergies and Immunologic Diseases
CHAPTER OUTLINE
Transient Lingual Papillitis
Recurrent Aphthous Stomatitis
Minor Aphthous Ulcerations
Major Aphthous Ulcerations
Herpetiform Aphthous Ulcerations
Behçet’s Syndrome
Sarcoidosis
Orofacial Granulomatosis
Wegener’s Granulomatosis
Allergic Mucosal Reactions to Systemic Drug
Administration
Allergic Contact Stomatitis
Perioral Dermatitis
Contact Stomatitis from Artiﬁcial Cinnamon Flavoring
Lichenoid Contact Stomatitis from Dental Restorative
Materials
Angioedema
In one report the occurrence of the lesions appeared
to be associated with a food allergy.
In the second pattern the involvement is more gen-
eralized and affects a large percentage of the fungiform
papillae on the tip and lateral portions of the dorsal
surface (Fig. 9-2). Individual papillae are very sensitive,
enlarged, erythematous, and occasionally display focal
surface erosion. Fever and cervical lymphadenopathy
are not rare. In these cases, spread of the process
among family members has been reported, suggesting
a possible correlation to an unknown virus. Spontane-
ous resolution occurs in about 7 days, with occasional
recurrences reported.
The third pattern of transient lingual papillitis also
demonstrates more diffuse involvement. The altered
papillae are asymptomatic, appear as elevated white to
yellow papules, and have been termed the papulokera-
totic variant because of a thickened parakeratotic cap
(Fig. 9-3). Although these lesions could be the result of
a topical allergy, the histopathology demonstrates fea-
tures similar to chronic nibbling and suggests the possi-
bility of an unusual pattern of frictional hyperkeratosis.
HISTOPATHOLOGIC FEATURES
On histopathologic examination of the ﬁrst two vari-
ants, affected papillae demonstrate normal surface
epithelium that may reveal focal areas of exocytosis or
TRANSIENT LINGUAL PAPILLITIS
Transient lingual papillitis (lie bumps, tongue
torches) represents a common oral pathosis that, for
some reason, rarely has been documented. Affected
patients experience clinical alterations that involve a
variable number of fungiform papillae of the tongue.
The pathogenesis currently is unknown, but the lesions
most likely arise from a variety of inﬂuences. Suggested
causes include local irritation, stress, gastrointestinal
disease, hormonal ﬂuctuation, upper respiratory tract
infection, viral infection, and topical hypersensitivity to
foods, drinks, or oral hygiene products.
CLINICAL FEATURES
Three patterns of transient lingual papillitis have been
documented. The ﬁrst pattern is localized and involves
one to several fungiform papillae that become enlarged
and present as elevated papules that are red but may
demonstrate a yellow, ulcerated cap (Fig. 9-1). The
lesions appear most frequently on the anterior portion
of the dorsal surface, are associated with mild to mod-
erate pain, and resolve spontaneously within hours to
several days. In a survey of 163 dental school staff
members, 56% reported previous episodes of transient
lingual papillitis. There was a female predominance,
and the vast majority reported a single affected papilla. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 331
ulceration. The underlying lamina propria exhibits a
proliferation of numerous small vascular channels and
a mixed inﬂammatory cellular inﬁltrate. Investigation
for evidence of human papillomavirus (HPV), herpes
simplex, and fungal infestation has been negative.
The papulokeratotic variant demonstrates marked
hyperparakeratosis in which the surface is ragged and
reveals bacterial colonization. A chronic lymphocytic
inﬁltrate is noted in the superﬁcial lamina propria with
extension into the basilar portion of the adjacent
epithelium.
TREATMENT AND PROGNOSIS
Although transient lingual papillitis resolves without
therapy, topical corticosteroids, anesthetics, and coating
agents have been used to reduce the pain or duration.
In an attempt to eliminate the pain, occasional patients
have reported removing the affected papillae with
devices such as ﬁngernail clippers. The papulokera-
totic variant is asymptomatic and requires no therapy.
Although frequently unsuccessful, search for a local or
systemic triggering event seems prudent.
RECURRENT APHTHOUS STOMATITIS
(RECURRENT APHTHOUS
ULCERATIONS; CANKER SORES)
Recurrent aphthous stomatitis is one of the most
common oral mucosal pathoses. The reported preva-
lence in the general population varies from 5% to 66%,
with a mean of 20%. The hypotheses of its pathogenesis
are numerous. As soon as one investigator claims to
have discovered the deﬁnitive cause, a subsequent
report discredits the discovery. Different subgroups of
patients appear to have different causes for the occur-
rence of aphthae. These factors suggest a disease
process that is triggered by a variety of causative agents,
each of which is capable of producing the disease in
certain subgroups of patients. To state it simply, the
cause appears to be “different things in different
people.”
Although no single triggering agent is responsible,
the mucosal destruction appears to represent a T cell–
mediated immunologic reaction. Analysis of the periph-
eral blood in patients with aphthae shows a decreased
ratio of CD4+ to CD8+ T lymphocytes, increased T
cell–receptor γδ
+
cells, and increased tumor necrosis
factor-α (TNF-α). Many investigators agree that the epi-
thelial destruction appears to be a local T cell–medi-
ated response and involves T cells with TNF-α generated
by these cells, macrophages, and mast cells. Evidence
of the destruction of the oral mucosa mediated by these
Fig. 9-1 Transient lingual papillitis. Tender, yellow-pink
papule on the dorsum of the tongue.
Fig. 9-2 Transient lingual papillitis. Multiple painful white
papules on the lateral dorsum and tip of tongue.
Fig. 9-3 Transient lingual papillitis. Clusters of
asymptomatic, elevated, yellow papules on the dorsolateral
surface of the tongue. (Courtesy of Dr. Craig Fowler.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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332 ORAL AND MAXILLOFACIAL PATHOLOGY
lymphocytes is strong, but the initiating causes are
elusive and most likely highly variable.
The following all have been reported to be respon-
sible in certain subgroups of patients (and each dis-
counted in other subgroups!):
● Allergies
● Genetic predisposition
● Hematologic abnormalities
● Hormonal inﬂuences
● Immunologic factors
● Infectious agents
● Nutritional deﬁciencies
● Smoking cessation
● Stress
● Trauma
When all the various subgroups are combined, the
various causes cluster into three categories:
1.Primary immunodysregulation
2.Decrease of the mucosal barrier
3.Increase in antigenic exposure
One or more of these three factors may be involved in
subgroups of patients.
Recurrent aphthous stomatitis demonstrates a deﬁ-
nite tendency to occur along family lines. When both
parents have a history of aphthous ulcers, there is a
90% chance that their children will develop the lesions.
In addition, several investigators have shown an asso-
ciation with certain histocompatibility antigen (HLA)
types in subgroups of patients. Stress, with its presumed
effects on the immune system, directly correlates with
the presence of aphthous stomatitis in some groups. In
studies of professional students, recurrences clustered
around stressful periods of the academic year; con-
versely, periods of vacation were associated with a low
frequency of lesions.
Aphthouslike ulcerations have occurred in patients
with systemic immunodysregulations. Patients with
cyclic neutropenia (see page 583) occasionally have
cycles of aphthouslike ulcerations that correspond to
the periods of severe immunodysregulation. In addi-
tion, patients with acquired immunodeﬁciency syn-
drome (AIDS) have an increased frequency of severe
aphthous stomatitis (see page 278), a fact that is not
surprising considering the elevated CD8+/CD4+ ratio
as the result of the reduction of CD4+ T lymphocytes.
The mucosal barrier appears to be important in the
prevention of aphthous stomatitis and might explain
the almost exclusive presence of aphthous stomatitis
on nonkeratinized mucosa. Numerous factors that
decrease the mucosal barrier increase the frequency of
occurrence (e.g., trauma, nutritional deﬁciencies,
smoking cessation); conversely, those associated with
an increased mucosal barrier have been correlated
with decreased ulcerations (e.g., smoking, hormonal
changes, marked absence of aphthae on mucosa bound
to bone). In a small subset of female patients, a negative
association was reported between the occurrence of
aphthae and the luteal phase of the menstrual cycle—a
period of mucosal proliferation and keratinization. In
addition, these same patients often experience ulcer-
free periods during pregnancy.
An antigenic stimulus appears to be the primary
initiating factor in the immune-mediated cytotoxic
destruction of the mucosa in many patients. The list
seems endless, and every item on the list may be impor-
tant in small subsets of patients. Commonly mentioned
potential antigens include sodium lauryl sulfate in
toothpaste, many systemic medications (e.g., nonsteroi-
dal antiinﬂammatory drugs [NSAIDs], various beta
blockers, nicorandil), microbiologic agents (e.g., L
forms of streptococci, Helicobacter pylori, herpes simplex
virus [HSV], varicella-zoster virus [VZV], adenovirus,
and cytomegalovirus [CMV]), and many foods (e.g.,
cheese, chocolate, coffee, cow’s milk, gluten, nuts,
strawberries, tomatoes, dyes, ﬂavoring agents,
preservatives).
An increased prevalence of aphthouslike ulcerations
has been noted in a variety of systemic disorders (Box
9-1). These ulcerations typically are identical clinically
and histopathologically to those noted in otherwise
healthy individuals. In many cases, resolution of the
systemic disorder produces a decreased frequency and
severity of the mucosal ulcerations.
Three clinical variations of aphthous stomatitis are
recognized:
Box 9-1
Systemic Disorders Associated With
Recurrent Aphthous Stomatitis
● Behçet’s syndrome
● Celiac disease
● Cyclic neutropenia
● Nutritional deﬁciencies (iron, folate, zinc, B
1, B
2, B
6,
B12)
● IgA deﬁciency
●Immunocompromised conditions, including human
immunodeﬁciency virus (HIV) disease
● Inﬂammatory bowel disease
●MAGIC syndrome (mouth and genital ulcers with
inﬂamed cartilage)
●PFAPA syndrome (periodic fever, aphthous
stomatitis, pharyngitis, cervical adenitis)
● Reactive arthritis
● Sweet’s syndrome
●Ulcus vulvae acutum `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 333
1. Minor
2. Major
3. Herpetiform
Minor aphthous ulcerations (Mikulicz’s aphthae)
are the most common and represent the pattern present
in more than 80% of those affected. Major aphthous
ulcerations (Sutton’s disease or periadenitis mucosa
necrotica recurrens [PMNR]) occur in approximately
10% of the patients referred for treatment. The remain-
ing patients have herpetiform aphthous ulcerations.
The minor and major forms most likely represent vari-
ations of the same process, although herpetiform
aphthae demonstrate a unique pattern. Some investi-
gators differentiate the herpetiform variant because of
supposed evidence of a viral cause, but the proof is
weak and does not justify its distinction from the other
aphthous ulcerations. Some authors include Behçet’s
syndrome as an additional variation of aphthous sto-
matitis, but this multisystem disorder is more complex
and is considered later in this chapter.
CLINICAL FEATURES
Aphthous ulcerations are noted more frequently in
children and young adults, with approximately 80% of
affected individuals reporting their ﬁrst ulceration
before the age of 30. In one large series of 17,235
adults older than 17 years of age, the point prevalence
of aphthous ulcerations was 0.89%, with the annual
incidence in adults younger than 40 years old being
almost twice that of older adults (22.5% versus
13.4%).
MINOR APHTHOUS ULCERATIONS
Patients with minor aphthous ulcerations experience
the fewest recurrences, and the individual lesions
exhibit the shortest duration of the three variants. The
ulcers arise almost exclusively on nonkeratinized
mucosa and may be preceded by an erythematous
macule in association with prodromal symptoms of
burning, itching, or stinging. The ulceration demon-
strates a yellow-white, removable ﬁbrinopurulent
membrane that is encircled by an erythematous halo
(Fig. 9-4). Classically, the ulcerations measure between
3 and 10 mm in diameter and heal without scarring in
7 to 14 days (Fig. 9-5). From one to ﬁve lesions typically
are present during each episode, and the pain often is
out of proportion for the size of the ulceration. The
buccal and labial mucosae are affected most frequently,
followed by the ventral surface of the tongue, muco-
buccal fold, ﬂoor of the mouth, and soft palate (Fig.
9-6). Involvement of keratinized mucosa (e.g., hard
palate, gingiva, dorsal surface of the tongue, and ver-
milion border) is rare and usually represents extension
from adjacent nonkeratinized epithelium. The recur-
Fig. 9-4 Minor aphthous ulceration. Erythematous halo
encircling a yellowish ulceration of the lower labial mucosa.
(Courtesy of Dr. Dean K. White.)
Fig. 9-5 Minor aphthous ulcerations. Two ulcerations of
different sizes located on the maxillary labial mucosa.
Fig. 9-6 Minor aphthous ulceration. Single ulceration of
the anterior buccal mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

334 ORAL AND MAXILLOFACIAL PATHOLOGY
rence rate is highly variable, ranging from one ulcer-
ation every few years to two episodes per month.
MAJOR APHTHOUS ULCERATIONS
Major aphthous ulcerations are larger than minor
aphthae and demonstrate the longest duration per
episode. The number of lesions usually is intermediate
between that seen in the minor and herpetiform vari-
ants. The ulcerations are deeper than the minor variant,
measure from 1 to 3 cm in diameter, take from 2 to 6
weeks to heal, and may cause scarring (Fig. 9-7). The
number of lesions varies from 1 to 10. Any oral surface
area may be affected, but the labial mucosa, soft palate,
and tonsillar fauces are involved most commonly (Fig.
9-8). The onset of major aphthae is after puberty, and
recurrent episodes may continue to develop for up to
20 years or more. With time, the associated scarring
can become signiﬁcant, and in rare instances may lead
to a restricted mouth opening.
HERPETIFORM APHTHOUS ULCERATIONS
Herpetiform aphthous ulcerations demonstrate the
greatest number of lesions and the most frequent
recurrences. The individual lesions are small, averag-
ing 1 to 3 mm in diameter, with as many as 100 ulcers
present in a single recurrence. Because of their small
size and large number, the lesions bear a superﬁcial
resemblance to a primary HSV infection, leading to the
confusing designation, herpetiform. It is common
for individual lesions to coalesce into larger irregular
ulcerations (Fig. 9-9). The ulcerations heal within 7
to 10 days, but the recurrences tend to be closely
spaced. Many patients are affected almost constantly
for periods as long as 3 years. Although the nonkera-
tinized, movable mucosa is affected most frequently,
any oral mucosal surface may be involved. There is a
female predominance, and typically the onset is in
adulthood.
Further classiﬁcation of all three types is valuable
when planning the most appropriate diagnostic evalu-
ation and therapy. The lesions are diagnosed as simple
aphthosis when they appear in patients with few
lesions that heal within 1 to 2 weeks and recur infre-
quently. In contrast, patients with complex aphthosis
have multiple (≥3) and almost constant oral ulcerations
that often develop as older lesions resolve. Severe pain
and large size are common. Although associated genital
or perianal lesions also may be present, there is no
other evidence of an associated systemic disease.
HISTOPATHOLOGIC FEATURES
The histopathologic picture of aphthous stomatitis is
characteristic but not pathognomonic. The early ulcer-
ative lesions demonstrate a central zone of ulceration,
Fig. 9-7 Major aphthous ulceration. Large, deep, and
irregular ulceration of the posterior buccal mucosa. Note
extensive scarring of the anterior buccal mucosa from
previous ulcerations.
Fig. 9-8 Major aphthous ulceration. Large, irregular
ulceration of the soft palate.
Fig. 9-9 Herpetiform aphthous ulcerations. Numerous
pinhead ulcerations of the ventral surface of the tongue,
several of which have coalesced into larger, more irregular
areas of ulceration. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 335
which is covered by a ﬁbrinopurulent membrane.
Deep to the area of ulceration, the connective tissue
exhibits an increased vascularity and a mixed inﬂam-
matory cellular inﬁltrate that consists of lymphocytes,
histiocytes, and polymorphonuclear leukocytes. The
epithelium at the margin of the lesion demonstrates
spongiosis and numerous mononuclear cells in the
basilar one third. A band of lymphocytes intermixed
with histiocytes is present in the superﬁcial connective
tissue and surrounding deeper blood vessels.
DIAGNOSIS
No laboratory procedure provides deﬁnitive diagnosis.
The diagnosis is made from the clinical presentation
and from exclusion of other diseases that produce
ulcerations that closely resemble aphthae (see Box
9-1). In patients with complex aphthous ulcerations, a
systematic evaluation for an underlying trigger or asso-
ciated systemic condition is prudent. In a review of 244
patients with complex aphthous ulcerations, an associ-
ated triggering condition (e.g., hematologic deﬁciency,
gastrointestinal disease, immunodeﬁciency, drug reac-
tion) was discovered in almost 60%. Because the histo-
pathologic features are nonspeciﬁc, a biopsy is useful
only in eliminating differential possibilities and is not
beneﬁcial in arriving at the deﬁnitive diagnosis.
TREATMENT AND PROGNOSIS
The patient’s medical history should be reviewed for
signs and symptoms of any systemic disorder that may
be associated with aphthouslike ulcerations. Most
patients with mild aphthosis receive either no treat-
ment, therapy with a number of over-the-counter anes-
thetics or protective bioadhesive products, or periodic
topical medicaments that minimize the frequency and
severity of the attacks.
In patients with mild disease, the mainstay of therapy
is the use of topical corticosteroids, and the list of
possible choices is long. Most patients with diffuse
minor or herpetiform aphthae respond well to 0.01%
dexamethasone elixir used in a rinse-and-expectorate
method. Patients with localized ulcerations can be
treated successfully with 0.05% augmented betametha-
sone dipropionate gel or 0.05% ﬂuocinonide gel.
Adrenal suppression does not occur with appropriate
use of these medications. Major aphthous ulcerations
are more resistant to therapy and often warrant
more potent corticosteroids (Fig. 9-10). The individual
lesions may be injected with triamcinolone acetonide
or covered with 0.05% clobetasol propionate gel or
0.05% halobetasol propionate ointment. Triamcinolone
tablets also can be dissolved directly over the lesions.
In hard-to-reach areas, such as the tonsillar pillars,
beclomethasone dipropionate aerosol spray can be
used. In resistant cases, systemic corticosteroids may
be required to supplement the topical medications
and gain control. In such instances, prednisolone or
betamethasone syrup in a swish-and-swallow method
is preferable to prednisone tablets. In this way the
ulcerations will receive both topical and systemic
therapy.
Numerous alternatives to corticosteroid agents have
been used to treat patients suffering from aphthous
ulcerations (the most widely accepted are highlighted
in bold). Caution should be exercised, however, because
many of these agents have not been examined in a
double-blind, placebo-controlled fashion to assess the
degree of effectiveness compared with placebo. Fur-
BA
Fig. 9-10 Major aphthous ulceration. A, Large ulceration of the left anterior buccal mucosa.
B, Same lesion after 5 days of therapy with betamethasone syrup used in a swish-and-swallow
method. The patient was free of pain by the second day of therapy. The ulceration healed
completely during the next week. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

336 ORAL AND MAXILLOFACIAL PATHOLOGY
thermore, some of these treatments may have signiﬁ-
cant side effects or may be quite expensive. Included
within the list of therapies are acyclovir, amlexanox,
topical 5-aminosalicylic acid, azelastine hydrochloride,
benzydamine hydrochloride, carbenoxolone sodium,
chemical cauterizing agents, chlorhexidine, colchi-
cine, cyclosporine, dapsone, deglycyrrhizinated
liquorice, gamma globulin, hydrogen peroxide, hydroxy-
propyl cellulose ﬁlms, interferon-α, irsogladine maleate,
levamisole, LongoVital, monoamine oxidase (MAO)
inhibitors, pentoxifylline, prostaglandin E-2 gel, sucral-
fate, sodium cromoglycate (cromolyn), tacrolimus, tet-
racyclines, thalidomide, transfer factor (extract of
immunocytes), triclosan, and vitamin and mineral sup-
plements (especially zinc sulfate). The success of these
therapies is highly variable. These treatments do not
resolve the underlying problem and are merely an
attempt to “beat back brush ﬁres.” Recurrences often
continue, although breaking up the cycle may induce
longer disease-free intervals between attacks. Surgical
removal of aphthous ulcerations has been used but is
an inappropriate therapy. Although laser ablation
shortens the duration and decreases associated symp-
toms, its use is of very limited practical beneﬁt because
patients cannot return on each recurrence.
Chemical cautery with silver nitrate continues to be
suggested as an effective therapy, but it can no longer
be recommended because of the numerous safer alter-
natives and its rare association with massive necrosis
(see page 292) and systemic argyria (see page 315). An
over-the-counter cautery that uses sulfuric acid and
phenolic agents is indicated in certain situations, but
patients must be warned of the potential for signiﬁcant
local tissue necrosis related to its misuse.
Patients with complex aphthosis require a more
extensive evaluation for occult systemic disease and a
search for possible triggers of the immune-mediated
mucosal destruction. To go beyond the management of
individual recurrences is difﬁcult, expensive, and often
frustrating. In spite of this, patients with severe disease
should be offered the opportunity to investigate the
underlying causes.
As previously mentioned, the immune attacks are
usually a result of immunodysregulation, a decreased
mucosal barrier, or an elevated antigenic stimulus. The
evaluation for systemic disorders usually eliminates
the ﬁrst two causes. Typically, this is followed by patch
tests for antigen stimuli or an elimination diet for pos-
sible offending foods. Therapeutic trials might be insti-
tuted against the viruses and bacteria that have been
implicated in subsets of patients with aphthous stoma-
titis. The investigator should explain to the patient that
the underlying causation is diverse; even with the most
exhaustive search, the answer may be elusive. In many
cases, stress appears involved, and all evaluations in
these patients will be within normal limits. In spite of
the high likelihood of an expensive and negative evalu-
ation, discovery of an underlying abnormality that can
be treated often leads to permanent resolution or dra-
matic improvement in the course of the recurrences.
BEHÇET’S SYNDROME (BEHÇET’S
DISEASE; ADAMANTIADES
SYNDROME)
The combination of chronic ocular inﬂammation and
orogenital ulcerations was reported as early as the era
of the ancient Greeks and later described in 1931
by a Greek ophthalmologist, Benedict Adamantiades.
The classic triad was not delineated until 1937, when
a Turkish dermatologist, Hulusi Behçet, deﬁned the
disease that bears his name. Although the disease has
been traditionally thought primarily to affect the oral,
genital, and ocular regions, it now is recognized to be
a multisystem disorder.
Although no clear causation has been established,
Behçet’s syndrome has an immunogenetic basis
because of strong associations with certain HLA types.
As in aphthous stomatitis, the disorder appears to be
an immunodysregulation that may be primary or sec-
ondary to one or more triggers. Investigators have cor-
related attacks to a number of environmental antigens,
including bacteria (especially streptococci), viruses,
pesticides, and heavy metals.
Histocompatibility antigen B-51 (HLA-B51) has
been linked closely to Behçet’s syndrome, and the fre-
quency of both the disease (approximately 1 in 1000)
and the haplotype is high in Turkey, Japan, and the
Eastern Mediterranean countries. This distribution
appears correlated to the ancient “Silk Route” that
extended from China to Rome and was traveled by the
Turks. Sexual reproduction between immigrants and
locals along the route appears to have spread the
genetic vulnerability. Interestingly, when predisposed
populations migrate to nonendemic locations, the
prevalence decreases, suggesting environmental factors
also are involved.
CLINICAL FEATURES
As mentioned previously, the highest prevalence occurs
in the Middle East and Japan, with a much lower fre-
quency noted in northern Europe, the United States,
and the United Kingdom. At the time of discovery,
most patients are young adults, with the disease diag-
nosed uncommonly in blacks, children, and older
adults.
Oral involvement is an important component of
Behçet’s syndrome, and it is the ﬁrst manifestation in
25% to 75% of the cases. Oral lesions occur at some `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 337
point during the disease in 99% of the patients and
typically precede other sites of involvement.
The lesions are similar to aphthous ulcerations
occurring in otherwise healthy individuals and demon-
strate the same duration and frequency. In spite of this,
investigators have shown several statistically signiﬁ-
cant clinical variations that are different from typical
aphthous ulcerations and may be used to increase the
index of suspicion for Behçet’s syndrome. When com-
pared with patients with aphthae, a larger percentage
of those with Behçet’s syndrome demonstrate six or
more ulcerations. The lesions commonly involve the
soft palate and oropharynx, which are usually infre-
quent sites for the occurrence of routine aphthae. The
individual lesions vary in size, have ragged borders,
and are surrounded by a larger zone of diffuse ery-
thema (Fig. 9-11).
All three forms of oral aphthous stomatitis may be
seen. Although the majority of affected patients have
lesions that resemble minor aphthous ulcerations,
some reports have documented a prevalence of major
aphthae that approaches 40% in patients affected with
Behçet’s syndrome. The herpetiform variant remains
uncommon and is noted in approximately 3%. Patients
with major aphthae often demonstrate more frequent
recurrences and more ulcerations per relapse. In spite
of more severe oral disease, the presence of major
aphthae in Behçet’s syndrome does not correlate
with an increased risk for more severe systemic
expression.
The genital lesions are similar in appearance to the
oral ulcerations. They occur in 75% of the patients and
appear on the vulva, vagina, glans penis, scrotum, and
perianal area (Fig. 9-12). These lesions recur less fre-
quently than do the oral ulcerations, are deeper, and
tend to heal with scarring. The genital ulcerations
cause more symptoms in men than in women and
may be discovered only by a routine examination in
women.
Common cutaneous lesions include erythematous
papules, vesicles, pustules, pyoderma, folliculitis, acne-
iform eruptions, and erythema nodosum–like lesions.
From a diagnostic standpoint, one of the most impor-
tant skin manifestations is the presence of positive
“pathergy.” One or 2 days after the oblique insertion of
a 20-gauge or smaller needle under sterile conditions,
a tuberculin-like skin reaction or sterile pustule devel-
ops (Fig. 9-13). This skin hyperreactivity (pathergy)
Fig. 9-11 Behçet’s syndrome. Diffuse erythema
surrounding numerous irregular ulcerations of the soft palate.
Fig. 9-12 Behçet’s syndrome. Numerous irregular
ulcerations of the labia majora and perineum. (From Helm TN,
Camisa C, Allen C et al: Clinical features of Behçet’s disease, Oral Surg Oral
Med Oral Pathol 72:30, 1991.)
Fig. 9-13 Behçet’s syndrome. Sterile pustule of the skin
that developed 1 day after injection of saline. This reaction is
termed cutaneous pathergy. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

338 ORAL AND MAXILLOFACIAL PATHOLOGY
appears to be unique to Behçet’s syndrome and is
present in 40% to 88% of patients with this disorder.
Ocular involvement is present in 70% to 85% of the
cases and is more frequent and severe in males. The
most common ﬁndings are posterior uveitis, conjuncti-
vitis, corneal ulceration, papilledema, and arteritis.
Although Behçet originally described hypopyon (pus in
the anterior chamber) as a cause of blindness, this
ﬁnding currently is rare. The most common secondary
ocular complications are cataracts, glaucoma, and neo-
vascularization of the iris and retina.
Arthritis is one of the more common minor mani-
festations of the disease and is usually self-limiting and
nondeforming. The knees, wrists, elbows, and ankles
are affected most frequently.
Central nervous system (CNS) involvement is not
common but, when present, is associated with a poor
prognosis. From 10% to 25% of the patients demon-
strate CNS involvement, and the alterations produced
result in a number of changes that include paralysis
and severe dementia.
Other alterations may be seen that involve the car-
diovascular, gastrointestinal, hematologic, pulmonary,
muscular, and renal systems. These most likely occur
secondary to vasculitis and create a variety of clinical
presentations.
DIAGNOSIS
No laboratory ﬁnding is diagnostic of Behçet’s syn-
drome. In an attempt to standardize diagnoses, deﬁni-
tive criteria have been developed. Table 9-1 delineates
the requirements proposed by the Behçet’s Interna-
tional Study Group. Although this system is used widely,
many authorities exclude acneiform skin lesions in
young adults from the criteria because of the high
prevalence of this ﬁnding in an otherwise normal
population.
HISTOPATHOLOGIC FEATURES
The histopathologic features are not speciﬁc for
Behçet’s syndrome and can be seen in many disorders,
including aphthous stomatitis. The pattern most fre-
quently seen is called leukocytoclastic vasculitis. The
ulceration is similar in appearance to that seen in aph-
thous stomatitis, but the small blood vessels classically
demonstrate intramural invasion by neutrophils, kary-
orrhexis of neutrophils, extravasation of red blood cells,
and ﬁbrinoid necrosis of the vessel wall.
TREATMENT AND PROGNOSIS
The oral and genital ulcerations typically respond well
to potent topical or intralesional corticosteroids or
topical tacrolimus. In more severe cases, this therapy
can be combined with oral colchicine or dapsone.
Patients who fail this initial conservative approach
often respond to thalidomide, low-dose methotrexate,
systemic corticosteroids, or inﬂiximab (anti–TNF-α
antibody). Severe ocular or systemic disease often
necessitates combined use of systemic immuno-
suppressive and immunomodulatory agents (e.g.,
corticosteroids, cyclosporine, azathioprine, interferon-
α2a, cyclophosphamide).
Behçet’s syndrome has a highly variable course. A
relapsing and remitting pattern is typical, with attacks
becoming more intermittent after 5 to 7 years. The
major morbidity and mortality of the disease appear
conﬁned to the years immediately after the initial diag-
nosis; therefore, early aggressive therapy is recom-
mended for patients with severe clinical manifestations.
Mortality is typically low; when noted, it most fre-
quently is secondary to pulmonary hemorrhage, CNS
hemorrhage, or bowel perforation. In the absence of
CNS disease or signiﬁcant vascular complications, the
prognosis is generally good.
SARCOIDOSIS
Sarcoidosis is a multisystem granulomatous disorder
of unknown cause. Jonathan Hutchinson initially
described the disease in 1875, but Boeck coined the
term sarcoidosis (Greek meaning “ﬂeshlike condition”)
14 years later. The evidence implicates improper deg-
radation of antigenic material with the formation of
noncaseating granulomatous inﬂammation. The nature
Table 9-1 International Study Group Criteria for the Diagnosis of Behçet’s Disease
Recurrent oral ulceration Minor, major, or herpetiform aphthae
Plus two of the following:
Recurrent genital ulcerations Aphthaelike ulcerations
Eye lesions Anterior or posterior uveitis, cells in vitreous on slit-lamp examination, or retinal vasculitis
Skin lesions Erythema nodosum, pseudofolliculitis or papulopustular lesions, or acneiform nodules
noted in postadolescent patients not receiving corticosteroids
Positive pathergy test Read by physician at 24-48 hours `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 339
of the antigen is unknown, and probably several dif-
ferent antigens may be responsible. Possible involved
antigens include infectious agents (e.g., mycobacte-
rium, propionibacteria, Epstein-Barr virus, human her-
pesvirus 8 [HHV-8]) and a number of environmental
factors (e.g., wood dust, pollen, clay, mold, silica). The
inappropriate defense response may result from pro-
longed or heavy antigenic exposure, an immunodys-
regulation (genetic or secondary to other factors) that
prevents an adequate cell-mediated response, a defec-
tive regulation of the initial immune reaction, or a
combination of all three of these factors. Several inves-
tigators have conﬁrmed a genetic predisposition and
positive associations with certain HLA types.
CLINICAL FEATURES
Sarcoidosis has a worldwide distribution but is recog-
nized more commonly in the developed world. In
North America, blacks are affected 10 to 17 times
more frequently than whites. There is a slight female
predominance, and the disease exhibits a bimodal age
distribution, with the ﬁrst peak between 25 and 35
years of age and the second peak between 45 and 65
years of age.
Sarcoidosis most commonly appears acutely over a
period of days to weeks, and the symptoms are vari-
able. Common clinical symptoms include dyspnea, dry
cough, chest pain, fever, malaise, fatigue, arthralgia,
and weight loss. Less frequently, sarcoidosis arises
insidiously over months to years, without signiﬁcant
symptoms; when clinically evident, pulmonary symp-
toms are most common. Approximately 20% of patients
have no symptoms, and the disease is discovered on
routine chest radiographs.
Although any organ may be affected, the lungs,
lymph nodes, skin, eyes, and salivary glands are the
predominant sites. Lymphoid tissue is involved in
almost all cases. The mediastinal and paratracheal
lymph nodes are involved commonly, and chest radio-
graphs frequently reveal bilateral hilar lymphadenopa-
thy. Approximately 90% of affected patients will reveal
an abnormal chest radiograph sometime during the
course of the disease. Cutaneous manifestations occur
about 25% of the time. These often appear as chronic,
violaceous, indurated lesions that are termed lupus
pernio and frequent the nose, ears, lips, and face (Fig.
9-14). Symmetrical, elevated, indurated, purplish
plaques also are seen commonly on the limbs, back,
and buttocks. Scattered, nonspeciﬁc, tender erythema-
tous nodules, known as erythema nodosum, fre-
quently occur on the lower legs.
Ocular involvement is noted in 25% of the cases and
most often appears as anterior uveitis. Lesions of the
conjunctiva and retina may occur. Involvement of the
lacrimal glands often produces keratoconjunctivitis
sicca; the salivary glands can be altered similarly, with
resultant clinical enlargement and xerostomia. Signiﬁ-
cant enlargement can occur in any major or minor
salivary gland. Removal of intraoral mucoceles that
occur in the salivary glands affected by the granuloma-
tous process has led to the initial diagnosis in some
cases. The salivary gland enlargement, xerostomia, and
keratoconjunctivitis sicca can combine to mimic
Sjögren syndrome (see page 466).
Although lymphoid, pulmonary, cutaneous, and
ocular lesions are most common, virtually any organ
system may be affected. Other potential sites include
the endocrine system, gastrointestinal tract, heart,
kidneys, liver, nervous system, and spleen. Intraosse-
ous lesions may occur and most commonly involve the
phalanges, metacarpals, and metatarsals. Less fre-
quently, the skull, nasal bones, ribs, and vertebrae are
affected.
Two distinctive clinical syndromes are associated
with acute sarcoidosis. Löfgren’s syndrome consists
of erythema nodosum, bilateral hilar lymphadenopa-
thy, and arthralgia. Patients with Heerfordt’s syn-
drome (uveoparotid fever) have parotid enlargement,
anterior uveitis of the eye, facial paralysis, and fever.
If salivary gland and lymph node involvement are
excluded, clinically evident oral manifestations in sar-
coidosis are uncommon. Any oral mucosal site can be
affected, most often appearing as a submucosal mass,
an isolated papule, an area of granularity, or an ulcer-
ation. The mucosal lesions may be normal in color,
brown-red, violaceous, or hyperkeratotic (Figs. 9-15
and 9-16). The most frequently affected intraoral soft
tissue site is the buccal mucosa, followed by the gingiva,
lips, ﬂoor of mouth, tongue, and palate. Most cases
appearing in the ﬂoor of the mouth involve salivary
Fig. 9-14 Sarcoidosis. Violaceous indurated plaques of the
right malar area and bridge of nose. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

340 ORAL AND MAXILLOFACIAL PATHOLOGY
glands and create mucus extravasation. Intraosseous
lesions affect either jaw and represent approximately
one fourth of all reported intraoral cases. Of these
cases, most appeared as ill-deﬁned radiolucencies that
occasionally eroded the cortex but never created
expansion. In a literature review of 45 reported cases
of intraoral sarcoidosis, the oral lesion was the ﬁrst
documented clinical manifestation of the disease in the
majority of patients.
HISTOPATHOLOGIC FEATURES
Microscopic examination of sarcoidosis exhibits a
classic picture of granulomatous inﬂammation. Tightly
clustered aggregates of epithelioid histiocytes are
present, with a surrounding rim of lymphocytes. Inter-
mixed with the histiocytes are scattered Langhans’ or
foreign body type giant cells (Fig. 9-17). The granulo-
mas often contain laminated basophilic calciﬁcations,
known as Schaumann bodies (degenerated lyso-
somes), or stellate inclusions, known as asteroid
bodies (entrapped fragments of collagen) (Fig. 9-18).
In lymph nodes, small yellow-brown structures called
Hamazaki-Wesenberg bodies (large lysosomes) may
be noted in the subcapsular sinus. None of these struc-
tures are speciﬁc for sarcoidosis. Special stains for
fungal and bacterial organisms are negative. No polar-
izable, dissolvable, or pigmented foreign material can
be detected.
DIAGNOSIS
The diagnosis is established by the clinical and radio-
graphic presentations, the histopathologic appearance,
and the presence of negative ﬁndings with both special
stains and cultures for organisms. Elevated serum
angiotensin-converting enzyme (ACE) levels and
appropriate documentation of pulmonary involvement
strongly support the diagnosis. Other laboratory
ab normalities that may be seen include eosinophilia;
Fig. 9-15 Sarcoidosis. Multiple erythematous macules of
the hard palate. (Courtesy of Dr. George Blozis.)
Fig. 9-16 Sarcoidosis. Erythematous macules with central
hyperkeratosis of the lower labial mucosa.
Fig. 9-17 Sarcoidosis. Photomicrograph of a labial minor
salivary gland demonstrating granulomatous inﬂammation
characterized by circumscribed collections of histiocytes,
lymphocytes, and multinucleated giant cells.
Fig. 9-18 Sarcoidosis. Photomicrograph illustrating
multinucleated giant cell with intracytoplasmic asteroid body. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 341
leukopenia; anemia; thrombocytopenia; and elevation
of the serum alkaline phosphatase level, erythrocyte
sedimentation rate, serum calcium concentration, and
urinary calcium level.
A skin test for sarcoidosis, the Kveim test, can be
performed by intradermal injection of a sterilized sus-
pension of human sarcoid tissue. The procedure is no
longer widely used because of difﬁculty in obtaining
material for the test, concern related to its accuracy,
and the inability to guarantee the absence of contami-
nation (e.g., prions) in this human tissue.
Minor salivary gland biopsy has been promoted as a
diagnostic aid in suspected cases of sarcoidosis (see Fig.
9-17). Investigators have documented success rates
between 38% and 58%. The misdiagnosis of Sjögren
syndrome from minor salivary gland biopsy specimens
has been reported in patients with sarcoidosis. Pre-
viously, biopsy of the parotid was avoided because of
the fear of salivary ﬁstula formation and damage to the
facial nerve. These concerns have been reduced through
biopsy of the posterior superﬁcial lobe of the parotid
gland, and conﬁrmation of sarcoidosis has been
reported in 93% of patients from this procedure.
TREATMENT AND PROGNOSIS
In approximately 60% of patients with sarcoidosis, the
symptoms resolve spontaneously within 2 years without
treatment. Most initial diagnoses are followed by a 3- to
12-month period of observation to deﬁne the general
course of the disease. Active intervention is recom-
mended for progressive disease and patients with
cardiac or neurologic involvement, hypercalcemia, dis-
ﬁguring skin disease, or serious ocular lesions that do
not respond to local therapy. In patients requiring
treatment, corticosteroids remain ﬁrst-line therapy,
but resistance and relapses are common. Medications
used in patients with refractory disease include metho-
trexate, azathioprine, chlorambucil, and cyclophospha-
mide. Several studies have shown promising results
with TNF-α antagonists such as etanercept, inﬂiximab,
pentoxyphylline, and thalidomide. Antimalarial medi-
cations, such as chloroquine, have demonstrated effec-
tiveness in resolving mucocutaneous sarcoidosis that
was resistant to steroids. In 10% to 20% of those affected
by sarcoidosis, resolution does not occur even with
treatment. CNS and chronic extrathoracic involvement
are associated with a poor response to therapy. Approx-
imately 4% to 10% of patients die of pulmonary, cardiac,
or CNS complications.
OROFACIAL GRANULOMATOSIS
Since Wiesenfeld introduced it 1985, orofacial gran-
ulomatosis has become a well-accepted and unifying
term encompassing a variety of clinical presentations
that, on biopsy, reveal the presence of nonspeciﬁc
granulomatous inﬂammation. The conditions previ-
ously designated as Melkersson-Rosenthal syndrome
and cheilitis granulomatosa of Miescher are subsets of
orofacial granulomatosis, and neither represents a
speciﬁc disease.
The disorder is somewhat analogous to aphthous
stomatitis, in that the cause is idiopathic but appears to
represent an abnormal immune reaction. Sometimes
oral lesions are seen that are identical to idiopathic
orofacial granulomatosis but represent a secondary
reaction to one or more of a variety of factors. Table 9-2
delineates systemic diseases that may mimic orofacial
granulomatosis, and Table 9-3 lists possible local
causes. Although many researchers have presented
evidence that the immune response appears secondary
to a chronic antigenic stimulus, the pathosis most likely
has numerous triggers, resulting in various theories
that are correct only in subsets of patients.
The majority of patients are adults; however, the
process may occur at any age. When noted in children
and adults younger than 30 years old, some investiga-
Table 9-2 Systemic Evaluation of Patients with Orofacial Granulomatosis
Systemic Cause Preliminary Screening Procedure
Chronic granulomatous disease Neutrophil nitroblue tetrazolium reduction test (perform if medical history of chronic
infections is noted)
Crohn’s disease Hematologic evaluation for evidence of gastrointestinal malabsorption (e.g., low albumin,
calcium, folate, iron, and red blood cell count; elevated erythrocyte sedimentation rate)
or leukocyte scintigraphy using
99m
Tc-HMPAO (hexamethylpropylene amine oxime); if
initial screen is positive, then recommend esophagogastroduodenoscopy,
ileocolonoscopy, and small-bowel radiographs
Sarcoidosis Serum angiotensin–converting enzyme and chest radiograph (hilar lymphadenopathy)
Tuberculosis Skin test and chest radiograph (negative acid-fast bacteria [AFB] stain on biopsy
specimen does not rule out mycobacterial infection) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

342 ORAL AND MAXILLOFACIAL PATHOLOGY
tors have found an increased association with an
asymptomatic gastrointestinal inﬂammatory process
that is not consistent with Crohn’s disease and possibly
may be associated with a dietary trigger. A positive
response has been seen in patients maintaining a diet
free of two common food allergens, cinnamon and ben-
zoate. In another cohort, allergy testing and dietary
restriction also proved beneﬁcial.
Because clinical and histopathologic features of oro-
facial granulomatosis can be produced by a variety of
underlying causes, this diagnosis is the beginning, not
the end, of the patient’s evaluation. After initial diagno-
sis, the patient should be evaluated for several systemic
diseases and local processes (see Tables 9-2 and 9-3)
that may be responsible for similar oral lesions. If fea-
tures diagnostic of one of these more speciﬁc disorders
are discovered, then the ﬁnal diagnosis is altered
appropriately.
CLINICAL FEATURES
The clinical presentation of orofacial granulomatosis is
highly variable. By far, the most frequent site of involve-
ment is the lips. The labial tissues demonstrate a non-
tender, persistent swelling that may involve one or
both lips (Fig. 9-19). On rare occasions, superﬁcial
amber vesicles, resembling lymphangiomas, are found.
When these signs are combined with facial paralysis
and a ﬁssured tongue, the clinical presentation is called
Melkersson-Rosenthal syndrome (Figs. 9-20 and
9-21). Involvement of the lips alone is called cheilitis
granulomatosa (of Miescher). Some consider cheili-
tis granulomatosa an oligosymptomatic form of
Melkersson-Rosenthal syndrome, but it appears best to
include all of these under the term orofacial granuloma-
tosis. In addition to labial edema, swelling of other parts
of the face may be seen, and cervical lymphadenopathy
rarely has been noted.
Intraoral sites also can be affected, and the predomi-
nant lesions are edema, ulcers, and papules. The tongue
may develop ﬁssures, edema, paresthesia, erosions, or
taste alteration. The gingiva can develop swelling,
erythema, pain, or erosions. The buccal mucosa
often exhibits a cobblestone appearance of edematous
mucosa or focal areas of submucosal enlargement.
Linear hyperplastic folds may occur in the mucobuccal
Table 9-3 Interventions to Rule Out Local Causes for Orofacial Granulomatosis
Local Cause Intervention
Chronic oral infection Eliminate all oral foci of infection.
Foreign material The foreign debris noted in iatrogenic gingivitis is often subtle and difﬁcult to associate
deﬁnitively with the diffuse inﬂammatory process. If lesions are nonmigrating and isolated
to gingiva, then response to local excision of a single focus should be evaluated.
Allergy Cosmetics, foods, food additives, ﬂavorings, oral hygiene products (e.g., toothpaste, mouth
rinses), and dental restorative metals have been implicated. Patch testing (i.e., contact
dermatitis standard series with oral battery) or elimination diet may discover the offending
antigen.
Fig. 9-19 Orofacial granulomatosis (cheilitis
granulomatosa). Nontender, persistent enlargement of the
upper lip. (From: Allen CM, Camisa C: Diseases of the mouth and lips.
In Sams WM, Lynch P, editors: Principles of dermatology, New York, 1990,
Churchill Livingstone.)
Fig. 9-20 Melkersson-Rosenthal syndrome. Persistent
enlargement of the lower lip. (Courtesy of Dr. Richard Ziegler.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 343
fold, with linear ulcerations appear in the base of these
folds (Fig. 9-22). The palate may have papules or large
areas of hyperplastic tissue. Hyposalivation rarely is
reported.
HISTOPATHOLOGIC FEATURES
In classic cases of cheilitis granulomatosa, edema is
present in the superﬁcial lamina propria with dilation
of lymphatic vessels and scattered lymphocytes seen
diffusely and in clusters. Fibrosis may be present in
long-term lesions. Scattered aggregates of noncaseating
granulomatous inﬂammation, consisting of lympho-
cytes and epithelioid histiocytes, are present, with or
without multinucleated giant cells. Typically, the gran-
ulomas appear to cluster around scattered vessels and
are not as well formed or discrete as those seen in sar-
coidosis (Fig. 9-23).
Special stains for fungal organisms and acid-fast
bacteria are negative. No dissolvable, pigmented, or
polarizable foreign material should be present. When
the lesions are conﬁned to the gingiva, a thorough
search should be made, because many cases of granu-
lomatous gingivitis are due to subtle collections of
foreign material (see page 160).
DIAGNOSIS
The initial diagnosis of orofacial granulomatosis is
made on histopathologic demonstration of granuloma-
tous inﬂammation that is associated with negative
special stains for organisms and no foreign material.
Based on the clinical and historical ﬁndings, one or
more conditions may have to be considered in the dif-
ferential diagnosis. It should be stressed that no one
cause for the granulomas will be found when large
groups of patients with orofacial granulomatosis are
studied. (See Tables 9-2 and 9-3 for a list of conditions
and suggested procedures that may be appropriate to
arrive at a more deﬁnitive diagnosis.)
TREATMENT AND PROGNOSIS
The ﬁrst goal of management should be discovery of
the initiating cause, although this may be difﬁcult
because the trigger often is elusive. In children and
Fig. 9-21 Melkersson-Rosenthal syndrome. Same patient
as depicted in Fig. 9-20. Note numerous furrows on the
dorsal surface of the tongue. (Courtesy of Dr. Richard Ziegler.)
Fig. 9-22 Orofacial granulomatosis. Hemorrhagic and
hyperplastic mucosa of the posterior mandibular mucobuccal
fold. (Courtesy of Dr. Russell Spinazze.)
Fig. 9-23 Orofacial granulomatosis. Clusters of
granulomatous inﬂammation around scattered vessels. The
inset illustrates the histiocytes and multinucleated giant cells
within the granulomas. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

344 ORAL AND MAXILLOFACIAL PATHOLOGY
young adults, the search for a dietary allergen or an
association with underlying gastrointestinal disease
should be considered. Local measures to resolve the
clinical manifestations can be attempted but, as would
be expected, recurrences are common. The individual
lesions have been treated with a variety of interven-
tions, with variable results. Topical or intralesional
corticosteroids, radiotherapy, salazosulfapyridine (sul-
fasalazine), hydroxychloroquine sulfate, azathioprine,
cyclosporine A, methotrexate, danazol, dapsone, TNF-
α antagonists (inﬂiximab, thalidomide), clofazimine,
metronidazole, and numerous other antibiotics have
been tried. Currently, most investigators administer
intralesional delayed-release high-concentrate triam-
cinolone to control the progression of this disease
(Figs. 9-24 and 9-25). Of the alternatives, clofazimine
(antileprosy agent with antigranulomatous properties)
is mentioned most frequently as the second choice
after corticosteroids. Because of the natural variability
of the disease’s progression and the occurrence of
A B
Fig. 9-24 Orofacial granulomatosis. A, Diffuse enlargement of the upper lip. B, Same
patient after intralesional triamcinolone injections.
A B
Fig. 9-25 Orofacial granulomatosis. Same patient depicted in Fig. 9-24. A, Clinical
appearance before local therapy. B, Signiﬁcant resolution after intralesional corticosteroid
therapy. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 345
spontaneous remissions, therapies are difﬁcult to
assess. In the absence of a response to other treatments,
surgical recontouring has been used by some but
carries a considerable risk of recurrence and rarely
appears to be warranted. After excision, some clini-
cians recommend intralesional steroids to slow
recurrences.
The prognosis is highly variable. No therapy has
proved to be the “silver bullet” in resolving the indi-
vidual lesions. In some cases, lesions resolve spontane-
ously, with or without therapy; in others, they continue
to progress in spite of a myriad of therapeutic attempts
to stop the progression. The “lucky” subset of patients
includes those who have found an initiating causation
and have resolved their problems by the exclusion of
the offending agent.
WEGENER’S GRANULOMATOSIS
Wegener’s granulomatosis is a well-recognized,
although uncommon, disease process of unknown
cause. The initial description of the syndrome by
Wegener included necrotizing granulomatous lesions
of the respiratory tract, necrotizing glomerulonephri-
tis, and systemic vasculitis of small arteries and veins.
Hypotheses about the cause of the disease include an
abnormal immune reaction secondary to a nonspeciﬁc
infection or an aberrant hypersensitivity response to an
inhaled antigen. A possible hereditary predisposition
has been mentioned in some cases.
Before the current treatment modalities were initi-
ated, the disorder was uniformly fatal. The disease
begins as a localized process, which may become more
widely disseminated if left untreated. Most patients
respond favorably to treatment; consequently, early
diagnosis and appropriate therapy are critical.
CLINICAL FEATURES
Wegener’s granulomatosis demonstrates a wide age
range from childhood to old age, with a mean of
approximately 40 years and no sex predilection. The
disease can involve almost every organ system in the
body. With classic Wegener’s granulomatosis, patients
initially show involvement of the upper and lower
respiratory tract; if the condition remains untreated,
then renal involvement often rapidly develops (gener-
alized Wegener’s granulomatosis).
Limited Wegener’s granulomatosis is diagnosed
when there is involvement of the respiratory system
without rapid development of renal lesions. One subset
of patients exhibits lesions primarily of the skin and
mucosa, a condition termed superﬁcial Wegener’s
granulomatosis. In this form of the disease, systemic
involvement develops slowly. These three different
clinical patterns highlight the variability of the clinical
aggressiveness that can occur in patients with Wegen-
er’s granulomatosis.
Purulent nasal drainage, chronic sinus pain, nasal
ulceration, congestion, and fever are frequent ﬁndings
from upper respiratory tract involvement. Persistent
otitis media, sore throat, and epistaxis also are reported.
With progression, destruction of the nasal septum can
result in a saddle-nose deformity. Patients with lower
respiratory tract involvement may be asymptomatic, or
they may have dry cough, hemoptysis, dyspnea, or
chest pain. Renal involvement usually occurs late in
the disease process and is the most frequent cause of
death. The glomerulonephritis results in proteinuria
and red blood cell casts. Occasionally, the eyes, ears,
and skin also are involved.
Oral lesions are seen in the minority of those
affected; occasionally, the oral changes may be the only
clinically evident ﬁnding. The most characteristic oral
manifestation is strawberry gingivitis. This distinc-
tive but uncommon pattern of gingival alteration
appears to be an early manifestation of Wegener’s
granulomatosis and has been documented before renal
involvement in most cases. The affected gingiva dem-
onstrates a ﬂorid and granular hyperplasia. The surface
forms numerous short bulbous projections, which are
hemorrhagic and friable; this red, bumpy surface is
responsible for the strawberry-like appearance (Fig.
9-26). The buccal surfaces are affected more frequently,
and the alterations are classically conﬁned to the
attached gingiva. The process appears to begin in the
interdental region and demonstrates lateral spread to
adjacent areas. At the time of diagnosis, the involve-
ment may be localized or generalized to multiple quad-
rants. Destruction of underlying bone with the
development of tooth mobility has been reported.
Fig. 9-26 Wegener’s granulomatosis. Hemorrhagic and
friable gingiva (strawberry gingivitis). (Courtesy of Dr. Sam
McKenna.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

346 ORAL AND MAXILLOFACIAL PATHOLOGY
Oral ulceration also may be a manifestation of
Wegener’s granulomatosis. Unlike the strawberry
gingiva, the ulcerations do not form a pattern that is
unique. These lesions are clinically nonspeciﬁc and
may occur on any mucosal surface (Fig. 9-27). In con-
trast to the gingival changes, the oral ulcerations are
diagnosed at a later stage of the disease, with more than
60% of the affected patients demonstrating renal
involvement. Other less common orofacial manifesta-
tions include facial paralysis, labial mucosal nodules,
sinusitis-related toothache, arthralgia of the temporo-
mandibular joint (TMJ), jaw claudication, palatal ulcer-
ation from nasal extension, oral-antral ﬁstulae, and
poorly healing extraction sites.
Enlargement of one or more major salivary glands
from primary involvement of the granulomatous
process also has been reported. The glandular involve-
ment also appears early in the course of the disease and
may lead to early diagnosis and treatment.
HISTOPATHOLOGIC FEATURES
Wegener’s granulomatosis appears as a pattern of
mixed inﬂammation centered around blood vessels.
Involved vessels demonstrate transmural inﬂamma-
tion, often with areas of heavy neutrophilic inﬁltration,
necrosis, and nuclear dust (leukocytoclastic vasculitis).
The connective tissue adjacent to the vessel has an
inﬂammatory cellular inﬁltrate, which contains a vari-
able mixture of histiocytes, lymphocytes, eosinophils,
and multinucleated giant cells (Fig. 9-28). Special
stains for organisms are negative, and no foreign mate-
rial can be found. In oral biopsy specimens, the oral
epithelium may demonstrate pseudoepitheliomatous
hyperplasia and subepithelial abscesses. Because of the
paucity of large vessels in many oral mucosal biopsies,
vasculitis may be difﬁcult to demonstrate, and the his-
topathologic presentation may be one of ill-deﬁned
collections of epithelioid histiocytes intermixed with
eosinophils, lymphocytes, and multinucleated giant
cells. In addition, the lesions of strawberry gingivitis
typically demonstrate prominent vascularity with
extensive red blood cell extravasation (Fig. 9-29).
DIAGNOSIS
The diagnosis of Wegener’s granulomatosis is made
from the combination of the clinical presentation and
the microscopic ﬁnding of necrotizing and granuloma-
tous vasculitis. Radiographic evaluation of the chest
and sinuses is recommended to document possible
involvement of these areas. The serum creatinine and
urinalysis results are used to rule out signiﬁcant renal
alterations.
Fig. 9-27 Wegener’s granulomatosis. Deep, irregular
ulceration of the hard palate on the left side. (From Allen CM,
Camisa C, Salewski C et al: Wegener’s granulomatosis: report of three cases
with oral lesions, J Oral Maxillofac Surg 49:294-298, 1991.)
Fig. 9-28 Wegener’s granulomatosis. Connective tissue
containing proliferation of numerous vascular channels and
a heavy inﬂammatory inﬁltrate consisting of lymphocytes,
neutrophils, eosinophils, and multinucleated giant cells.
Fig. 9-29 Wegener’s granulomatosis. Gingival biopsy
specimen showing a mixed inﬂammatory cellular inﬁltrate
obscured by extensive extravasation of red blood cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 347
A laboratory marker for Wegener’s granulomatosis
has been identiﬁed. Indirect immunoﬂuorescence for
serum antibodies directed against cytoplasmic com-
ponents of neutrophils has been used to support a
diagnosis of Wegener’s granulomatosis. There are two
reaction patterns of these antineutrophil cytoplasm
antibodies (ANCA):
1. Perinuclear (p-ANCA)
2. Cytoplasmic (c-ANCA)
Cytoplasmic localization (c-ANCA) is the most useful
in the diagnosis of Wegener’s granulomatosis. Positive
immunoﬂuorescence for c-ANCA should be conﬁrmed
with a speciﬁc enzyme-linked immunosorbent assay
(ELISA) test for antibodies against proteinase 3 (PR3),
the major antigen for c-ANCA that resides in the azu-
rophilic granules of neutrophils. These combined tests
are associated with a sensitivity of 73% and a diagnostic
speciﬁcity of 99% for Wegener’s granulomatosis. False
positives are uncommon and may be associated with a
variety of other diseases. In contrast, p-ANCAs are
detected in several vasculitides that typically do not
present in the oral cavity. With ELISA testing, antibod-
ies directed against myeloperoxidase, a lysosomal
enzyme in neutrophils, will be identiﬁed.
TREATMENT AND PROGNOSIS
The mean survival of untreated patients with dissemi-
nated classic Wegener’s granulomatosis is 5 months;
80% of the patients are dead at 1 year and 90% within
2 years. The prognosis is better for the limited and
superﬁcial forms of the disease, although a proportion
of patients with localized disease eventually will
develop classic Wegener’s granulomatosis.
The ﬁrst line of therapy is oral prednisone and
cyclophosphamide. On remission, the prednisone is
gradually discontinued, with continuation of the cyclo-
phosphamide for at least 1 year. Relapse is not uncom-
mon, especially during tapering of the therapy.
Although high response rates are noted, serious side
effects related to the therapy are not rare. Tri-
methoprim-sulfamethoxazole has been used success-
fully in localized cases and when the immunosuppressive
regimen has failed. Low-dose methotrexate and corti-
costeroids also have been used in patients whose
disease is not immediately life threatening or has not
responded appropriately to cyclophosphamide. Addi-
tional treatment options under study for generalized
Wegener’s granulomatosis include cyclosporine, tacro-
limus, mycophenolate mofetil, plasmapheresis, anti-
lymphocytic monoclonal antibodies, and intravenous
pooled immunoglobulin.
Treatment has a profound effect on the progression
of the disease. With appropriate therapy, prolonged
remission is noted in up to 75% of affected patients; a
cure often is attainable when the disease is diagnosed
and appropriately treated while the involvement is
localized. Because of a relapse rate up to 30%, mainte-
nance therapy is necessary in many patients. The
c-ANCA levels can be used to monitor the disease
activity. Patients appear less likely to have relapses
if their antineutrophilic antibodies disappear during
treatment; in contrast, patients whose levels of antibod-
ies persist are at greater risk for relapse.
ALLERGIC MUCOSAL REACTIONS TO
SYSTEMIC DRUG ADMINISTRATION
The future of dentistry and medicine will involve a
high volume of patients suffering from adverse drug
reactions. By 2030, 20% of the population will be more
than 65 years old. As the population ages and those
affected with chronic diseases increase, patients taking
multiple medications most likely will escalate. In the
United States during the year 2000, more than 2.8
billion prescriptions were ﬁlled, enough to supply each
inhabitant with 10 prescriptions annually. Although
use of two medications is associated with a 6% risk of
an adverse reaction, the frequency rises to 50% with
ﬁve drugs and almost a 100% when eight or more med-
ications are used simultaneously.
The list of offending medications and their resultant
side effects appears almost endless. In a short and
highly beneﬁcial article, Matthews listed more than
150 frequently prescribed medications and related
them to 46 oral and perioral side effects associated
with their use. Despite such excellent articles, it may
be helpful for health care practitioners to use one of
the excellent drug reference programs available on
compact disk or online to create an adverse reaction
and drug interaction document for patients in their
practice and to update these on a regular basis.
In addition to common drug-related problems such
as xerostomia (see page 464), dysgeusia (see page 875),
and gingival hyperplasia (see page 163), medications
can induce a wide variety of mucosal ulcerations and
erosions. An allergic reaction of the oral mucosa to the
systemic administration of a medication is called sto-
matitis medicamentosa. Besides erythema multi-
forme (see page 776), several different patterns of oral
mucosal disease can be seen:
● Anaphylactic stomatitis
● Intraoral ﬁxed drug eruptions
●Lichenoid drug reactions
●Lupus erythematosus–like eruptions
●Pemphigus-like drug reactions
● Nonspeciﬁc vesiculoerosive or aphthouslike
lesions
Anaphylactic stomatitis arises after the allergen
enters the circulation and binds to IgE–mast cell `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

348 ORAL AND MAXILLOFACIAL PATHOLOGY
complexes. Although systemic anaphylactic shock can
result, localized alterations also occur. Fixed drug erup-
tions are inﬂammatory alterations of the mucosa or
skin that recur at the same site after the administration
of any allergen, often a medication.
The vast number of medications capable of produc-
ing anaphylactic stomatitis precludes their listing, but
common culprits are antibiotics (especially penicillin)
and sulfa drugs. Medications reported to be associated
with ﬁxed drug eruptions are listed in Box 9-2, lichen-
oid drug eruptions in Box 9-3, lupus erythematosus–
like drug eruptions in Box 9-4, pemphigus-like drug
reactions in Box 9-5, and nonspeciﬁc vesiculoerosive
or aphthouslike eruptions in Box 9-6.
CLINICAL FEATURES
The patterns of mucosal alterations associated with the
systemic administration of medications are varied,
almost as much as the number of drugs that result in
these changes. Anaphylactic stomatitis may occur alone
or in conjunction with urticarial skin lesions or other
signs and symptoms of anaphylaxis (e.g., hoarseness,
respiratory distress, vomiting). The affected mucosa
Box 9-2
Medications Implicated in Fixed
Drug Eruptions
● Analgin
● Barbiturates
● Co-trimoxazole
● Dapsone
● Phenazone derivatives
● Phenolphthalein
● Salicylates
● Sulfonamides
● Tetracycline
Box 9-3
Medications Implicated in
Lichenoid Eruptions
● Allopurinol
● Amiphenazole
● Amphotericin
● Arsenicals
● Bismuth
● Captopril
● Carbamazepine
● Chloroquine
● Chlorothiazide
● Chlorpropamide
● Cimetidine
● Cyanamide
● Dapsone
● Fenclofenac
● Furosemide
● Gold salts
● Hydroxychloroquine
● Ketoconazole
● Levamisole
● Lithium
● Lorazepam
● Mercury
● Methyldopa
● Metopromazine
● Oxyprenolol
● Palladium
● Paraaminosalicylic acid
● Penicillamine
● Phenothiazines
● Phenylbutazone
● Practolol
● Propranolol
● Pyrimethamine
● Pyritinol
● Quinacrine
● Quinidine
● Spironolactone
● Streptomycin
● Sulfonylureas
● Tetracycline
● Tolbutamide
● Triprolidine
Box 9-4
Medications Implicated in Lupus
Erythematosus–Like Eruptions
● Carbamazepine
● Chlorpromazine
● Etanercept
● Ethosuximide
● Gold
● Griseofulvin
● Hydantoins
● Hydralazine
● Inﬂiximab
● Isoniazid
● Lithium
● Methyldopa
● Penicillamine
● Primidone
● Procainamide
● Quinidine
● Reserpine
● Streptomycin
● Thiouracil
● Trimethadione
Box 9-5
Medications Implicated in
Pemphigus-Like Eruptions
●α-Mercaptopropionyl
glycine
● Ampicillin
● Captopril
● Cephalexin
● Ethambutol
● Glibenclamide
● Gold
● Heroin
● Ibuprofen
● Penicillamine
● Phenobarbital
● Phenylbutazone
● Piroxicam
● Practolol
● Propranolol
● Pyritinol chlorhydrate
● Rifampin
● Thiopromine
Box 9-6
Drugs Associated with Nonspeciﬁc
Vesiculoerosive or Aphthouslike Lesions
● Captopril
● Gold salts
● Hydroxyurea
● Indomethacin
● Losartan
● Meprobamate
● Methyldopa
● Naproxen
● Nicorandil
● Penicillamine
● Phenylbutazone
● Propranolol
● Spironolactone
● Thiazide diuretics
● Tolbutamide `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 349
may exhibit multiple zones of erythema or numerous
aphthouslike ulcerations. Mucosal ﬁxed drug eruptions
appear as localized areas of erythema and edema,
which can develop into vesiculoerosive lesions and are
located most frequently on the labial mucosa. Lichen-
oid, lupuslike, and pemphigus-like drug reactions
resemble their namesakes clinically, histopathologi-
cally, and immunologically (Fig. 9-30). These latter
chronic drug reactions may involve any mucosal
surface, but the most common sites are the posterior
buccal mucosa and the lateral borders of the tongue
(Figs. 9-31 and 9-32). Bilateral and symmetrical lesions
are fairly common.
HISTOPATHOLOGIC FEATURES
Anaphylactic stomatitis typically reveals a nonspeciﬁc
pattern of subacute mucositis that contains lympho-
cytes intermixed with eosinophils and neutrophils.
Fixed drug eruptions also reveal a mixed inﬂammatory
cellular inﬁltrate that consists of lymphocytes, eosino-
phils, and neutrophils, often combined with spongiosis
and exocytosis of the epithelium. Vacuolar change of
the basal cell layer and individual necrotic epithelial
cells are occasionally noted. The drug reactions that
simulate lichen planus, lupus erythematosus, and pem-
phigus resemble their namesakes. The histopathologic
and immunologic features of these chronic drug reac-
tions cannot be used reliably to separate them from
their associated primary immunologic disease.
Immunoﬂuorescence has been used in an attempt
to separate drug reactions from primary vesiculoero-
sive disease. In most instances, this technique has
proven to be unsatisfactory. In spite of these ﬁndings,
a unique pattern of reaction has been seen when indi-
rect immunoﬂuorescence for IgG has been performed
in patients with lichenoid drug reactions. In many of
these patients, a distinctive annular ﬂuorescent pattern,
termed string of pearls, has been noted along the cell
membrane of the basal cell layer of stratiﬁed squamous
epithelium. The detected circulating antibody has been
termed basal cell cytoplasmic antibody. Although
further study is desirable, this technique may prove to
be a useful adjunct during evaluation of oral lichenoid
lesions.
DIAGNOSIS
A detailed medical history must be obtained, and the
patient should be questioned closely concerning the
use of both prescription and over-the-counter medica-
Fig. 9-30 Allergic mucosal reaction to systemic drug
administration. Mucosal lesions associated with use of
oxybutynin chloride (anticholinergic therapy for urinary
incontinence). Note lichen planus–like striae. In addition,
multiple superﬁcial mucoceles occurred on the soft palate,
ﬂoor of the mouth, and bilaterally on the buccal mucosa.
Fig. 9-31 Lichenoid drug reaction to allopurinol. Irregular
area of superﬁcial erosion of the left buccal mucosa. Lesions
were also present on the contralateral buccal mucosa and
bilaterally on the lateral borders of the tongue.
Fig. 9-32 Allergic mucosal reaction to systemic drug
administration. Large irregular erosion of the right ventral
surface of the tongue. The lesion arose secondary to use of
oxaprozin, a nonsteroidal antiinﬂammatory drug (NSAID). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

350 ORAL AND MAXILLOFACIAL PATHOLOGY
tions. Once a potentially offending medication is dis-
covered, a temporal relationship between the drug’s
use and the mucosal alteration must be established.
The association may be acute and obvious, or the onset
of the oral lesions may be delayed. If more than one
medication is suspected, then serial elimination of the
medications can be performed in collaboration with
the patient’s physician until the offending agent is
discovered.
In chronic drug reactions, deﬁnitive diagnosis can
be made if the mucosal alterations resolve after resolu-
tion of the medication and recur on reintroduction of
the agent. Presumptive diagnosis is usually sufﬁcient
and justiﬁed when the mucosal alterations clear after
cessation of the offending medication.
In possible lupuslike drug reactions, serum evalua-
tion for generic antinuclear antibodies (ANAs) and
antibodies against double-stranded DNA and histones
often can be beneﬁcial. Lupuslike drug reactions typi-
cally are associated with circulating generic ANAs and
antibodies against histones, whereas lupus erythema-
tosus also reveals antibodies to double-stranded DNA
(a ﬁnding not typically noted in drug reactions). This
pattern does not hold true in reactions associated with
the TNF-α antagonists, inﬂiximab and etanercept,
which simulate systemic lupus erythematosus (SLE)
very closely and are associated with antibodies to
double-stranded DNA.
TREATMENT AND PROGNOSIS
The responsible medication should be discontinued
and, if necessary, replaced with another drug that pro-
vides a similar therapeutic result. Localized acute reac-
tions can be resolved with topical corticosteroids.
When systemic manifestations are present, anaphylac-
tic stomatitis often warrants systemic administration
of adrenaline (epinephrine), corticosteroids, or antihis-
tamines. Chronic oral lesions often resolve on cessa-
tion of the offending drug, but topical corticosteroids
may sometimes be required for complete resolution.
If discontinuation of the medication is contraindi-
cated, palliative care can be provided; however, corti-
costeroids often are ineffective as long as the offending
medication is continued.
ALLERGIC CONTACT STOMATITIS
(STOMATITIS VENENATA)
The list of agents reported to cause allergic contact
stomatitis reactions in the oral cavity is extremely
diverse. Numerous foods, food additives, chewing
gums, candies, dentifrices, mouthwashes, glove and
rubber dam materials, topical anesthetics, restorative
metals, acrylic denture materials, dental impression
materials, and denture adhesive preparations have
been mentioned. Two types of allergens, cinnamon and
dental restorative materials, demonstrate clinical and
histopathologic patterns that are sufﬁciently unique to
justify separate descriptions.
Although the oral cavity is exposed to a wide variety
of antigens, the frequency of a true allergic reaction to
any one antigen from this contact appears to be rare.
This was veriﬁed in a prospective study of 13,325
dental patients, in which only seven acute and 15
chronic cases of adverse effects were attributed to
dental materials. The oral mucosa is much less sensi-
tive than the surface of the skin; this is most likely
because of the following:
●The period of contact is often brief.
● The saliva dilutes, digests, and removes many
antigens.
●The limited keratinization of oral mucosa makes
hapten binding more difﬁcult, and the high vascu-
larity tends to remove any antigen quickly.
●The allergen may not be recognized (because of
the lower density of Langerhans cells and T
lymphocytes).
If the skin has been sensitized originally, the mucosa
may or may not demonstrate future clinical sensitiza-
tion. In contrast, if the mucosa is sensitized initially,
then the skin usually demonstrates similar changes
with future exposure. Long-term oral exposure may
induce tolerance and reduce the prevalence of cutane-
ous sensitivity in some instances. For example, expo-
sure to nickel-containing orthodontic hardware has
been associated with a reduced prevalence of future
cutaneous sensitivity to nickel jewelry.
In addition to oral lesions, allergic contact reactions
may produce exfoliative cheilitis (see page 304) or
perioral dermatitis (see next section). As mentioned in
Chapter 8, most cases of chronic cheilitis represent
local irritation, usually from chronic lip licking. In spite
of this, investigation has revealed that approximately
25% of affected cases are allergic contact cheilitis from
a variety of antigens that include medications, lipsticks,
sunscreens, toothpaste, dental ﬂoss, nail polishes, and
cosmetics.
CLINICAL FEATURES
Allergic contact stomatitis can be acute or chronic. Of
those cases diagnosed, there is a distinct female pre-
dominance in both forms. After eliminating focal
trauma, localized signs and symptoms suggest mucosi-
tis from an isolated allergen (e.g., dental metal); in con-
trast, widespread mouth pain suggests an association
with a more diffuse trigger such as food, drink, ﬂavor-
ings, or oral hygiene materials. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 351
In patients with acute contact stomatitis, burning is
the most frequent symptom. The appearance of the
affected mucosa is variable, from a mild and barely
visible redness to a brilliantly erythematous lesion with
or without edema. Vesicles are rarely seen and, when
present, rapidly rupture to form areas of erosion (Fig.
9-33). Superﬁcial ulcerations that resemble aphthae
occasionally arise. Itching, stinging, tingling, and edema
may be noted.
In chronic cases the affected mucosa is typically in
contact with the causative agent and may be erythema-
tous or white and hyperkeratotic. Periodically, erosions
may develop within the affected zones. Some allergens,
especially toothpastes, can cause widespread erythema,
with desquamation of the superﬁcial layers of the epi-
thelium (Fig. 9-34). Allergic contact cheilitis demon-
strates clinical features identical to those cases created
through chronic irritation, and it most frequently
appears as chronic dryness, scaling, ﬁssuring, or crack-
ing of the vermilion border of the lip. Rarely, symptoms
identical to orolingual paresthesia can be present
without any clinically evident signs. One distinctive
pattern, plasma cell gingivitis, is discussed elsewhere
(see page 159).
DIAGNOSIS
Usually, the diagnosis of acute contact stomatitis is
straightforward because of the temporal relationship
between the use of the agent and the resultant erup-
tion. If an acute oral or circumoral reaction is noted
within 30 minutes of a dental visit, then allergy to all
used dental materials, local anesthetics, and gloves
should be investigated.
The diagnosis of chronic contact stomatitis is much
more difﬁcult. Most investigators require good oral
health, elimination of all other possible causes, and
visible oral signs, together with a positive history of
allergy and a positive skin test result to the suspected
allergen. If allergic contact stomatitis is strongly sus-
pected but skin test results are negative, then direct
testing of the oral mucosa can be attempted. The
antigen can be placed on the mucosa in a mixture
with Orabase or in a rubber cup that is ﬁxed to the
mucosa.
TREATMENT AND PROGNOSIS
In mild cases of acute contact stomatitis, removal of the
suspected allergen is all that is required. In more severe
cases, antihistamine therapy, which is combined with
topical anesthetics (e.g., dyclonine HCl), is usually
beneﬁcial. Chronic reactions respond to removal of
the antigenic source and application of a topical corti-
costeroid, such as ﬂuocinonide gel or dexamethasone
elixir.
When attempting to discover the source of a diffuse
allergic mucositis, use of plain baking soda or tooth-
paste that is free of ﬂavoring or preservatives is recom-
mended. The patient also should be instructed to avoid
mouthwash, gum, mints, chocolate, cinnamon-contain-
ing products, carbonated drinks, and excessively salty,
spicy, or acidic foods. If an association cannot be found,
then cutaneous patch testing may provide helpful
information.
Fig. 9-33 Allergic contact stomatitis to aluminum
chloride. Mucosal erythema and vesicles of the lower labial
mucosa caused by use of aluminum chloride on gingival
retraction cord.
Fig. 9-34 Allergic contact stomatitis to toothpaste.
Erythematous mucosa with superﬁcial epithelial
desquamation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

352 ORAL AND MAXILLOFACIAL PATHOLOGY
PERIORAL DERMATITIS
Perioral dermatitis refers to a unique inﬂammatory
skin disease that involves the circumoral area. Although
the exact mechanism is uncertain, many investigators
believe the process arises from an idiosyncratic
response to a variety of exogenous substances; once this
process is initiated, potent topical corticosteroid use
worsens the condition. Although the vast majority of
affected patients report topical corticosteroid use, only
a minority initiate this therapy before initial develop-
ment of the dermatitis. Exogenous substances reported
to initiate the rash include tartar-control toothpaste,
bubble gum, moisturizers, night creams, and other
cosmetic products (e.g., foundation). Some of these
substances may initially induce an irritant or allergic
contact dermatitis, whereas others are thought to
produce inappropriate occlusion of the skin surface
with subsequent proliferation of skin ﬂora.
CLINICAL FEATURES
Perioral dermatitis appears with persistent erythema-
tous papules and papulopustules that involve the skin
surrounding the vermilion border of the upper and
lower lips (Fig. 9-35). Classically, there is a zone of
spared skin immediately adjacent to the vermilion
border. Pruritus is variable. In adults, more than 90%
of affected patients are women, lending further support
to the association with cosmetic use. The prevalence of
perioral dermatitis appears to be increasing and may
be related to the greater percentage of cosmetic-
wearing women in the workforce. In children, the
female predominance is dramatically reduced or is
nonexistent in some studies. In addition, an identical
pattern of periorbital and perinasal dermatitis often
Fig. 9-35 Perioral dermatitis. Multiple erythematous
papules of the skin surrounding the vermilion border of the
lips. (Courtesy of Dr. Charles Camisa.)
is present in younger patients with classic perioral
lesions.
Some investigators have reported perioral dermati-
tis that has arisen solely from use of tartar-control
toothpaste (irritant contact dermatitis from pyrophos-
phate compounds), but close inspection reveals a dif-
ferent clinical presentation. In these reports the
dermatitis appears as a zone of erythema without
papules or pustules; it involves only the skin immedi-
ately adjacent to the vermilion border, without the
classic sparing of this area. This pathosis is classiﬁed
most appropriately as circumoral dermatitis and does
not fulﬁll the classic criteria for perioral dermatitis.
HISTOPATHOLOGIC FEATURES
Biopsy of perioral dermatitis demonstrates a variable
pattern. In many cases there is a chronic lymphohistio-
cytic dermatitis that often exhibits spongiosis of the
hair follicles. In other patients a rosacea-like pattern is
noted in which there is perifollicular granulomatous
inﬂammation. On occasion, this histopathologic pattern
has been misdiagnosed as sarcoidosis.
TREATMENT AND PROGNOSIS
The ﬁrst step in management is discontinuation of
potent topical corticosteroid use, if present. Often, this
is followed by a period of exacerbation, which can be
minimized by substitution of a less potent corticoste-
roid before total cessation. Oral tetracycline has been
shown to be effective by many investigators, with eryth-
romycin substituted during childhood and pregnancy.
Topical metronidazole or erythromycin also has been
used successfully in several studies. The pathosis typi-
cally demonstrates signiﬁcant improvement within
several weeks and total resolution in a few months.
Recurrence is uncommon.
CONTACT STOMATITIS FROM
ARTIFICIAL CINNAMON FLAVORING
Mucosal abnormalities secondary to the use of artiﬁ-
cially ﬂavored cinnamon products are fairly common,
but the range of changes was not widely recognized
until the late 1980s. Cinnamon oil is used as a ﬂavoring
agent in confectionery, ice cream, soft drinks, alcoholic
beverages, processed meats, gum, candy, toothpaste,
breath fresheners, mouthwashes, and even dental ﬂoss.
Concentrations of the ﬂavoring are up to 100 times
that in the natural spice. The reactions are documented
most commonly in those products associated with pro-
longed or frequent contact, such as candy, chewing
gum, and toothpaste. The anticalculus components of
tartar-control toothpastes have a strong bitter ﬂavor `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 353
and require a signiﬁcant concentration of ﬂavoring
agents including cinnamon to hide the taste, resulting
in a greater chance these formulations will cause oral
mucosal lesions. Although much less common, reac-
tions to cinnamon in its natural spice form have been
documented.
CLINICAL FEATURES
The clinical presentations of contact stomatitis vary
somewhat, according to the medium of delivery. Tooth-
paste results in a more diffuse pattern; the signs associ-
ated with chewing gum and candy are more localized.
Pain and burning are common symptoms in all cases.
The gingiva is the most frequent site affected by
toothpaste, often resembling plasma cell gingivitis
(see page 159); enlargement, edema, and erythema are
common. Sloughing of the superﬁcial oral epithelium
without creation of an erosion is seen commonly. Ery-
thematous mucositis, occasionally combined with
erosion, has been reported on the buccal mucosa and
tongue. Exfoliative cheilitis and circumoral dermatitis
also may occur.
Reactions from chewing gum and candy are more
localized and typically do not affect the lip vermilion
or perioral skin. Most of the lesions appear on the
buccal mucosa and lateral borders of the tongue. Buccal
mucosal lesions often are oblong patches that are
aligned along the occlusal plane (Fig. 9-36). Individual
lesions have an erythematous base but often are pre-
dominantly white as a result of hyperkeratosis of the
surface epithelium. Ulceration within the lesions may
occur. Hyperkeratotic examples often exhibit a ragged
surface and occasionally may resemble the pattern
seen in morsicatio (see page 286). Lingual involvement
may become extensive and spread to the dorsal surface
(Fig. 9-37). Signiﬁcant thickening of the surface epithe-
lium can occur and may raise clinical concern for oral
hairy leukoplakia (OHL) (see page 268) or carcinoma
(Fig. 9-38).
HISTOPATHOLOGIC FEATURES
Usually, the epithelium in contact stomatitis from arti-
ﬁcial cinnamon ﬂavoring is acanthotic, often with elon-
gated rete ridges and thinning of the suprapapillary
plates. Hyperkeratosis and extensive neutrophilic exo-
cytosis may be present. The superﬁcial lamina propria
demonstrates a heavy inﬂammatory cell inﬁltrate that
consists predominantly of lymphocytes that may be
intermixed with plasma cells, histiocytes, or eosino-
phils. This inﬁltrate often obscures the epithelium and
connective tissue interface (Fig. 9-39). A characteristic
Fig. 9-36 Contact stomatitis from cinnamon ﬂavoring.
Oblong area of sensitive erythema with overlying shaggy
hyperkeratosis.
Fig. 9-37 Contact stomatitis from cinnamon ﬂavoring.
Sensitive and thickened hyperkeratosis of the lateral and
dorsal surface of the tongue on the right side.
Fig. 9-38 Contact stomatitis from cinnamon ﬂavoring.
Left lateral border of the tongue demonstrating linear rows of
hyperkeratosis that resemble oral hairy leukoplakia (OHL). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

354 ORAL AND MAXILLOFACIAL PATHOLOGY
feature in localized cases caused by gum, mints, or
candies is the frequent presence of an obvious perivas-
cular inﬂammatory inﬁltrate that extends well below
the interface zone (Fig. 9-40).
DIAGNOSIS
With a high index of suspicion and knowledge of the
variations of the clinical pattern, the diagnosis of local-
ized contact stomatitis often can be made from the
clinical appearance and the history of cinnamon use.
Often biopsies are performed for atypical or extensive
cases because of the differential diagnosis, which
includes several signiﬁcant vesiculoerosive and neo-
plastic conditions. The histopathologic features are not
speciﬁc, but they are sufﬁcient to raise a high index of
suspicion in an oral and maxillofacial pathologist
who is familiar with the pattern. Use of cinnamon-
containing toothpaste should be investigated in every
patient with an atypical pattern of gingivitis. Diet-
related examples often are the most difﬁcult to diag-
nose and may necessitate cutaneous allergy patch
testing or a diet diary to isolate the cause.
TREATMENT AND PROGNOSIS
Typically, the signs and symptoms disappear within
1 week after the discontinuation of the cinnamon
product. If the patient resumes intake of the product,
then the lesions reappear, usually within 24 hours.
On occasion, resolution is more gradual and the
patient may beneﬁt from short-term use of a topical
corticosteroid.
LICHENOID CONTACT
STOMATITIS FROM DENTAL
RESTORATIVE MATERIALS
Since the nineteenth century when dental amalgam
began to have widespread use, the material has been
associated in the lay press with almost every medical
ailment known to man. Such accusations tend to occur
in cycles. Mercury within amalgam has been accused
of producing Alzheimer’s disease, neurotoxicity, kidney
dysfunction, reduced immunocompetence, alterations
of oral and intestinal bacteria, birth defects, and adverse
effects on general health. In spite of intense scrutiny,
there appears to be no relationship between any of
these physical disorders and the use of amalgam resto-
rations (see the discussion of systemic intoxiﬁcation
from mercury, page 313). An investigation of patients
with concerns associated with their amalgam restora-
tions reveals that most of their complaints can be asso-
ciated with oral, dental, or medical problems unrelated
to the restorations.
A review of the ill effects of mercury in dental
amalgam demonstrates that the occurrence of toxicity
is negligible, but a small percentage (1% to 2%) of those
who are allergic to mercury can react to the mercury
released from dental amalgams. The frequency of
adverse effects to dental amalgam is estimated to be
one case per million. Acute hypersensitivity reactions
typically appear 2 to 24 hours after the removal and
replacement of dental amalgam, and the symptoms
disappear after 10 to 14 days.
In contrast, chronic reactions are not rare and may
arise from hypersensitivity or a chronic toxic reaction
from almost any dental metal. When the reaction is
related to hypersensitivity, the most frequent antigen
is mercury or a mercury compound; gold is a distant
second. Even less commonly, copper, palladium, silver,
tin, zinc, beryllium, chromium, cobalt, or platinum is
responsible. Some investigators have called these alter-
ations “galvanic lesions,” but neither clinical nor experi-
Fig. 9-39 Contact stomatitis from cinnamon ﬂavoring.
Oral mucosa demonstrating signiﬁcant interface mucositis
and deeper perivascular inﬂammation.
Fig. 9-40 Contact stomatitis from cinnamon ﬂavoring.
Perivascular inﬂammatory inﬁltrate consisting predominantly
of lymphocytes and plasma cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 355
mental studies support the electrogalvanic hypothesis
of origin.
Hypersensitivity to dental resins is quite rare, and
many cases have been proven to be secondary to excess
monomer in cold-cure denture resin, not a true allergy.
Reports have documented resin-induced contact sto-
matitis that resolved after boiling of the denture (which
removed the residual free monomer). Free monomer
is unusual in heat-cured denture resin and composite
restorations, making true contact hypersensitivity
very rare.
Contact stomatitis appears clinically and histopath-
ologically similar to lichen planus (see page 782) but
demonstrates a difference in evolution. When patients
with true oral lichen planus are examined, the lesions
migrate and exhibit no direct correlation to contact
with dental materials. In addition, these patients do not
demonstrate a signiﬁcantly increased positive patch
testing to dental restorative materials and exhibit
minimal-to-no clinical improvement on removal of
their amalgams.
However, there is a subgroup of patients whose
lichenoid lesions do not migrate and usually involve
only the mucosa adjacent to a dental metal. On patch
testing, the vast majority of these patients react to the
offending metal, and the lesions resolve rapidly after
removal of adjacent amalgams. This pathosis should be
diagnosed as lichenoid contact stomatitis to a dental
restorative material, not as true lichen planus.
The results of cutaneous patch testing cannot be
applied uniformly to the oral cavity. For a metal to
become allergenic, it must undergo corrosion and
release of metallic ions. Amalgams that have been in
place for many years typically are responsible for the
vast majority of lichenoid contact stomatitis lesions.
Positive cutaneous patch testing to gold and nickel is
common and greatly outnumbers reactivity to mercury
compounds. In spite of this, intraoral reactions to gold
and nickel are very uncommon, most likely the result
of the low level of corrosion in these metals. Patients
with lichenoid contact stomatitis to a single amalgam
support this concept, although their mucosa contacts
numerous other similar restorations. When such a
patient also demonstrates positive patch testing, the
anomaly most likely is due to variable corrosion of the
restorations. On occasion, patients can demonstrate a
contact reaction but reveal negative patch testing. In
these cases, the mucosal alterations most likely are due
to local irritation of the old restoration (Koebner phe-
nomenon), and studies of these patients have shown a
lower long-term response to replacement of the metal-
lic restorations.
CLINICAL FEATURES
The most commonly affected sites for lichenoid contact
stomatitis are the posterior buccal mucosa and the
ventral surface of the lateral borders of the tongue.
Gingival cuffs adjacent to subgingival metallic restora-
tions and porcelain-fused-to-metal (PFM) crowns with
metal collars also may be affected. The lesions usually
are conﬁned to the area of contact but may extend up
to 1 cm beyond the point of mucosal association. The
affected mucosa may be white or erythematous, with
or without peripheral striae (Fig. 9-41). Most patients
have no symptoms, but periodic erosion may be noted.
A B
Fig. 9-41 Oral mucosal contact reaction to dental amalgam. A, Hyperkeratotic lesion with
a peripheral radiating pattern on the lateral border of the tongue on the right side; the altered
mucosa contacted the amalgams of the adjacent mandibular molar teeth. The lesion remained
in the same location for 5 years and periodically became erosive and symptomatic. Smoothing
and polishing of the adjacent restorations had no effect. B, Appearance of previously altered
area of the tongue 14 days after removal of adjacent amalgams. Note total resolution of the
mucosal alterations. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

356 ORAL AND MAXILLOFACIAL PATHOLOGY
In all likelihood, many of the lesions previously reported
as the so-called plaque type of lichen planus were, in
reality, lichenoid contact stomatitis.
DIAGNOSIS
The diagnosis is made from the clinical appearance of
the lesions, the lack of migration, and the correlation
to adjacent dental metal (Fig. 9-42). Although the his-
topathologic features may be indistinguishable from
lichen planus, biopsy occasionally is performed to
conﬁrm the clinical impression and to rule out other
pathoses such as epithelial dysplasia. Although patch
testing is not necessary for a strong presumptive diag-
nosis, the procedure does help identify patients who
are predisposed to react to the metal (possibly advanta-
geous in a patient with a single site of lichenoid stoma-
titis who also has numerous similar, but less corroded,
restorations demonstrating mucosal contact). In addi-
tion, the patch testing will include a battery of addi-
tional dental metals that will assist in the choice of
material for future restorations.
HISTOPATHOLOGIC FEATURES
Biopsy of allergic contact stomatitis from dental mate-
rials exhibits numerous features of lichen planus. The
surface epithelium may be hyperkeratotic, atrophic, or
ulcerated. Areas of hydropic degeneration of the basal
cell layer often are present. The superﬁcial lamina
propria contains a dense bandlike chronic inﬂamma-
tory cellular inﬁltrate consisting predominantly of lym-
phocytes, but there may be scattered plasma cells. On
occasion, deeper lymphoid aggregates may be noted,
often in a perivascular orientation.
TREATMENT AND PROGNOSIS
Local measures, such as improved oral hygiene,
smoothing, polishing, and recontouring, should be
attempted before more aggressive measures, because
clinically similar lesions have been noted as a result of
surface plaque accumulation. If this is unsuccessful,
then the amalgam in question should be replaced with
a nonmetallic restoration, if possible. Other material
choices include yellow gold, white gold, and PFM
crowns. As mentioned, cutaneous patch testing not
only conﬁrms the diagnosis but also can be used as a
guide during the selection of future restorative
materials.
ANGIOEDEMA (ANGIONEUROTIC
EDEMA; QUINCKE’S DISEASE)
Angioedema is a diffuse edematous swelling of the
soft tissues that most commonly involves the subcuta-
neous and submucosal connective tissues but may
affect the gastrointestinal or respiratory tract, occasion-
ally with fatal results. The disorder has been referred
to as Quincke’s disease, after the clinician who ini-
tially related the changes to an alteration in vascular
permeability. The outdated term angioneurotic
edema also has been used, because affected patients
often complained of a choking sensation and were
labeled neurotic.
The most common cause is mast cell degranulation,
which leads to histamine release and the typical clini-
cal alterations. IgE-mediated hypersensitivity reactions
caused by drugs, foods, plants, dust, and inhalants
produce mast cell degranulation and are fairly common.
Contact allergic reactions to foods, cosmetics, topical
medications, and even dental rubber dams also have
been responsible. Mast cell degranulation can even
result from physical stimuli, such as heat, cold, exer-
cise, emotional stress, solar exposure, and signiﬁcant
vibration.
An unusual pattern of drug reaction that can produce
severe forms of angioedema that are not mediated by
IgE is the type associated with use of drugs called angio-
tensin-converting enzyme (ACE) inhibitors. These medica-
tions are a popular treatment of essential hypertension
and chronic heart failure; commonly prescribed ACE
inhibitors include captopril, enalapril, and lisinopril.
The swelling associated with these drugs does not
respond well to antihistamines and was thought to be
the result of excess bradykinin (ACE degrades brady-
kinin). In an attempt to avoid this angioedema, a second
generation of medications called angiotensin II receptor
blockers (e.g., losartan, valsartan) was developed speciﬁ-
cally to avoid any inhibition of bradykinin degradation.
These newer medications lower the frequency of
angioedema, but do not eliminate the adverse reaction.
Fig. 9-42 Oral mucosal contact reaction to dental
amalgam. Radiating pattern of hyperkeratotic striae on the
posterior buccal mucosa that contacts a large distobuccal
amalgam of the permanent mandibular second molar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 357
The prevalence of this pattern of angioedema is esti-
mated to be 0.1% to 0.2% of those who use ACE inhibi-
tors. In the majority of affected patients, the angioedema
arises within hours of initial use of the drug. In up to
30% of the cases, the angioedema is delayed, with the
longest reported interval between drug use initiation
and the initial attack being 7 years. Attacks precipi-
tated by dental procedures have been reported in long-
term users of ACE inhibitors. Many clinicians overlook
the association between angioedema and ACE inhibi-
tors, with studies demonstrating continued administra-
tion of the medication in more than 50% of affected
patients.
Angioedema also can result from activation of
the complement pathway. This may be hereditary or
acquired. Two rare autosomal dominant hereditary
forms are seen. Type I, comprising 85% of the heredi-
tary cases, is caused by a quantitative reduction in the
inhibitor that prevents the transformation of C1 to C1
esterase. Without adequate levels of C1 esterase inhib-
itor (C1-INH), C1 esterase cleaves C4 and C2 and
results in angioedema. Type II exhibits normal levels
of C1-INH, but the inhibitor is dysfunctional.
The acquired type of C1-INH deﬁciency is seen in
association with certain types of lymphoproliferative
diseases or in patients who develop speciﬁc autoanti-
bodies. In lymphoproliferative diseases, monoclonal
antibodies directed against the tumor cells activate C1
and lead to consumption of C1-INH. In the autoim-
mune variant, the antibody attaches to the C1 receptor
on the C1-INH molecule, leading to decreased func-
tional C1-INH and consumption of C1. In both the
acquired and the hereditary forms of abnormal C1-
INH activity, minor trauma, such as a dental proce-
dure, can precipitate an attack.
Finally, angioedema has been seen in the presence
of high levels of antigen-antibody complexes (e.g., lupus
erythematosus, viral or bacterial infections) and in
patients with grossly elevated peripheral blood eosino-
phil counts.
CLINICAL FEATURES
Angioedema is characterized by the relatively rapid
onset of soft, nontender tissue swelling, which may
be solitary or multiple (Fig. 9-43). In the hereditary
forms, the initial onset typically is noted in childhood
or adolescence. The episodes are unpredictable and
intermixed with edema-free intervals. Recurrent skin
swelling and abdominal pain are the most frequent
presentations. The extremities are the most common
cutaneous sites of involvement, although the face, geni-
tals, trunk, and neck also can be affected. Although not
individually frequent, edema of the larynx, pharynx,
uvula, or soft palate may be noted when patients are
monitored for extended periods (and may be associ-
ated with respiratory distress). A deeper voice, hoarse-
ness, aphonia, and dyspnea are important warning
signs. Recurrent snoring-induced edema of the soft
palate has been reported and associated with severe
dyspnea. Isolated tongue involvement is uncommon.
Involvement of the skin and mucous membranes can
cause enlargements that may measure up to several
centimeters in diameter (Fig. 9-44). Although pain is
unusual, itching is common and erythema may be
present. The enlargement typically resolves over 24 to
72 hours. In contrast to the hereditary variants, aller-
gic, acquired, and ACE inhibitor–associated angio-
edema demonstrate signiﬁcant involvement of the
head and neck, such as the face, lips, tongue, ﬂoor of
mouth, pharynx, and larynx. The risk of angioedema
associated with ACE inhibitors is signiﬁcantly greater
in blacks (three to four times that of other races), and
this pattern is the type most frequently encountered by
oral health practitioners.
DIAGNOSIS
In cases of allergic causation, the diagnosis of angio-
edema often is made from the clinical presentation in
conjunction with the known antigenic stimulus. When
multiple antigenic exposures occur, the diagnosis of
the offending agent can be difﬁcult and involves dietary
diaries and antigenic testing.
Those patients whose conditions cannot be related
to antigenic exposure or medications should be evalu-
ated for the presence of adequate functional C1-INH.
In the hereditary types, both forms exhibit normal
levels of C1 and decreased levels of functional C1-INH.
Type I demonstrates a decreased quantity of C1-INH;
type II exhibits normal levels of the inhibitor (but it is
not functional). Both acquired forms demonstrate low
levels of both C1-INH and C1.
Fig. 9-43 Angioedema. Diffuse upper lip swelling that
arose rapidly. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

358 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The treatment of allergic angioedema usually consists
of oral antihistamine therapy. If the attack is not con-
trolled or if laryngeal involvement is present, then
intramuscular epinephrine should be administered. If
the epinephrine does not stop the attack, then intrave-
nous corticosteroids and antihistamines should be
given.
Cases of angioedema related to ACE inhibitors
are not IgE-mediated and often do not respond to
antihistamines and corticosteroids. Because the
airway may have to be opened, affected patients are
kept under close observation until the swelling
begins to subside. Although the mechanism is unclear,
some patients with ACE inhibitor–associated angio-
edema have responded to C1-INH concentrate.
Patients experiencing ACE inhibitor–associated
angioedema should avoid all medications in this
class of drugs, and their physicians should consider
alternative hypertension management strategies.
Angiotensin II receptor blockers do not appear to be
safe alternatives.
Those cases related to C1-INH deﬁciency also do
not respond to antihistamine, corticosteroid, or adren-
ergic therapy. Intubation and tracheostomy may be
required for laryngeal involvement. Fresh freeze-dried
plasma has been used; however, some investigators do
not recommend its use because there is a risk of trans-
mitting infection, and it replaces not only C1-INH but
also potentially harmful C1 esterase, C1, C2, and C4.
C1-INH concentrate and esterase-inhibiting drugs
(aprotinin or tranexamic acid) are the treatments of
choice for acute attacks. Because acute attacks of
hereditary angioedema are not only unpleasant but
also potentially life threatening, prevention is para-
mount. Patients should avoid violent physical activity
and trauma. Medical prophylaxis is recommended
before any dental or surgical procedure. All patients
should carry medical warning cards that state the
diagnosis and list elementary precautions. Prophylaxis
for C1-INH deﬁciency is recommended in patients
who have more than three attacks per year. Androgens
induce hepatic synthesis of C1-INH, and either of the
attenuated androgens (danazol or stanozolol) is used
for both the hereditary forms and the acquired type
that is related to lymphoproliferative disorders. The
autoimmune acquired type is best prevented through
the use of corticosteroids.
A B
Fig. 9-44 Angioedema. A, Soft, nontender tissue swelling of the face arose relatively rapidly
after dental treatment. B, Facial appearance after resolution of edematous facial enlargement. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 359
BIBLIOGRAPHY
Transient Lingual Papillitis
Brannon RB, Flaitz CM: Transient lingual papillitis: a papulo-
keratotic variant, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 96:187-191, 2003.
Flaitz CM, Chavarria C: Painful tongue lesions associated with a
food allergy, Pediatr Dent 23:506-507, 2001.
Lacour J-P, Perrin C: Eruptive familial lingual papillitis: a new
entity, Pediatr Dermatol 14:13-16, 1997.
Roux O, Lacour JP: Eruptive lingual papillitis with household
transmission: a prospective clinical study, Br J Dermatol
150:299-303, 2004.
Whitaker SB, Krupa JJ, Singh BB: Transient lingual papillitis,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:441-445,
1996.
Recurrent Aphthous Stomatitis
Brooke RI, Sapp JP: Herpetiform ulceration, Oral Surg Oral Med
Oral Pathol 12:182-188, 1976.
Eisen D, Lynch DP: Selecting topical and systemic agents for
recurrent aphthous stomatitis, Cutis 68:201-206, 2001.
Hay KD, Reade PC: The use of an elimination diet in the treat-
ment of recurrent aphthous ulceration of the oral cavity, Oral
Surg Oral Med Oral Pathol 57:504-507, 1984.
Jurge S, Kuffer R, Scully C et al: Mucosal disease series. Number
IV. Recurrent aphthous stomatitis, Oral Dis 12:1-21, 2006.
Natah SS, Konttinen YT, Enattah NS et al: Recurrent aphthous
ulcers today: a review of the growing knowledge, Int J Oral
Maxillofac Surg 33:221-234, 2004.
Nolan A, Lamey P-J, Milligan KA et al: Recurrent aphthous ulcer-
ation and food sensitivity, J Oral Pathol Med 20:473-475,
1991.
Pedersen A, Hougen HP, Kenrad B: T-lymphocyte subsets in oral
mucosa of patients with recurrent aphthous ulceration, J Oral
Pathol Med 21:176-180, 1992.
Rivera-Hidalgo F, Shulman JD, Beach MM: The association of
tobacco and other factors with recurrent aphthous in a U.S.
adult population, Oral Dis 10:335-345, 2004.
Rogers RS: Complex aphthosis, Adv Exp Med Biol 528:311-316,
2003.
Scully C, Gorsky M, Lozada-Nur F: The diagnosis and manage-
ment of recurrent aphthous stomatitis, J Am Dent Assoc
134:200-207, 2003.
Ship JA: Recurrent aphthous stomatitis: an update, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 81:141-147, 1996.
Vincent SD, Lilly GE: Clinical, historic, and therapeutic features
of aphthous stomatitis: literature review and open clinical
trial employing steroids, Oral Surg Oral Med Oral Pathol 74:79-
86, 1992.
Wray D, Graykowski EA, Notkins AL: Role of mucosal injury in
initiating recurrent aphthous stomatitis, Br Med J 283:1569-
1570, 1981.
Behçet’s Syndrome
Escudier M, Bagan J, Scully C: Mucosal disease series. Number
VII. Behçet’s disease (Adamantiades syndrome), Oral Dis
12:78-84, 2006.
Evereklioglu C: Managing the symptoms of Behçet’s disease,
Expert Opin Pharmacother 5:317-328, 2004.
Helm TN, Camisa C, Allen C et al: Clinical features of Behçet’s
disease: report of four cases, Oral Surg Oral Med Oral Pathol
72:30-34, 1991.
International Study Group for Behçet’s Disease: Criteria for diag-
nosis for Behçet’s disease, Lancet 335:1078-1080, 1990.
Krause I, Rosen Y, Kaplan I et al: Recurrent aphthous stomatitis
in Behçet’s disease: clinical features and correlation with sys-
temic disease expression and severity, J Oral Pathol Med
28:193-196, 1999.
McCarty MA, Garton RA, Jorizzo JL: Complex aphthosis and
Behçet’s disease, Dermatol Clin 21:41-48, 2003.
Sarcoidosis
Batal H, Chou LL, Cottrell DA: Sarcoidosis: medical and dental
implications, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
88:386-390, 1999.
Marx RE, Hartman KS, Rethman KV: A prospective study com-
paring incisional labial to incisional parotid biopsies in the
detection and conﬁrmation of sarcoidosis, Sjögren’s disease,
sialosis and lymphoma, J Rheumatol 15:621-629, 1988.
Saboor SA, Johnson NM: Sarcoidosis, Br J Hosp Med 48:293-302,
1992.
Suresh L, Aguirre A, Buhite RJ et al: Intraosseous sarcoidosis of
the jaws mimicking aggressive periodontitis: a case report
and literature review, J Periodontol 75:478-182, 2004.
Suresh L, Radfar L: Oral sarcoidosis: a review of the literature,
Oral Dis 11:138-145, 2005.
Tozman ECS: Sarcoidosis: clinical manifestations, epidemiology,
therapy, and pathophysiology, Curr Opin Rheumatol 3:155-
159, 1991.
Orofacial Granulomatosis
Allen CM, Camisa C, Hamzeh S et al: Cheilitis granulomatosa:
report of six cases and review of the literature, J Am Acad
Dermatol 23:444-450, 1990.
Gibson J, Neilly JB, Wray APM et al:
99
Tc
m
-HMPAO leucocyte
labelling in orofacial granulomatosis and gastrointestinal
Crohn’s disease in childhood and early adulthood, Nucl Med
Commun 21:155-158, 2000.
Kauzman A, Quesnel-Mercier A, Lalonde B: Orofacial granulo-
matosis: 2 case reports and literature review, J Can Dent Assoc
72:325-329, 2006.
Leão JC, Hodgson T, Scully C et al: Review article: orofacial
granulomatosis, Aliment Pharmacol Ther 20:1019-1027, 2004.
Mignogna MD, Fedele S, LoRusso L et al: Effectiveness of small-
volume, intralesional, delayed-release triamcinolone injec-
tions in orofacial granulomatosis: a pilot study, J Am Acad
Dermatol 51:265-268, 2004.
Patton DW, Ferguson MM, Forsyth A et al: Oro-facial granulo-
matosis: a possible allergic basis, Br J Oral Maxillofac Surg
23:235-242, 1985.
Rees TD: Orofacial granulomatosis and related conditions,
Periodontol 2000 21:145-157, 1999.
Sanderson J, Numes C, Escudier M et al: Oro-facial granulmato-
sis: Crohn’s disease or a new inﬂammatory bowel disease,
Inﬂamm Bowel Dis 11:840-846, 2005.
van der Waal RIF, Schulten EAJM, van der Meij EH et al: Chei-
litis granulomatosa: overview of 13 patients with long-term
follow-up—results of management, Int J Dermatol 41:225-229,
2002.
White A, Nunes C, Escudier M et al: Improvement of orofacial
granulomatosis on a cinnamon- and benzoate-free diet,
Inﬂamm Bowel Dis 12:508-514, 2006.
Wiesenfeld D, Ferguson MM, Mitchell DN et al: Oro-facial gran-
ulomatosis—a clinical and pathological analysis, Q J Med
54:101-113, 1985.
Worsaae N, Christensen KC, Schiödt M et al: Melkersson-
Rosenthal and cheilitis granulomatosa: a clinicopathologic
study of thirty-three patients with special reference to their
oral lesions, Oral Surg Oral Med Oral Pathol 54:404-413,
1982. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

360 ORAL AND MAXILLOFACIAL PATHOLOGY
Wray D, Rees SR, Gibson J et al: The role of allergy in oral
mucosal diseases, Q J Med 93:507-511, 2000.
Wysocki GP, Brooke RI: Oral manifestations of chronic granulo-
matous disease, Oral Surg Oral Med Oral Pathol 46:815-819,
1978.
Zimmer WM, Rogers RS, Reeve CM et al: Orofacial manifesta-
tions of Melkersson-Rosenthal syndrome: a study of 42
patients and review of 220 cases from the literature, Oral Surg
Oral Med Oral Pathol 74:610-619, 1992.
Wegener’s Granulomatosis
Ah-See KW, McLaren K, Maran AGD et al: Wegener’s granulo-
matosis presenting as major salivary gland enlargement,
J Laryngol Otol 110:691-693, 1996.
Allen CM, Camisa C, Salewski C et al: Wegener’s granulomato-
sis: report of three cases with oral lesions, J Oral Maxillofac
Surg 49:294-298, 1991.
Chegar BE, Kelley RT: Wegener’s granulomatosis presenting as
unilateral parotid enlargement, Laryngoscope 114:1730-1733,
2004.
Euﬁnger H, Machtens E, Akuamoa-Boateng E: Oral manifesta-
tions of Wegener’s granulomatosis: review of the literature
and report of a case, Int J Oral Maxillofac Surg 21:50-53,
1992.
Fauci AS, Haynes BF, Katz P et al: Wegener’s granulomatosis:
prospective clinical and therapeutic experience with 85
patients for 21 years, Ann Intern Med 98:76-85, 1983.
Handlers JP, Waterman J, Abrams AM et al: Oral features of
Wegener’s granulomatosis, Arch Otolaryngol 111:267-270,
1985.
Knight JM, Hayduk MJ, Summerlin D-J et al: “Strawberry” gingi-
val hyperplasia. A pathognomonic mucocutaneous ﬁnding in
Wegener’s granulomatosis, Arch Dermatol 136:171-173,
2000.
Magliulo G, Varacalli S, Sepe C: Wegener’s granulomatosis pre-
senting as facial palsy, Am J Otolaryngol 20:43-45, 1999.
Patten SF, Tomecki JT: Wegener’s granulomatosis: cutaneous
and oral mucosal disease, J Am Acad Dermatol 28:710-718,
1993.
Ponniah I, Shaheen A, Shankar KA et al: Wegener’s granuloma-
tosis: the current understanding, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 100:265-270, 2005.
Allergic Mucosal Reactions to Systemic Drug Administration
Eversole LR: Allergic stomatitides, J Oral Med 34:93-102, 1979.
Felder RS, Millar SB, Henry RH: Oral manifestations of drug
therapy, Spec Care Dent 8:119-124, 1988.
Jacobsen PL, Chávez EM: Clinical management of the dental
patient taking multiple drugs, J Contemp Dent Pract 6:144-
151, 2005.
Jain VK, Dixit VB, Archana: Fixed drug eruption of the oral
mucous membrane, Ann Dent 50:9-11, 1991.
Kane M, Zacharczenko N: Oral side effects of drugs, N Y State
Dent J 59:37-40, 1993.
Lamey P-J, McCartan BE, MacDonald DG et al: Basal cell cyto-
plasmic autoantibodies in oral lichenoid reactions, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 79:44-49, 1995.
Matthews TG: Medication side effects of dental interest, J Prosthet
Dent 64:219-226, 1990.
McCartan BE, McCreary CE: Oral lichenoid drug eruptions, Oral
Dis 3:58-63, 1997.
Parks ET: Disorders affecting the oral cavity. Lesions associated
with drug reactions, Dermatol Clin 14:327-337, 1996.
Scully C, Azul AM, Crighton A et al: Nicorandil can induce
severe oral ulceration, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 91:189-193, 2001.
Wright JM: Oral manifestations of drug reactions, Dent Clin North
Am 28:529-543, 1984.
Allergic Contact Stomatitis
De Rossi SS, Greenberg MS: Intraoral contact allergy: a literature
review and case reports, J Am Dent Assoc 129:1435-1441,
1998.
Eversole LR: Allergic stomatitides, J Oral Med 34:93-102, 1979.
Fisher AA: Contact stomatitis, glossitis, and cheilitis, Otolaryngol
Clin North Am 7:827-843, 1974.
Fisher AA: Reactions of the mucous membrane to contactants,
Clin Dermatol 5:123-136, 1987.
Kallus T, Mjör IA: Incidence of adverse effects of dental materi-
als, Scand J Dent Res 99:236-240, 1991.
LeSueur BW, Yiannias JA: Contact stomatitis, Dermatol Clin
21:105-114, 2003.
Ophaswongse S, Maibach HI: Allergic contact cheilitis, Contact
Dermatitis 33:365-370, 1995.
Shah M, Lewis FM, Gawkrodger DJ: Contact allergy in patients
with oral symptoms: a study of 47 patients, Am J Contact
Dermat 7:146-151, 1996.
Stenman E, Bergman M: Hypersensitivity reactions to dental
materials in a referred group of patients, Scand J Dent Res
97:76-83, 1989.
Tosti A, Piraccini BM, Peluso AM: Contact and irritant stomatitis,
Semin Cutan Med Surg 16:314-319, 1997.
van Loon LAJ, Bos JD, Davidson CL: Clinical evaluation of ﬁfty-
six patients referred with symptoms tentatively related to
allergic contact stomatitis, Oral Surg Oral Med Oral Pathol
74:572-575, 1992.
Perioral Dermatitis
Beacham BE, Kurgansky D, Gould WM: Circumoral dermatitis
and cheilitis caused by tartar control dentifrices, J Am Acad
Dermatol 22:1029-1032, 1990.
Boeck K, Abeck D, Werfel S et al: Perioral dermatitis in
children—clinical presentation, pathogenesis-related factors
and response to topical metronidazole, Dermatology 195:235-
238, 1997.
Hafeez ZH: Perioral dermatitis: an update, Int J Dermatol 42:514-
517, 2003.
Hogan DJ: Perioral dermatitis, Curr Probl Dermatol 22:98-104,
1995.
Malik R, Quirk CJ: Topical applications and perioral dermatitis,
Aust J Dermatol 41:34-38, 2000.
Nguyen V, Eichenﬁeld LF: Perioriﬁcial dermatitis in children
and adolescents, J Am Acad Dermatol 55:781-785, 2006.
Weber K, Thurmayr R: Critical appraisal of reports on the
treatment of perioral dermatitis, Dermatology 210:300-307,
2005.
Cinnamon-Induced Contact Stomatitis
Allen CM, Blozis GG: Oral mucosal reactions to cinnamon-ﬂa-
vored chewing gum, J Am Dent Assoc 116:664-667, 1988.
Drake TE, Maibach HI: Allergic contact dermatitis and stomatitis
caused by a cinnamic aldehyde-ﬂavored toothpaste, Arch Der-
matol 112:202-203, 1976.
Endo H, Rees TD: Clinical features of cinnamon-induced contact
stomatitis, Compend Contin Educ Dent 27:403-409, 2006.
Lamey P-J, Ress TD, Forsyth A: Sensitivity reaction to the cinna-
maldehyde component of toothpaste, Br Dent J 168:115-118,
1990.
Mihail RC: Oral leukoplakia caused by cinnamon food allergy,
J Otolaryngol 21:366-367, 1992.
Miller RL, Gould AR, Bernstein ML: Cinnamon-induced stoma-
titis venenata. Clinical and characteristic histopathologic fea-
tures, Oral Surg Oral Med Oral Pathol 73:708-716, 1992. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 9 ALLERGIES AND IMMUNOLOGIC DISEASES 361
Lichenoid Contact Stomatitis from Dental
Restorative Materials
Bergman M: Side-effects of amalgam and its alternatives:
local, systemic and environmental, Int Dent J 40:4-10,
1990.
Bolewska J, Hansen HJ, Holmstrup P et al: Oral mucosal lesions
related to silver amalgam restorations, Oral Surg Oral Med
Oral Pathol 70:55-58, 1990.
Eley BM: The future of dental amalgam: a review of the literature.
Part 6: possible harmful effects of mercury from dental
amalgam, Br Dent J 182:455-459, 1997.
Holmstrup P: Oral mucosa and skin reactions related to amalgam,
Adv Dent Res 6:120-124, 1992.
Holmstrup P: Reaction of the oral mucosa related to silver
amalgam: a review, J Oral Pathol Med 20:1-7, 1991.
Jameson MW, Kardos TB, Kirk EE et al: Mucosal reactions to
amalgam restorations, J Oral Rehabil 17:293-301, 1990.
Laeijendecker R, Dekker SK, Burger PM et al: Oral lichen planus
and allergy to dental amalgam restorations, Arch Dermatol
140:1434-1438, 2004.
Mallo-Pérez L, Diaz-Donado C: Intraoral contact allergy to mate-
rials used in dental practice. A critical review, Med Oral
8:334-347, 2003.
Meurman JH, Porko C, Murtomaa H: Patients complaining
about amalgam-related symptoms suffer more often from ill-
nesses and chronic craniofacial pain than their controls,
Scand J Dent Res 98:167-172, 1990.
Rogers RS, Bruce AJ: Lichenoid contact stomatitis. Is organic
mercury the culprit? Arch Dermatol 140:1524-1525, 2004.
Angioedema
Abdi R, Dong VM, Lee CJ et al: Angiotensin II receptor blocker-
associated angioedema: on the heels of ACE inhibitor angio-
edema, Pharmacotherapy 22:1173-1175, 2002.
Angostoni A, Cicardi M: Hereditary and acquired C1-inhibitor
deﬁciency: biological and clinical characteristics in 235
patients, Medicine 71:206-215, 1992.
Bork K, Meng G, Staubach P et al: Hereditary angioedema: new
ﬁndings concerning symptoms, affected organs, and course,
Am J Med 119:267-274, 2006.
Dobson G, Edgar D, Trinder J: Angioedema of the tongue due to
acquired C1 esterase inhibitor deﬁciency, Anaesth Intensive
Care 31:99-102, 2003.
Greaves M, Lawlor F: Angioedema: manifestations and manage-
ment, J Am Acad Dermatol 25:155-165, 1991.
Megerian CA, Arnold JE, Berer M: Angioedema: 5 years’ experi-
ence, with a review of the disorder’s presentation and treat-
ment, Laryngoscope 102:256-260, 1992.
Nielsen EW, Gramstad S: Angioedema from angiotensin-
converting enzyme (ACE) inhibitor treated with complement
1 (C1) inhibitor concentrate, Acta Anaesthesiol Scand 50:
120-122, 2006.
Rees SR, Gibson J: Angioedema and swellings of the orofacial
region, Oral Dis 3:39-42, 1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

362
10
Epithelial Pathology
Revised by ANGELA C. CHI
CHAPTER OUTLINE
Spitz Nevus
Blue Nevus
Leukoplakia
Erythroplakia
Smokeless Tobacco Use and Smokeless Tobacco
Keratosis
Oral Submucous Fibrosis
Nicotine Stomatitis
Actinic Keratosis
Actinic Cheilosis
Keratoacanthoma
Squamous Cell Carcinoma
Verrucous Carcinoma
Spindle Cell Carcinoma
Adenosquamous Carcinoma
Basaloid Squamous Carcinoma
Carcinoma of the Maxillary Sinus
Sinonasal Undifferentiated Carcinoma
Nasopharyngeal Carcinoma
Basal Cell Carcinoma
Merkel Cell Carcinoma
Melanoma
Squamous Papilloma
Verruca Vulgaris
Condyloma Acuminatum
Multifocal Epithelial Hyperplasia
Sinonasal Papillomas
Fungiform Papilloma
Inverted Papilloma
Cylindrical Cell Papilloma
Molluscum Contagiosum
Verruciform Xanthoma
Seborrheic Keratosis
Sebaceous Hyperplasia
Ephelis
Actinic Lentigo
Lentigo Simplex
Melasma
Oral Melanotic Macule
Oral Melanoacanthoma
Acquired Melanocytic Nevus
Variants of Melanocytic Nevus
Congenital Melanocytic Nevus
Halo Nevus
SQUAMOUS PAPILLOMA
The squamous papilloma is a benign proliferation of
stratiﬁed squamous epithelium, resulting in a papillary
or verruciform mass. Presumably, this lesion is induced
by the human papillomavirus (HPV). HPV comprises
a large family (more than 100 types) of double-stranded
DNA viruses of the papovavirus subgroup A. Research
has shown that 81% of normal adults have buccal
epithelial cells that contain at least one type of HPV,
although case control studies using more rigorous cri-
teria usually have shown distinct differences, with high
levels of HPV in oral lesions and low levels in normal
controls. The virus is capable of becoming totally inte-
grated with the DNA of the host cell, and at least 24
types are associated with lesions of the head and neck.
HPV can be identiﬁed by in situ hybridization, immu- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 363
nohistochemical analysis, and polymerase chain reac-
tion (PCR) techniques, but it is not visible with routine
histopathologic staining. Viral subtypes 6 and 11 have
been identiﬁed in up to 50% of oral papillomas, as
compared with less than 5% in normal mucosal cells.
The exact mode of transmission is unknown. Trans-
mission by sexual and nonsexual person-to-person
contact, contaminated objects, saliva, or breast milk
has been proposed. In contrast to other HPV-induced
lesions, the viruses in oral squamous papillomas appear
to have an extremely low virulence and infectivity rate.
A latency or incubation period of 3 to 12 months has
been suggested.
The squamous papilloma occurs in one of every 250
adults and makes up approximately 3% of all oral
lesions submitted for biopsy. In addition, researchers
have estimated that oral squamous papillomas
comprise 7% to 8% of all oral masses or growths in
children.
CLINICAL FEATURES
The squamous papilloma occurs with equal frequency
in both men and women. Some authors have asserted
that it develops predominantly in children, but epide-
miologic studies indicate that it can arise at any age
and, in fact, is diagnosed most often in persons 30 to
50 years of age. Sites of predilection include the tongue,
lips, and soft palate, but any oral surface may be
affected. This lesion is the most common of the soft
tissue masses arising from the soft palate.
The squamous papilloma is a soft, painless, usually
pedunculated, exophytic nodule with numerous ﬁn-
gerlike surface projections that impart a “cauliﬂower”
or wartlike appearance (Fig. 10-1). Projections may be
pointed or blunted (Figs. 10-2 and 10-3), and the lesion
may be white, slightly red, or normal in color, depend-
ing on the amount of surface keratinization. The papil-
loma is usually solitary and enlarges rapidly to a
maximum size of about 0.5 cm, with little or no change
thereafter. However, lesions as large as 3.0 cm in great-
est diameter have been reported.
It is sometimes difﬁcult to distinguish this lesion
clinically from verruca vulgaris (see page 364), condy-
loma acuminatum (see page 366), verruciform
xanthoma (see page 372), or multifocal epithelial
hyperplasia (see page 367). In addition, extensive
coalescing papillary lesions (papillomatosis) of the
oral mucosa may be seen in several skin disorders,
including nevus unius lateris, acanthosis nigricans, and
focal dermal hypoplasia (Goltz-Gorlin) syndrome.
Laryngeal papillomatosis, a rare and potentially dev-
astating disease of the larynx and hypopharynx, has
two distinct types: (1) juvenile-onset and (2) adult-
Fig. 10-1 Squamous papilloma. An exophytic lesion of the
soft palate with multiple short, white surface projections.
Fig. 10-2 Squamous papilloma. A pedunculated lingual
mass with numerous long, pointed, and white surface
projections. Note the smaller projections around the base of
the lesion.
Fig. 10-3 Squamous papilloma. A pedunculated mass of
the buccal commissure, exhibiting short or blunted surface
projections and minimal white coloration. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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364 ORAL AND MAXILLOFACIAL PATHOLOGY
onset. Hoarseness is the usual presenting feature, and
rapidly proliferating papillomas in the juvenile-onset
type may obstruct the airway. The strongest risk factor
for juvenile-onset laryngeal papillomatosis is a mater-
nal history of genital warts; transmission of HPV infec-
tion via the birth canal, the placenta, or amniotic ﬂuid
has been hypothesized.
HISTOPATHOLOGIC FEATURES
The papilloma is characterized by a proliferation of
keratinized stratiﬁed squamous epithelium arrayed in
ﬁngerlike projections with ﬁbrovascular connective
tissue cores (Fig. 10-4). The connective tissue cores
may show inﬂammatory changes, depending on the
amount of trauma sustained by the lesion. The keratin
layer is thickened in lesions with a whiter clinical
appearance, and the epithelium typically shows a
normal maturation pattern. Occasional papillomas
demonstrate basilar hyperplasia and mitotic activity,
which can be mistaken for mild epithelial dysplasia.
Koilocytes, virus-altered epithelial clear cells with
small dark (pyknotic) nuclei, are sometimes seen high
in the prickle cell layer.
TREATMENT AND PROGNOSIS
Conservative surgical excision, including the base of
the lesion, is adequate treatment for the oral squamous
papilloma, and recurrence is unlikely. Frequently,
lesions have been left untreated for years with no
reported transformation into malignancy, continuous
enlargement, or dissemination to other parts of the oral
cavity.
Although spontaneous remission is possible, juve-
nile-onset laryngeal papillomatosis tends to be continu-
ously proliferative, sometimes leading to death by
asphyxiation. Some investigators have noted especially
aggressive behavior among cases associated with
HPV type 11 infection. The papillomatosis is treated
by repeated surgical debulking procedures to relieve
airway obstruction. Adjuvant therapy with agents such
as α-interferon may be used for cases exhibiting rapid
regrowth or distant spread. Adult-onset lesions are
typically less aggressive and tend to be single. Conser-
vative surgical removal may be necessary to eliminate
hoarseness from vocal cord involvement. In rare
instances, squamous cell carcinoma will develop in
long-standing laryngeal papillomatosis, sometimes in a
smoker or a patient with a history of irradiation to the
larynx.
A vaccine targeted against HPV types 6, 11, 16, and
18 has been introduced recently for the prevention of
cervical cancer and genital warts. It is possible that this
vaccine may prevent HPV-related lesions of the head
and neck as well, such as oral squamous papilloma,
laryngeal papillomatosis, and perhaps some cases of
oral and oropharyngeal squamous cell carcinoma.
VERRUCA VULGARIS
(COMMON WART)
Verruca vulgaris is a benign, virus-induced, focal
hyperplasia of stratiﬁed squamous epithelium. One or
more of the associated human papillomavirus (HPV)
types 2, 4, 6, and 40 are found in virtually all examples.
Verruca vulgaris is contagious and can spread to other
parts of a person’s skin or mucous membranes by way
of autoinoculation. It infrequently develops on oral
mucosa but is extremely common on the skin.
CLINICAL FEATURES
Verruca vulgaris is frequently discovered in children,
but occasional lesions may arise even into middle age.
The skin of the hands is usually the site of infection (Fig.
10-5). When the oral mucosa is involved, the lesions
are usually found on the vermilion border, labial
mucosa, or anterior tongue.
Typically, the verruca appears as a painless papule
or nodule with papillary projections or a rough pebbly
surface (Figs. 10-6 and 10-7). It may be pedunculated
or sessile. Cutaneous lesions may be pink, yellow, or
white; oral lesions are almost always white. Verruca
vulgaris enlarges rapidly to its maximum size (usually
<5 mm), and the size remains constant for months or
years thereafter unless the lesion is irritated. Multiple
or clustered lesions are common. On occasion, extreme
accumulation of compact keratin may result in a hard
surface projection several millimeters in height, termed
a cutaneous horn or keratin horn. Other cutaneous
Fig. 10-4 Squamous papilloma. Low-power view showing
a pedunculated squamous epithelial proliferation. There are
multiple papillary projections with ﬁbrovascular connective
tissue cores. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 365
lesions, including seborrheic keratosis (see page 374),
actinic keratosis (see page 404), and squamous cell
carcinoma, may also create a cutaneous horn.
HISTOPATHOLOGIC FEATURES
The verruca vulgaris is characterized by a proliferation
of hyperkeratotic stratiﬁed squamous epithelium
arranged into ﬁngerlike or pointed projections with
connective tissue cores (Fig. 10-8). Chronic inﬂamma-
tory cells often inﬁltrate the supporting connective
tissue. Elongated rete ridges tend to converge toward
the center of the lesion, producing a “cupping” effect.
A prominent granular cell layer (hypergranulosis)
exhibits coarse, clumped keratohyaline granules.
Abundant koilocytes are often seen in the superﬁcial
spinous layer. Koilocytes are HPV-altered epithelial
cells with perinuclear clear spaces and small, dark
nuclei (pyknosis). Eosinophilic intranuclear viral
inclusions are often noted within the cells of the
granular layer.
Fig. 10-5 Verruca vulgaris. Several warts on the ﬁnger,
exhibiting a rough, papillary surface.
Fig. 10-6 Verruca vulgaris. Nodular lesion of the skin
exhibiting numerous short papillary projections.
Fig. 10-7 Verruca vulgaris. Exophytic, white, papillary
lesion of the lateral soft palate.
Fig. 10-8 Verruca vulgaris. A, Numerous papillary
projections are covered by hyperkeratotic stratiﬁed squamous
epithelium. Elongated rete ridges at the edge of the lesion
converge toward the center. B, High-power view showing
clear koilocytes in the upper epithelial layers.
A
B `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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366 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
Skin verrucae are treated effectively by topical salicylic
acid, topical lactic acid, or liquid nitrogen cryotherapy.
Surgical excision is indicated only for cases with an
atypical clinical presentation in which the diagnosis
is uncertain. Skin lesions that recur or are resistant
to standard therapy may be treated by alternative
methods, such as intralesional bleomycin, topical or
intralesional 5-ﬂuorouracil, or photodynamic therapy.
Oral lesions are usually surgically excised, or they
may be destroyed by a laser, cryotherapy, or electrosur-
gery. Cryotherapy induces a subepithelial blister that
lifts the infected epithelium from the underlying con-
nective tissue, allowing it to slough away. All destruc-
tive or surgical treatments should extend to include the
base of the lesion.
Recurrence is seen in a small proportion of treated
cases. Without treatment, verrucae do not transform
into malignancy, and two thirds will disappear sponta-
neously within 2 years, especially in children.
CONDYLOMA ACUMINATUM
(VENEREAL WART)
Condyloma acuminatum is a virus-induced prolifera-
tion of stratiﬁed squamous epithelium of the genitalia,
perianal region, mouth, and larynx. One or more of the
human papillomavirus (HPV) types 2, 6, 11, 53, and 54
are usually detected in the lesion. However, the high-
risk types 16, 18, and 31 also may be present, especially
in anogenital lesions. Condyloma is considered to be a
sexually transmitted disease (STD), with lesions devel-
oping at a site of sexual contact or trauma. This lesion
represents 20% of all STDs diagnosed in STD clinics
and may be an indicator of sexual abuse when diag-
nosed in young children. In addition, studies of oral and
pharyngeal HPV infection in infants have suggested
that vertical transmission from mothers with genital
HPV infection may occur perinatally or perhaps in
utero; however, reported transmission rates have varied
widely (ranging from 4% to >80%). It is not unusual for
oral and anogenital condylomata to be present concur-
rently. The incubation period for a condyloma is 1 to 3
months from the time of sexual contact. Once present,
autoinoculation to other mucosal sites is possible.
CLINICAL FEATURES
Condylomata are usually diagnosed in teenagers and
young adults, but people of all ages are susceptible.
Oral lesions most frequently occur on the labial mucosa,
soft palate, and lingual frenum. The typical condyloma
appears as a sessile, pink, well-demarcated, nontender
exophytic mass with short, blunted surface projections
(Fig. 10-9). The condyloma tends to be larger than the
papilloma and is characteristically clustered with other
condylomata. The average lesional size is 1.0 to 1.5 cm,
but oral lesions as large as 3 cm have been reported.
HISTOPATHOLOGIC FEATURES
Condyloma acuminatum appears as a benign prolifera-
tion of acanthotic stratiﬁed squamous epithelium with
mildly keratotic papillary surface projections (Fig.
10-10). Thin connective tissue cores support the papil-
lary epithelial projections, which are more blunted and
broader than those of squamous papilloma and verruca
vulgaris, imparting an appearance of keratin-ﬁlled
crypts between prominences. In some cases, lesions
extending from the surface mucosa to involve underly-
ing salivary ductal epithelium have been reported;
such lesions should be distinguished from salivary
ductal papillomas (see page 485).
The covering epithelium is mature and differenti-
ated, but the prickle cells often demonstrate pyknotic,
crinkled (or “raisinlike”) nuclei surrounded by clear
zones (koilocytes), a microscopic feature of HPV infec-
Fig. 10-9 Condyloma acuminatum. Two lesions of the
upper lip mucosa exhibit short, blunted projections. (Courtesy
of Dr. Brian Blocher.)
Fig. 10-10 Condyloma acuminatum. Medium-power
photomicrograph showing acanthotic stratiﬁed squamous
epithelium forming a blunted projection. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 367
tion (Fig. 10-11). Koilocytes may be less prominent in
oral lesions compared with genital lesions, in which
case distinction from squamous papilloma may be
difﬁcult. Ultrastructural examination reveals virions
within the cytoplasm or nuclei of koilocytes, and the
virus also can be demonstrated by immunohistochemi-
cal analysis, in situ hybridization, and PCR techniques.
TREATMENT AND PROGNOSIS
The oral condyloma is usually treated by conservative
surgical excision. Laser ablation also has been used, but
this treatment has raised some question as to the air-
borne spread of HPV through the aerosolized micro-
droplets created by the vaporization of lesional tissue.
Nonsurgical, patient-applied topical agents such as
imiquimod or podophyllotoxin are becoming the main-
stay of treatment for anogenital condylomata, although
such treatments are not typically used for oral lesions.
Regardless of the method used, a condyloma should be
removed because it is contagious and can spread to
other oral surfaces and to other persons through direct
(usually sexual) contact. In the anogenital area, condy-
lomata infected with HPV-16 or HPV-18 are associ-
ated with an increased risk of malignant transformation
to squamous cell carcinoma, but this has not been dem-
onstrated in oral lesions.
MULTIFOCAL EPITHELIAL
HYPERPLASIA (HECK’S DISEASE;
MULTIFOCAL PAPILLOMA VIRUS
EPITHELIAL HYPERPLASIA; FOCAL
EPITHELIAL HYPERPLASIA)
Multifocal epithelial hyperplasia is a virus-induced,
localized proliferation of oral squamous epithelium
that was ﬁrst described in Native Americans and Inuit.
Currently, it is known to exist in many populations and
ethnic groups and is apparently produced by human
papillomavirus (HPV) types 13 and 32. In some popu-
lations, as many as 39% of children are affected. The
condition often affects multiple members of a given
family; this familial tendency may be related to either
genetic susceptibility or HPV transmission between
family members. An association with the HLA-DR4
(DRB1*0404) allele was found in a recent study of
Mexican patients with this condition. Lower socio-
economic status, crowded living conditions, and poor
hygiene appear to be additional risk factors. Multiple
papillary lesions similar to multifocal epithelial hyper-
plasia arise with increased frequency in patients with
acquired immunodeﬁciency syndrome (AIDS) (see
page 276).
CLINICAL FEATURES
Although multifocal epithelial hyperplasia is usually a
childhood condition, it occasionally affects young and
middle-aged adults. Previous studies have reported
either a slight female predilection or no signiﬁcant
gender bias. The most common sites of involvement
include the labial, buccal, and lingual mucosa, but gin-
gival, palatal, and tonsillar lesions also have been
reported. In addition, involvement of the conjunctiva
has been described very rarely.
This disease typically appears as multiple soft,
nontender, ﬂattened or rounded papules, which are
usually clustered and the color of normal mucosa,
although they may be scattered, pale, or rarely white
(Fig. 10-12). Occasional lesions show a slight papillary
surface change (Fig. 10-13). Individual lesions are
small (0.3 to 1.0 cm), discrete, and well demarcated,
but they frequently cluster so closely together that
the entire area takes on a cobblestone or ﬁssured
appearance.
Fig. 10-11 Condyloma acuminatum. High-power
photomicrograph demonstrating koilocytes (arrows) in the
spinous layer.
Fig. 10-12 Multifocal epithelial hyperplasia. Multiple, ﬂat-
topped papules and nodules of normal coloration are seen on
the lower lip of a child. (Courtesy of Dr. Mark Casafrancisco.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

368 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
The hallmark of multifocal epithelial hyperplasia is
an abrupt and sometimes considerable acanthosis of
the oral epithelium (Fig. 10-14). Because the thickened
mucosa extends upward, not down into underlying con-
nective tissues, the lesional rete ridges are at the same
depth as the adjacent normal rete ridges. The ridges
themselves are widened, often conﬂuent, and some-
times club shaped. Some superﬁcial keratinocytes show
a koilocytic change similar to that seen in other HPV
infections. Others occasionally demonstrate an altered
nucleus that resembles a mitotic ﬁgure (mitosoid cell)
(Fig. 10-15). Viruslike particles have been noted ultra-
structurally within both the cytoplasm and the nuclei of
cells within the prickle cell layer, and the presence of
HPV has been demonstrated with both DNA in situ
hybridization and immunohistochemical analysis.
TREATMENT AND PROGNOSIS
Spontaneous regression of multifocal epithelial hyper-
plasia has been reported after months or years and is
inferred from the rarity of the disease in adults. Con-
servative surgical excision may be performed for diag-
nostic or aesthetic purposes or for lesions subject to
recurrent trauma. Lesions also can be removed by
cryotherapy or carbon dioxide (CO
2) laser ablation.
Use of topical interferon-β and systemic interferon-α
has been reported in a few cases, although with vari-
able results. The risk of recurrence after therapy is
minimal, and there seems to be no malignant transfor-
mation potential.
SINONASAL PAPILLOMAS
Papillomas of the sinonasal tract are benign, localized
proliferations of the respiratory mucosa of this region.
This mucosa gives rise to three histomorphologically
distinct papillomas:
1. Fungiform
2. Inverted
3. Cylindrical cell
Lesions exhibiting features of both the inverted and
the cylindrical cell types may be termed mixed or hybrid
papillomas. In addition, a keratinizing squamous
papilloma, similar to the oral squamous papilloma (see
page 362), rarely may occur in the nasal vestibule.
Collectively, sinonasal papillomas represent 10%
to 25% of all tumors of the nasal and paranasal region.
Half of the sinonasal papillomas arise from the mucosa
of the lateral nasal wall; the remainder predominantly
involve the maxillary and ethmoid sinuses and the
nasal septum. Multiple lesions may be present.
Fig. 10-13 Multifocal epithelial hyperplasia. The lesions
may demonstrate a papillary surface change and paleness, as
demonstrated on this child’s tongue. (Courtesy of Dr. Román
Carlos.)
Fig. 10-14 Multifocal epithelial hyperplasia. Prominent
acanthosis of the epithelium with broad and elongated rete
ridges. The slightly papillary surface alteration noted here
may or may not be present.
Fig. 10-15 Multifocal epithelial hyperplasia. Mitosoid
cells (arrows) contain altered nuclei in this otherwise mature
and well-differentiated stratiﬁed squamous epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 369
The cause of sinonasal papillomas remains contro-
versial and unclear. Some authorities say that these
lesions represent neoplasms; others consider them to
be a reactive hyperplasia secondary to a variety of envi-
ronmental stimulants, such as allergy, chronic bacterial
or viral (HPV type 11) infection, and tobacco smoking.
Recent molecular genetic investigations have shown
that inverted papillomas arise from a single progenitor
cell (i.e., monoclonal), suggesting that these lesions are
neoplastic and recurrence may result from growth of
residual transformed cells.
FUNGIFORM (SEPTAL; SQUAMOUS;
EXOPHYTIC) PAPILLOMA
The fungiform papilloma bears some similarity to the
oral squamous papilloma, although it has a somewhat
more aggressive biologic behavior and more varied
epithelial types. It represents 18% to 50% of all sinona-
sal papillomas in various investigations. Almost all
examples are positive for HPV type 6 or 11.
CLINICAL FEATURES
The fungiform papilloma arises almost exclusively on
the nasal septum and is twice as common in men as in
women. It occurs primarily in people 20 to 50 years of
age. Typically, it exhibits unilateral nasal obstruction or
epistaxis and appears as a pink or tan, broad-based
nodule with papillary or warty surface projections
(Fig. 10-16).
HISTOPATHOLOGIC FEATURES
The fungiform papilloma has a microscopic appear-
ance similar to that of the oral squamous papilloma,
although the stratiﬁed squamous epithelium covering
the ﬁngerlike projections seldom is keratinized. Respi-
ratory epithelium or “transitional” epithelium (inter-
mediate between squamous and respiratory) may be
seen in some lesions. Mucous (goblet) cells and intraep-
ithelial microcysts containing mucus often are present.
Mitoses are infrequent, and dysplasia is rare. The
underlying connective tissue consists of delicate ﬁbrous
tissue with a minimal inﬂammatory component, unless
it is irritated.
TREATMENT AND PROGNOSIS
Complete surgical excision is the treatment of choice
for the fungiform papilloma. Recurrence is common,
developing in approximately one third of all cases;
however, this may be caused by incomplete excision.
Most authorities consider this lesion to have minimal
or no potential for malignant transformation.
INVERTED PAPILLOMA (INVERTED
SCHNEIDERIAN PAPILLOMA)
The most common (50% to 78%) sinonasal papilloma,
the inverted papilloma, is also the variant with the
greatest potential for local destruction and malignant
transformation. HPV types 6, 11, 16, and 18 have been
identiﬁed, with considerable variability in the reported
proportion of cases positive for HPV. This variability is
likely due to differences in detection methods used;
however, more recent studies using quantitative real-
time polymerase chain reaction (PCR) suggest that
HPV is present in approximately 18 to 30% of lesions.
CLINICAL AND RADIOGRAPHIC
FEATURES
The inverted papilloma seldom occurs in patients
younger than 20 years of age; the median age is 55
years. A strong male predilection is noted (3:1 male-to-
female ratio). This lesion arises predominantly from
the lateral nasal cavity wall or a paranasal sinus, usually
the antrum. Typically, the inverted papilloma results in
unilateral nasal obstruction; additional symptoms may
include pain, epistaxis, purulent discharge, or local
deformity. The papilloma appears as a soft, pink or tan,
polypoid or nodular growth. Multiple lesions may be
present.
Pressure erosion of the underlying bone is usually
present and may be visible radiographically as an irreg-
ular radiolucency. Primary sinus lesions may be distin-
guishable only as a soft tissue radiodensity or mucosal
thickening on radiographs; sinus involvement gener-
ally represents extension from the nasal cavity. Mag-
netic resonance imaging (MRI) can help to identify the
extent of the lesion (Fig. 10-17).
Fig. 10-16 Fungiform papilloma. Erythematous, papillary
growth on the nasal septum. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

370 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Microscopically, the inverted papilloma is character-
ized by squamous epithelial proliferation into the sub-
mucosal stroma (Fig. 10-18). The basement membrane
remains intact, and the epithelium appears to be
“pushing” into underlying connective tissue. Goblet
(mucous) cells and mucin-ﬁlled microcysts frequently
are noted within the epithelium. Keratin production is
uncommon, but thin surface keratinization may be
seen. Mitoses often are noted within the basilar or para-
basilar cells, and varying degrees of dysplasia may be
seen. Papillary surface projections are present, and
deep clefts may be seen between projections. The
stroma consists of dense ﬁbrous or loose myxomatous
connective tissue with or without inﬂammatory cells.
Destruction of underlying bone frequently is noted.
Immunohistochemical expression of CD44, a cell
adhesion molecule, is increased in this papilloma,
which may help to distinguish it from invasive papil-
lary squamous cell carcinoma, which lacks this feature.
Although some authors have suggested that hyperkera-
tosis, prominent epithelial hyperplasia, and high
mitotic index are negative prognostic indicators, no
histopathologic parameters have been found to be reli-
ably predictive of recurrence or malignant transforma-
tion among inverted papillomas.
TREATMENT AND PROGNOSIS
The inverted papilloma has a signiﬁcant growth poten-
tial and, if neglected, may extend into the nasopharynx,
middle ear, orbit, or cranial base. In some studies, recur-
rence after conservative surgical excision has occurred
in nearly 75% of all cases. However, with more aggres-
sive surgical therapy, consisting of medial maxillectomy
via a lateral rhinotomy or midfacial degloving approach,
recurrence rates of less than 14% have been reported.
Although an open surgical approach historically has
been regarded as the standard of care, advances in
transnasal endoscopic surgery have led to wider accep-
tance of this method as an alternative, particularly for
patients with limited and easily accessible disease.
Several investigators, using modern endoscopic tech-
niques and careful patient selection, have reported
recurrence rates comparable to those for conventional
lateral rhinotomy with medial maxillectomy. Recur-
rences are usually noted within 2 years of surgery but
can happen much later. Hence, long-term follow-up is
essential. Continued tobacco smoking is associated with
an increased risk of multiple recurrences.
The inverted papilloma also is associated with malig-
nancy, usually squamous cell carcinoma, in 3% to 24%
of cases. In such an eventuality, of course, the lesion
is treated as a malignancy, typically by performing
more radical surgery, with or without adjunctive
radiotherapy.
CYLINDRICAL CELL
PAPILLOMA (ONCOCYTIC
SCHNEIDERIAN PAPILLOMA)
The cylindrical cell papilloma accounts for less than
7% of sinonasal papillomas. This lesion is considered by
some authorities to be a variant of the inverted
Fig. 10-17 Inverted papilloma. T1-weighted coronal
magnetic resonance image (MRI) showing a tumor of the
right lateral nasal fossa. The tumor ﬁlls the right maxilla and
ethmoid sinuses and involves the ﬂoor of the orbit. (Courtesy of
Dr. Pamela Van Tassel.)
Fig. 10-18 Inverted papilloma. Low-power
photomicrograph showing a squamous epithelial
proliferation, with multiple “inverting” islands of epithelium
extending into the underlying connective tissue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 371
papilloma because of the similarity in clinical and
histopathologic features and a similarly low frequency
of HPV.
CLINICAL FEATURES
Cylindrical cell papilloma typically occurs in adults 20
to 50 years of age. There is a strong male predomi-
nance, with a predilection for the maxillary antrum,
lateral nasal cavity wall, and ethmoid sinus. The pre-
senting symptom is usually unilateral nasal obstruc-
tion, and it appears as a beefy-red or brown mass with
a multinodular surface.
HISTOPATHOLOGIC FEATURES
Microscopically, the cylindrical cell papilloma demon-
strates both endophytic and exophytic growth. Surface
papillary projections have a ﬁbrovascular connective
tissue core and are covered by a multilayered epithe-
lium of tall columnar cells with small, dark nuclei
and eosinophilic, occasionally granular, cytoplasm.
The lesional epithelial cell is similar to an oncocyte.
Cilia may be seen on the surface, and there are numer-
ous intraepithelial microcysts ﬁlled with mucin,
neutrophils, or both.
TREATMENT AND PROGNOSIS
Cylindrical cell papilloma is treated in the same
manner as inverted papilloma (see previous topic).
The potential for recurrence and malignant transfor-
mation seems to be lower than that of the inverted
papilloma.
MOLLUSCUM CONTAGIOSUM
Molluscum contagiosum is a virus-induced epithelial
hyperplasia produced by the molluscum contagiosum
virus, a member of the DNA poxvirus group. At least
6% of the population (more in older age groups) has
antibodies to this virus, although few ever develop
lesions. After an incubation period of 14 to 50 days,
infection produces multiple papules of the skin or,
rarely, mucous membranes. These remain small for
months or years and then spontaneously involute.
During its active phase, the molluscum contagiosum
virus is sloughed from a central core in each papule.
Routes of transmission include sexual contact (in
adults) and such nonsexual contacts (in children and
teenagers) as sharing clothing, wrestling, communal
bathing, and swimming. Lesions have a predilection for
warm portions of the skin and sites of recent injury.
Florid cases have been reported in immunocompro-
mised patients, and the prevalence among the human
immunodeﬁciency virus (HIV)-positive patient popula-
tion is estimated to be 5% to 18% (see page 278). Patients
with atopic dermatitis and Darier’s disease also are at
risk for developing severe and extensive disease.
CLINICAL FEATURES
Molluscum contagiosum is usually seen in children
and young adults. The papules almost always are mul-
tiple and occur predominantly on the skin of the
neck, face (particularly eyelids), trunk, and genitalia.
Infrequently, oral involvement occurs, usually on the
lips, buccal mucosa, palate, or gingiva.
Lesions are pink, smooth-surfaced, sessile, non-
tender, and nonhemorrhagic papules that are 2 to
4 mm in diameter (Fig. 10-19). Many show a small
central indentation or keratin-like plug from which a
curdlike substance can be expressed. Some are sur-
rounded by a mild inﬂammatory erythema and may be
slightly tender or pruritic. Eczematous eruptions occa-
sionally may develop in the vicinity of molluscum con-
tagiosum lesions, particularly in patients with atopic
dermatitis.
In immunocompromised patients, atypical lesions
that are unusually large, verrucous, or markedly hyper-
keratotic have been described.
HISTOPATHOLOGIC FEATURES
Molluscum contagiosum appears as a localized lobular
proliferation of surface stratiﬁed squamous epithelium
(Fig. 10-20). The central portion of each lobule is
ﬁlled with bloated keratinocytes that contain large,
intranuclear, basophilic viral inclusions called mollus-
cum bodies (or Henderson-Paterson bodies)
(Fig. 10-21). These bodies begin as small eosinophilic
structures in cells just above the basal layer. As they
Fig. 10-19 Molluscum contagiosum. Multiple, smooth-
surfaced papules, with several demonstrating small keratin-
like plugs, are seen on the neck of a child. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

372 ORAL AND MAXILLOFACIAL PATHOLOGY
approach the surface, these bodies increase so much in
size that they frequently become larger than the origi-
nal size of the invaded cells. A central crater is formed
at the surface as stratum corneum cells disintegrate to
release their molluscum bodies. These unique features
make the diagnosis readily apparent.
TREATMENT AND PROGNOSIS
In most cases of molluscum contagiosum, spontaneous
remission occurs within 6 to 9 months. For immuno-
competent patients, there is ongoing debate as to
whether the disease should be treated or allowed
to resolve on its own. Treatment may be performed to
decrease the risk of disease transmission, prevent auto-
inoculation, or provide symptomatic relief.
Few controlled studies of treatment efﬁcacy have
been performed, but lesions most commonly are
removed by curettage or cryotherapy. Alternative treat-
ment methods include CO
2 or pulsed dye laser therapy,
electrodessication, trichloroacetic acid, silver nitrate,
potassium hydroxide, or the topical blistering agent
cantharidin. Topical agents such as tretinoin, podo-
phyllotoxin, and imiquimod are additional alternatives,
although generally not as effective or rapid as in-ofﬁce
cryotherapy or curettage
In immunosuppressed patients with recalcitrant
lesions, the antiviral agent cidoﬁvir may be effective.
Moreover, in patients with AIDS, highly active antiret-
roviral therapy indirectly counteracts molluscum con-
tagiosum infection by increasing CD4+ T cell counts
and improving the immune response.
There is no apparent potential to transform into
carcinoma, and the lesions tend not to recur after
treatment.
VERRUCIFORM XANTHOMA
Verruciform xanthoma is a hyperplastic condition
of the epithelium of the mouth, skin, and genitalia,
with a characteristic accumulation of lipid-laden his-
tiocytes beneath the epithelium. First reported in 1971,
it remains largely an oral disease; its cause is still
unknown. Although verruciform xanthoma is a papil-
lary lesion, human papillomavirus (HPV) has been
identiﬁed in only a small number of cases, and no
deﬁnitive role for this virus in the pathogenesis of these
lesions has been established. The lesion probably rep-
resents an unusual reaction or immune response to
localized epithelial trauma or damage. This hypothesis
is supported by cases of verruciform xanthoma that
have developed in association with disturbed epithe-
lium (e.g., lichen planus, lupus erythematosus, epider-
molysis bullosa, epithelial dysplasia, squamous cell
carcinoma, pemphigus vulgaris, warty dyskeratoma,
graft-versus-host disease [GVHD]). The lesion is histo-
pathologically similar to other dermal xanthomas, but
it is not associated with diabetes, hyperlipidemia, or
any other metabolic disorder.
CLINICAL FEATURES
Verruciform xanthoma is typically seen in whites, 40
to 70 years of age, with a slight male predilection.
Approximately half of the intraoral lesions occur on the
gingiva and alveolar mucosa, but any oral site may be
involved.
Fig. 10-20 Molluscum contagiosum. Well-deﬁned
epidermal proliferation demonstrating a central craterlike
depression ﬁlled with virally altered keratinocytes.
Fig. 10-21 Molluscum contagiosum. Higher-power
photomicrograph showing keratinocytes with large,
basophilic viral inclusions (molluscum bodies) being sloughed
into the central crater (top). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 373
The lesion appears as a well-demarcated, soft, pain-
less, sessile, slightly elevated mass with a white, yellow-
white, or red color and a papillary or roughened
(verruciform) surface (Figs. 10-22 and 10-23). Rarely,
ﬂat-topped nodules are seen without surface projec-
tions. Most lesions are smaller than 2 cm in greatest
diameter; no oral lesion larger than 4 cm has been
reported. Multiple lesions occasionally have been
described. Clinically, verruciform xanthoma may be
similar to squamous papilloma, condyloma acumina-
tum, or early carcinoma.
HISTOPATHOLOGIC FEATURES
Verruciform xanthoma demonstrates papillary, acan-
thotic surface epithelium covered by a thickened layer
of parakeratin. On routine hematoxylin and eosin
(H&E) staining, the keratin layer often exhibits a dis-
tinctive orange coloration (Fig. 10-24). Clefts or crypts
between the epithelial projections are ﬁlled with para-
keratin, and rete ridges are elongated to a uniform
depth. The most important diagnostic feature is the
accumulation of numerous large macrophages with
foamy cytoplasm, which typically are conﬁned to the
connective tissue papillae. These foam cells, also known
as xanthoma cells, contain lipid and periodic acid-
Schiff (PAS)-positive, diastase-resistant granules.
With immunohistochemical stains, the xanthoma
cells are positive for markers consistent with mono-
cyte-macrophage lineage, including CD68 (KP1) and
cathepsin B.
TREATMENT AND PROGNOSIS
The verruciform xanthoma is treated with conservative
surgical excision. Recurrence after removal of the
lesion is rare, and no malignant transformation has
Fig. 10-22 Verruciform xanthoma. A well-demarcated,
slightly elevated lesion of the hard palate that demonstrates
a roughened or papillary surface.
Fig. 10-23 Verruciform xanthoma. A lesion of the ventral
tongue exhibits a biphasic appearance. The anterior aspect
demonstrates elongated white (well-keratinized) projections
(large arrow). The posterior aspect demonstrates a surface of
yellow, blunted projections (small arrow).
A
B
Fig. 10-24 Verruciform xanthoma. A, A slight papillary
appearance is produced by hyperparakeratosis, and the rete
ridges are elongated to a uniform depth. Note the
parakeratin plugging between the papillary projections.
B, The connective tissue papillae are composed almost
exclusively of xanthoma cells—large macrophages with foamy
cytoplasm. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

374 ORAL AND MAXILLOFACIAL PATHOLOGY
been reported. However, two cases have been reported
in which a verruciform xanthoma occurred in associa-
tion with carcinoma in situ or squamous cell carcinoma.
This does not necessarily imply that verruciform
xanthoma is a potentially malignant lesion; however, it
may indicate that hyperkeratotic or dysplastic oral
lesions can undergo degenerative changes to form a
verruciform xanthoma.
SEBORRHEIC KERATOSIS
Seborrheic keratosis is an extremely common skin
lesion of older people and represents an acquired,
benign proliferation of epidermal basal cells. The cause
is unknown, although there is a positive correlation
with chronic sun exposure, sometimes with a heredi-
tary (autosomal dominant) tendency. In addition,
recent genetic studies have suggested that somatic
mutations in the FGFR3 (ﬁbroblast growth factor
receptor 3) gene are important in the development of
these lesions. Seborrheic keratosis does not occur in
the mouth.
CLINICAL FEATURES
Seborrheic keratoses begin to develop on the skin of
the face, trunk, and extremities during the fourth
decade of life, and they become more prevalent with
each passing decade. Lesions are usually multiple,
beginning as small tan to brown macules that are indis-
tinguishable clinically from actinic lentigines (see
page 377), and which gradually enlarge and elevate
(Figs. 10-25 and 10-26). Individual lesions are sharply
demarcated plaques and have surfaces that are ﬁnely
ﬁssured, pitted, or verrucous, but may be smooth. They
tend to appear “stuck onto” the skin and are usually less
than 2 cm in diameter.
Dermatosis papulosa nigra is a form of seborrheic
keratosis that occurs in approximately 30% of blacks
and frequently has an autosomal dominant inheritance
pattern. This condition typically appears as multiple,
small (1 to 2 mm), dark-brown to black papules
scattered about the zygomatic and periorbital region
(Fig. 10-27).
HISTOPATHOLOGIC FEATURES
Seborrheic keratosis consists of an exophytic prolifera-
tion of basilar epithelial cells that exhibit varying
degrees of surface keratinization, acanthosis, and papil-
lomatosis (Fig. 10-28). Characteristically, the entire
epithelial hyperplasia extends upward, above the
normal epidermal surface. The lesion usually exhibits
deep, keratin-ﬁlled invaginations that appear cystic on
cross-section; hence, they are called horn cysts or
pseudo-horn cysts (Fig. 10-29). Melanin pigmenta-
tion often is seen within the basal layer.
Fig. 10-25 Seborrheic keratosis. Multiple brown plaques
on the face of an older man exhibit a ﬁssured surface. They
had been slowly enlarging for several years.
Fig. 10-26 Seborrheic keratosis. Crusted and pigmented
epidermal plaque.
Fig. 10-27 Dermatosis papulosa nigra. Multiple small
pigmented papules of the malar area. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 375
Several histopathologic patterns may be seen in seb-
orrheic keratoses. The most common is the acanthotic
form, which exhibits little papillomatosis and marked
acanthosis with minimal surface keratinization. The
hyperkeratotic form is characterized by prominent
papillomatosis and hyperkeratosis with minimal acan-
thosis. The adenoid form consists of anastomosing tra-
beculae of lesional cells with little hyperkeratosis or
papillomatosis. The lesions of dermatosis papulosa
nigra are predominantly of the adenoid and acanthotic
types.
Chronic trauma may alter these histopathologic fea-
tures, and the lesion known as inverted follicular
keratosis of Helwig is thought to represent an irri-
tated seborrheic keratosis. This lesion shows a mild
degree of proliferation into the connective tissue and a
chronic inﬂammatory cell inﬁltrate adjacent to the
lesion. Squamous metaplasia of the lesional cells
results in whorled epithelial patterns called squamous
eddies. Inﬂamed seborrheic keratosis may show
enough nuclear atypia and mitotic activity to cause
confusion with squamous cell carcinoma, but enough
of the basic attributes of seborrheic keratosis typically
remain to allow a proper diagnosis.
TREATMENT AND PROGNOSIS
Except for aesthetic purposes, a seborrheic keratosis
seldom is removed. Cryotherapy with liquid nitrogen
or simple curettage is the treatment of choice for
lesions that are removed. Although the keratosis has no
malignant potential, other more signiﬁcant skin lesions
may develop in areas contiguous to it. In rare cases,
melanomas may resemble seborrheic keratoses clini-
cally; thus it is important for a dermatologist or other
qualiﬁed clinician to determine whether it is most
appropriate to treat a lesion by cryotherapy or to excise
and submit it for histopathologic conﬁrmation. More-
over, the sudden appearance of numerous seborrheic
keratoses with pruritus has been associated with inter-
nal malignancy, a rare event called the Leser-Trélat
sign.
SEBACEOUS HYPERPLASIA
Sebaceous hyperplasia is characterized by a local-
ized proliferation of sebaceous glands of the skin. It has
no known cause and is common on the facial skin. In
some cases an association with cyclosporine, systemic
corticosteroids, hemodialysis, and Muir-Torre syn-
drome (a rare autosomal dominant disorder character-
ized by visceral malignancies, sebaceous adenomas
and carcinomas, and keratoacanthomas) has been
described. The major signiﬁcance of this entity is its
clinical similarity to more serious facial tumors, such
as basal cell carcinoma.
CLINICAL FEATURES
Cutaneous sebaceous hyperplasia usually affects adults
older than 40 years of age. It occurs most commonly
on the skin of the face, especially the nose, cheeks, and
forehead. Less commonly, lesions may involve the
genital area, chest, and areola. The condition is charac-
terized by one or more soft, nontender papules with
white, yellow, or normal coloration (Fig. 10-30). Lesions
are usually umbilicated, with a small central depres-
sion, representing the area where the ducts of the
involved sebaceous lobules terminate. Most lesions are
smaller than 5 mm in greatest diameter and take con-
siderable time to reach even this small size.
Fig. 10-28 Seborrheic keratosis. The acanthotic form
demonstrates considerable acanthosis, surface hyperkeratosis,
and numerous pseudocysts. The epidermal proliferation
extends upward, above the normal epidermal surface.
Fig. 10-29 Seborrheic keratosis. Pseudocysts are actually
keratin-ﬁlled invaginations, as seen toward the left in this
high-power photomicrograph. The surrounding epithelial cells
are basaloid in appearance. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

376 ORAL AND MAXILLOFACIAL PATHOLOGY
Compression of the lesion usually causes sebum, the
thick yellow-white product of the sebaceous gland, to
be expressed in the central depressed area. This feature
helps clinically to distinguish sebaceous hyperplasia
from basal cell carcinoma. An oral counterpart, which
probably has no relation to the skin lesion, appears as
a white to yellow papule or nodular mass with a “cau-
liﬂower” appearance, usually of the buccal mucosa.
HISTOPATHOLOGIC FEATURES
Histopathologically, sebaceous hyperplasia is charac-
terized by a collection of enlarged but otherwise nor-
mal sebaceous gland lobules grouped around one or
more centrally located sebaceous ducts (Fig. 10-31).
TREATMENT AND PROGNOSIS
No treatment is necessary for sebaceous hyperplasia
except for aesthetic reasons or unless basal cell
carcinoma cannot be eliminated from the clinical dif-
ferential diagnosis of cutaneous lesions. Excisional
biopsy is curative. Cryosurgery, electrodessication,
laser therapy, and photodynamic therapy are alterna-
tive methods for removal.
EPHELIS (FRECKLE)
An ephelis is a common small hyperpigmented ma-
cule of the skin that represents a region of increased
melanin production. Ephelides are seen most often on
the face, arms, and back of fair-skinned, blue-eyed, red-
or light-blond haired persons; they may be associated
with a strong genetic predilection (autosomal domi-
nant). Recent studies have demonstrated a strong
relationship between certain variants of the MC1R
(melanocortin-1-receptor) gene and the development
of ephelides. The skin discoloration is produced by a
relative excess of melanin deposition in the epidermis,
not by a local increase in the number of melanocytes.
CLINICAL FEATURES
Ephelides become noticeable during the ﬁrst decade
of life, and new macules seldom arise after the teenage
years. During adult life the macules typically become
less prominent. There is no sex predilection; however,
persons with blond or red hair are more likely to have
ephelides. The lesions become more pronounced after
sun exposure and are associated closely with a history
of painful sunburns in childhood.
Each individual macule is round or oval, and typi-
cally remains less than 3 mm in diameter (Fig. 10-32).
It has a uniform light-brown coloration and is sharply
demarcated from the surrounding skin. There is great
variability in the numbers of ephelides present. Many
individuals have less than 10, whereas some have hun-
dreds of macules. The brown color is not as dark as the
lentigo simplex (see page 378), and there is never ele-
Fig. 10-30 Sebaceous hyperplasia. Multiple soft papules of
the midface are umbilicated and small. Sebum can often be
expressed from the central depressed area.
Fig. 10-31 Sebaceous hyperplasia. Sebaceous glands are
enlarged and more numerous than normal, but they
demonstrate no other pathologic changes.
Fig. 10-32 Ephelides. Multiple brown macules over the
bridge of the nose. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 377
vation above the surface of the skin, as may occur in a
melanocytic nevus (see page 382).
HISTOPATHOLOGIC FEATURES
The ephelis is composed of stratiﬁed squamous epithe-
lium with abundant melanin deposition in the basal
cell layer. Despite the increased melanin, the number
of melanocytes is normal or may be somewhat reduced.
In contrast to lentigo simplex, there is no elongation of
rete ridges.
TREATMENT AND PROGNOSIS
No treatment is necessary for ephelides. The use of
sunscreens can prevent the appearance of new freckles
and help prevent the darkening of existing lesions.
ACTINIC LENTIGO (LENTIGO SOLARIS;
SOLAR LENTIGO; AGE SPOT; LIVER
SPOT; SENILE LENTIGO)
Actinic lentigo is a benign brown macule that results
from chronic ultraviolet (UV) light damage to the skin.
It is found in more than 90% of whites older than 70
years of age and rarely is seen before age 40. It does
not occur within the mouth but is seen frequently on
the facial skin. Persons who have facial ephelides
(freckles) in childhood are more likely to develop
actinic lentigines later in life. In a recent study of
actinic lentigines in older whites, patients with multi-
ple facial lesions typically were dark-skinned individu-
als who repeatedly received intermittent, intense sun
exposure during their lifetime and whose facial lesions
were preceded by the development of multiple actinic
lentigines on the upper back.
CLINICAL FEATURES
Actinic lentigo is common on the dorsa of the hands, on
the face, and on the arms of older whites (Figs. 10-33
and 10-34). It is typically multiple, but individual lesions
appear as uniformly pigmented brown to tan macules
with well-demarcated but irregular borders. Although
the lesion may reach more than 1 cm in diameter, most
examples are smaller than 5 mm. Adjacent lesions may
coalesce, and new ones continuously arise with age.
Unlike ephelides, no change in color intensity is seen
after exposure to UV light.
HISTOPATHOLOGIC FEATURES
Rete ridges are elongated and club shaped in actinic
lentigines, with thinning of the epithelium above the
connective tissue papillae (Fig. 10-35). The ridges
sometimes seem to coalesce with one another. Within
each rete ridge, melanin-laden basilar cells are inter-
mingled with excessive numbers of heavily pigmented
melanocytes.
TREATMENT AND PROGNOSIS
No treatment is required for actinic lentigo, except for
aesthetic reasons. Lesions may be treated by cryother-
apy, although hypopigmentation is a potential side
effect. Laser therapy or intense pulsed light also can be
effective. In addition, there is a wide range of topical
therapies currently available, including hydroquinone,
tretinoin, tazarotene, adapalene, and, more recently, a
stable ﬁxed combination of mequinol and tretinoin.
Generally, sunscreens are recommended as preventive
treatment and for maintenance of treatment success.
Actinic lentigo does not undergo malignant transfor-
Fig. 10-33 Actinic lentigines. Multiple lesions on the sun-
exposed skin of the hand of an older adult. Lesions are brown
macules with irregular borders.
Fig. 10-34 Actinic lentigo. Large, ﬂat, evenly pigmented
lesion on the forehead of an older adult man. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

378 ORAL AND MAXILLOFACIAL PATHOLOGY
mation; if removed, then it rarely recurs. New lesions,
however, can arise in adjacent or distant skin at any
time.
LENTIGO SIMPLEX
Lentigo simplex is one of several forms of benign
cutaneous melanocytic hyperplasia of unknown cause.
It usually occurs on skin that is not exposed to sunlight,
but it may occur on any skin surface and at any age. Its
color intensity does not change with variations in sun
exposure. Lentigo simplex is darker in color than the
common ephelis (see page 376). Ephelides, moreover,
are found predominantly on sun-exposed skin, become
more pronounced with increased sun exposure, and
represent merely an increase in local melanin produc-
tion rather than an increase in the number of produc-
tive melanocytes.
Some investigators believe that lentigo simplex rep-
resents the earliest stage of another common skin lesion,
the melanocytic nevus (see page 382). Oral lesions have
been reported, but they are rare and may be examples
of the oral melanotic macule (see page 379).
CLINICAL FEATURES
Lentigo simplex usually occurs in children but may
occur at any age. The typical lesion is a sharply demar-
cated macule smaller than 5 mm in diameter, with a
uniformly tan to dark-brown color (Fig. 10-36). It is
usually solitary, although some patients may have
several lesions scattered on the skin of the trunk and
extremities. Lentigo simplex reaches its maximum size
in a matter of months and may remain unchanged
indeﬁnitely thereafter.
Clinically, individual lesions of lentigo simplex are
indistinguishable from the nonelevated melanocytic
nevus. With multiple lesions, conditions such as len-
tiginosis profusa, Peutz-Jeghers syndrome (see page
753), and the multiple lentigines or LEOPARD* syn-
drome must be considered as diagnostic possibilities.
HISTOPATHOLOGIC FEATURES
Lentigo simplex shows an increased number of benign
melanocytes within the basal layer of the epidermis,
and these often are clustered at the tips of the rete
ridges. Abundant melanin is distributed among the
melanocytes and basal keratinocytes, as well as within
the papillary dermis in association with melanophages
(melanin incontinence).
TREATMENT AND PROGNOSIS
Lentigo simplex may fade spontaneously after many
years, but most lesions remain constant over time.
Treatment is not required, except for aesthetic reasons.
Conservative surgical excision is curative, and no
malignant transformation potential has been docu-
mented for lesions not removed.
MELASMA (MASK OF PREGNANCY)
Melasma is an acquired, symmetrical hyperpigmenta-
tion of the sun-exposed skin of the face and neck. The
cause is unknown, but it is classically associated with
pregnancy. Exposure to exogenous estrogen and pro-
gesterone in the form of either oral contraceptives
Fig. 10-35 Actinic lentigo. Rete ridges are elongated and
occasionally intertwining. Pigmented melanocytes (with clear
cytoplasm) are excessive and commingled with melanin-
laden basilar cells.
Fig. 10-36 Lentigo simplex. A sharply demarcated lesion
of uniform brown coloration is seen on the midface.
*Lentigines (multiple), electrocardiographic abnormalities, ocular hyper-
telorism, pulmonary stenosis, abnormalities of genitalia, retardation of
growth, and deafness (sensorineural). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 379
or hormone replacement therapy also may cause
melasma. Dark-complexioned persons—particularly
Asian and Hispanic women—are more likely to develop
this condition.
CLINICAL FEATURES
Melasma appears in adult women as bilateral light- to
dark-brown cutaneous macules that vary in size from
a few millimeters to more than 2 cm in diameter (Fig.
10-37). Lesions develop slowly with sun exposure and
occur primarily on the midface, forehead, upper lip,
chin, and (rarely) the arms. It is not unusual for the
entire face to be involved. The pigmentation may
remain faint or darken over time. Rarely, melasma is
seen in men.
HISTOPATHOLOGIC FEATURES
Melasma is characterized by increased melanin depo-
sition within an otherwise unremarkable epidermis.
Pigment also may be seen within numerous melano-
phages in the dermis.
TREATMENT AND PROGNOSIS
Melasma is difﬁcult to treat. First-line therapy typically
consists of triple-combination topical therapy, such as
Tri-Luma cream (a combination of 4% hydroquinone,
0.05% tretinoin, and 0.01% ﬂuocinolone acetonide).
Dual-ingredient topical agents (e.g., hydroquinone
combined with glycolic acid or kojic acid) or single
topical agents (e.g., 4% hydroquinone, 0.1% retinoic
acid, or 20% azelaic acid) are alternatives for patients
who are sensitive to triple-combination therapy.
Options for second-line therapy include glycolic acid
chemical peel, laser therapy, and dermabrasion,
although variable results have been reported with
these alternative therapies. Because sun exposure is an
important etiologic factor, sun avoidance and the use
of sunscreens containing zinc oxide or titanium dio-
xide are crucial for effective clinical management. The
lesions may resolve after parturition or after discon-
tinuing oral contraceptives. There is no potential for
malignant transformation.
ORAL MELANOTIC MACULE (FOCAL
MELANOSIS)
The oral melanotic macule is a ﬂat, brown, mucosal
discoloration produced by a focal increase in melanin
deposition and possibly a concomitant increase in the
number of melanocytes. The cause remains unclear.
Unlike the cutaneous ephelis (freckle), the melanotic
macule is not dependent on sun exposure. Some
authorities have questioned the purported lack of an
association with actinic irradiation for the melanotic
macule located on the vermilion border and prefer to
consider it a distinct entity (labial melanotic macule).
In one recent study of more than 773 solitary oral
melanocytic lesions submitted to an oral pathology
laboratory for histopathologic examination, oral and
labial melanotic macules were the most common and
comprised 86% of cases; oral and labial melanotic
macules were encountered much more frequently
than oral melanocytic nevi, melanoacanthomas, and
melanomas.
CLINICAL FEATURES
The oral melanotic macule occurs at any age in both
men and women; however, biopsy samples demon-
strate a 2:1 female predilection. The average age of
patients is 43 years at the time of diagnosis. The ver-
milion zone of the lower lip is the most common site
of occurrence (33%), followed by the buccal mucosa,
gingiva, and palate. Rare examples have been reported
on the tongue in newborns.
The typical lesion appears as a solitary (17% are mul-
tiple), well-demarcated, uniformly tan to dark-brown,
asymptomatic, round or oval macule with a diameter
of 7 mm or smaller (Figs. 10-38 and 10-39). Occa-
sional lesions may be blue or black. Lesions are not
reported to enlarge after diagnosis, which suggests that
the maximum dimension is achieved rather rapidly
and remains constant thereafter.
HISTOPATHOLOGIC FEATURES
The oral melanotic macule is characterized by an
increase in melanin (and perhaps melanocytes) in the
basal and parabasal layers of an otherwise normal
Fig. 10-37 Melasma. Diffuse hyperpigmentation of the
facial skin in a pregnant woman. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

380 ORAL AND MAXILLOFACIAL PATHOLOGY
stratiﬁed squamous epithelium (Fig. 10-40). Melanin
also may be seen free or within melanophages in the
subepithelial connective tissue (melanin inconti-
nence). The lesion typically does not show elongated
rete ridges like actinic lentigo (see page 377).
TREATMENT AND PROGNOSIS
Treatment is usually not required for the melanotic
macule, except for aesthetic considerations. When
necessary, excisional biopsy is the preferred treatment.
Electrocautery, laser ablation, or cryosurgery is effec-
tive, but no tissue remains for histopathologic examina-
tion after these procedures. The intraoral melanotic
macule has no malignant transformation potential, but
an early melanoma can have a similar clinical appear-
ance. For this reason, all oral pigmented macules
of recent onset, large size, irregular pigmentation,
unknown duration, or recent enlargement should be
submitted for microscopic examination.
On occasion, ﬂat pigmented lesions are encountered
that are clinically and microscopically similar to the
melanotic macule; however, these lesions represent a
sign of systemic or genetic disease or may be a conse-
quence of the use of certain medications. A list of these
conditions is shown in Box 10-1.
ORAL MELANOACANTHOMA
(MELANOACANTHOSIS)
Oral melanoacanthoma is a benign, relatively un-
common acquired pigmentation of the oral mucosa
characterized by dendritic melanocytes dispersed
throughout the epithelium. The lesion appears to be a
reactive process; in some cases an association with
trauma has been reported. Oral melanoacanthoma
appears to be unrelated to the melanoacanthoma of
skin, which most authorities believe represents a
variant of seborrheic keratosis.
CLINICAL FEATURES
Oral melanoacanthoma is seen almost exclusively in
blacks, shows a female predilection, and is most
common during the third and fourth decades of life.
Fig. 10-38 Oral melanotic macule. A single small,
uniformly pigmented brown macule on the lower lip
vermilion.
Fig. 10-39 Oral melanotic macule. A well-demarcated
brown macule of the gingival mucosa.
Fig. 10-40 Oral melanotic macule. A, Low-power view
showing increased melanin pigmentation distributed along
basal epithelial layer. B, High-power view showing granular
brown melanin pigment in the basilar cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 381
The buccal mucosa is the most common site of occur-
rence. The lips, palate, gingiva, and alveolar mucosa
also may be involved. Most patients exhibit solitary
lesions, although bilateral or multifocal involvement is
possible as well. Oral melanoacanthomas typically are
asymptomatic; however, pain, burning, and pruritus
have been reported in a few unusual cases. The lesion
is smooth, ﬂat or slightly raised, and dark-brown to
black in color (Fig. 10-41). Lesions often demonstrate
a rapid increase in size, and they occasionally reach a
diameter of several centimeters within a period of a
few weeks.
HISTOPATHOLOGIC FEATURES
The oral melanoacanthoma is characterized by
numerous benign dendritic melanocytes (cells that are
normally conﬁned to the basal cell layer) scattered
Fig. 10-41 Oral melanoacanthoma. A, Smooth, darkly
pigmented macule of the buccal mucosa in a young adult.
B, Appearance of the lesion 2 months later showing dramatic
enlargement. C, Resolution of the lesion 3 months after
incisional biopsy. (From Park SK, Neville BW: AAOMP case challenge:
rapidly enlarging pigmented lesion of the buccal mucosa, J Contemp Dent
Pract 3:69-73, 2002.)
Box 10-1
Associations with Melanin Pigmentation
of Oral Mucosa
PHYSIOLOGIC OR SYNDROMIC ASSOCIATIONS
●Racial or physiologic pigmentation
● Peutz-Jeghers syndrome
● McCune-Albright syndrome
●LEOPARD syndrome (lentiginosis profusa, no intra-
oral melanosis)
● Laugier-Hunziker syndrome
● Cronkhite-Canada syndrome
● Bloom syndrome
● Dunnigan syndrome
● Dyskeratosis congenita
●Endocrine candidiasis syndrome
● Incontinentia pigmenti
● Oculo-cerebro-cutaneous syndrome
● Rothmund-Thomson syndrome
●Trisomy 14 mosaicism
●Unusual facies, vitiligo, spastic paraplegia syndrome
● Xeroderma pigmentosum
● Addison’s disease
● Neuroﬁbromatosis type I
CHRONIC TRAUMA OR IRRITATION OR
ENVIRONMENTAL POLLUTANT
●Chronic mucosal trauma or irritation (chronic cheek
bite)
●Chronic autoimmune disease (erosive lichen planus,
pemphigoid)
● Smoker’s melanosis
●Yusho (chronic exposure to high levels of polychlori-
nated biphenyls [PCBs])
SYSTEMIC MEDICATIONS
●Chloroquine and other quinine derivatives
● Phenolphthalein
● Estrogen
● AIDS-related medications
From Bouquot JE, Nikai H: Lesions of the oral cavity. In Gnepp DR:
Diagnostic surgical pathology of the head and neck, pp 141-238,
Philadelphia, 2001, WB Saunders. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

382 ORAL AND MAXILLOFACIAL PATHOLOGY
throughout the lesional epithelium (Figs. 10-42 and
10-43). Basal layer melanocytes are also present in
increased numbers. Spongiosis and mild acanthosis
are typically noted. In addition, eosinophils and a mild
to moderate chronic inﬂammatory cell inﬁltrate are
usually seen within the underlying connective tissue.
TREATMENT AND PROGNOSIS
Because of the alarming growth rate of oral melanoac-
anthoma, incisional biopsy is usually indicated to rule
out the possibility of melanoma. Once the diagnosis has
been established, no further treatment is necessary. In
several instances, lesions have undergone spontane-
ous resolution after incisional biopsy. Recurrence or
development of additional lesions has been reported
only rarely. There is no potential for malignant
transformation.
ACQUIRED MELANOCYTIC NEVUS
(NEVOCELLULAR NEVUS; MOLE)
The generic term nevus refers to malformations of the
skin (and mucosa) that are congenital or developmen-
tal in nature. Nevi may arise from the surface epithe-
lium or any of a variety of underlying connective tissues.
The most commonly recognized nevus is the acquired
melanocytic nevus, or common mole—so much so
that the simple term nevus is often used synonymously
for these pigmented lesions. However, many other
developmental nevi also are recognized (Box 10-2).
The acquired melanocytic nevus represents a
benign, localized proliferation of cells from the neural
crest, often called nevus cells. Although there is little
debate as to their neural crest origin and their ability
to produce melanin, various authorities are divided on
the issue of whether these cells represent melanocytes
or are merely “ﬁrst cousins” of melanocytes. These
melanocytic cells migrate to the epidermis during
development, and lesions may ﬁrst appear shortly after
birth. The acquired melanocytic nevus is probably the
most common of all human “tumors,” and white adults
have an average of 10 to 40 cutaneous nevi per person.
Intraoral lesions occur but are not common.
CLINICAL FEATURES
Acquired melanocytic nevi begin to develop on the
skin during childhood, and most cutaneous lesions are
present before 35 years of age. They occur in both men
and women, although women usually have a few more
than men. Racial differences are seen. Whites have
more nevi than Asians or blacks. Most lesions are dis-
tributed above the waist, and the head and neck region
is a common site of involvement.
Fig. 10-42 Oral melanoacanthoma. Medium-power
photomicrograph showing acanthosis of the epithelium.
Spongiosis is demonstrated by intercellular spaces between
the keratinocytes.
Fig. 10-43 Oral melanoacanthoma. High-power view
showing numerous dendritic melanocytes extending between
the spinous epithelial cells.
Box 10-2
Types of Developmental Nevi
● Epidermal nevus
● Nevus sebaceus
● Nevus ﬂammeus (see page 543)
●Basal cell nevus (nevoid basal cell carcinoma) (see
page 688)
●White sponge nevus (see page 743) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 383
Acquired melanocytic nevi evolve through several
clinical stages, which tend to correlate with speciﬁc
histopathologic features. The earliest presentation
(known microscopically as a junctional nevus) is that
of a sharply demarcated, brown or black macule, typi-
cally less than 6 mm in diameter. Although this lesional
appearance may persist into adulthood, more often the
nevus cells proliferate over a period of years to produce
a slightly elevated, soft papule with a relatively smooth
surface (compound nevus). The degree of pigmenta-
tion becomes less; most lesions appear brown or tan.
As time passes, the nevus gradually loses its pig-
mentation, the surface may become somewhat
papillomatous, and hairs may be seen growing from
the center (intradermal nevus) (Figs. 10-44 and
10-45). However, the nevus usually remains less than
6 mm in diameter. Ulceration is not a feature unless,
for example, the nevus is situated in an area where a
belt or bra strap traumatizes it easily. Throughout the
adult years, many acquired melanocytic nevi will invo-
lute and disappear; therefore, fewer of these lesions
can be detected in older persons.
Intraoral melanocytic nevi are distinctly uncom-
mon. Most arise on the palate, mucobuccal fold, or
gingiva, although any oral mucosal site may be affected
(Fig. 10-46). Intraoral melanocytic nevi have an evolu-
tion and appearance similar to skin nevi, although
mature lesions typically do not demonstrate a papillary
surface change. More than one in ﬁve intraoral nevi
lack clinical pigmentation (Fig. 10-47). Approximately
two thirds of intraoral examples are found in females;
the average age at diagnosis is 35 years.
HISTOPATHOLOGIC FEATURES
The acquired melanocytic nevus is characterized by a
benign, unencapsulated proliferation of small, ovoid
cells (nevus cells). The lesional cells have small, uniform
Fig. 10-44 Melanocytic (intradermal) nevus. A well-
demarcated, dome-shaped papule is seen at the edge of the
vermilion border of the upper lip.
Fig. 10-45 Melanocytic (intradermal) nevus. Small nodule
on the skin of the lower lip.
Fig. 10-46 Intramucosal melanocytic nevus. Pigmented
lesion of the anterior hard palate. (Courtesy of Dr. Lewis Claman.)
Fig. 10-47 Intramucosal melanocytic nevus. This
intramucosal nevus (arrow) of the mandibular gingiva is
nonpigmented. (Courtesy of Dr. John Lenox.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

384 ORAL AND MAXILLOFACIAL PATHOLOGY
nuclei and a moderate amount of eosinophilic cyto-
plasm, with indistinct cell boundaries. These cells dem-
onstrate a variable capacity to produce melanin, with
the pigment primarily evident in the superﬁcial aspects
of the lesion. Nevus cells typically lack the dendritic
processes that melanocytes possess. A characteristic
microscopic feature is that the superﬁcial nevus cells
tend to be organized into small, round aggregates
(thèques).
Melanocytic nevi are classiﬁed histopathologically
according to their stage of development, which is
reﬂected by the relationship of the nevus cells to the
surface epithelium and underlying connective tissue.
In the early stages, thèques of nevus cells are found
only along the basal cell layer of the epithelium, espe-
cially at the tips of the rete ridges. Because the lesional
cells are found at the junction between the epithelium
and the connective tissue, this stage is known as a junc-
tional nevus (Fig. 10-48). As the nevus cells prolifer-
ate, groups of cells begin to drop off into the underlying
dermis or lamina propria. Because cells are now
present along the junctional area and within the under-
lying connective tissue, the lesion then is called a
compound nevus (Fig. 10-49).
In the later stages, nests of nevus cells are no longer
found within the epithelium but are found only within
the underlying connective tissue. Because of the con-
nective tissue location of the lesional cells, on the skin
this stage is called an intradermal nevus. The intra-
oral counterpart is called an intramucosal nevus (Fig.
10-50). Zones of differentiation often are seen through-
out the lesion. The superﬁcial cells typically appear
larger and epithelioid, with abundant cytoplasm, fre-
quent intracellular melanin, and a tendency to cluster
into thèques. Nevus cells of the middle portion of the
lesion have less cytoplasm, are seldom pigmented, and
appear much like lymphocytes. Deeper nevus cells
appear elongated and spindle shaped, much like
Schwann cells or ﬁbroblasts. Some authorities classify
these variations as type A (epithelioid), type B (lympho-
cyte-like), and type C (spindle shaped) nevus cells.
Most intraoral melanocytic nevi are classiﬁed micro-
scopically as intramucosal nevi. However, this probably
reﬂects the age (average, 35 years) at which most oral
nevi undergo biopsy and diagnosis, because these
lesions would have earlier evolved through junctional
and compound stages.
TREATMENT AND PROGNOSIS
No treatment is indicated for a cutaneous melanocytic
nevus unless it is cosmetically unacceptable, is chroni-
cally irritated by clothing, or shows clinical evidence
of a change in size or color. By midlife, cutaneous
Fig. 10-48 Junctional nevus. Nests of melanocytic nevus
cells along the basal layer of the epithelium.
Fig. 10-49 Compound nevus. High-power view showing
nests of pigmented nevus cells within the epithelium and the
superﬁcial lamina propria.
Fig. 10-50 Intramucosal nevus. Collections of melanocytic
nevus cells within the lamina propria. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 385
melanocytic nevi tend to regress; by age 90, very few
remain. If removal is elected, then conservative surgi-
cal excision is the treatment of choice; recurrence is
unlikely.
At least some skin melanomas arise from long-
standing or irritated nevi of the skin. Overall, the risk
of transformation of a particular acquired melanocytic
nevus to melanoma is approximately 1 in 1 million.
However, because oral melanocytic nevi clinically can
mimic an early melanoma, it is generally advised that
biopsy be performed for all unexplained pigmented
oral lesions, especially because of the extremely poor
prognosis for oral melanoma discovered in its later
stages.
VARIANTS OF MELANOCYTIC NEVUS
CONGENITAL MELANOCYTIC NEVUS
Congenital melanocytic nevus affects approximately
1% of newborns in the United States. This entity is
usually divided into two types: (1) small (<20 cm in
diameter) and (2) large (>20 cm in diameter). Approxi-
mately 15% of congenital nevi are found in the head
and neck area, although intraoral involvement is quite
rare.
CLINICAL FEATURES
The small congenital melanocytic nevus may be similar
in appearance to an acquired melanocytic nevus, but
it is frequently larger in diameter (Figs. 10-51 and
10-52). The large congenital lesion classically appears
as a brown to black plaque, usually with a rough surface
or multiple nodular areas. However, the clinical appear-
ance often changes with time. Early lesions are ﬂat and
light tan, becoming elevated, rougher, and darker with
age. A common feature is the presence of hypertricho-
sis (excess hair) within the lesion, which may become
more prominent with age (giant hairy nevus). A very
large congenital nevus sometimes may be referred to
as bathing trunk nevus or garment nevus, because
it gives the appearance of the patient wearing an article
of clothing.
HISTOPATHOLOGIC FEATURES
The histopathologic appearance of the congenital
melanocytic nevus is similar to that of the acquired
melanocytic nevus, and some small congenital nevi
cannot be distinguished microscopically from the
acquired nevus. Both congenital and acquired types
are composed of nevus cells, which may have a junc-
tional, compound, or intradermal pattern. The con-
genital nevus is usually of the compound or intradermal
type. In contrast to the acquired melanocytic nevus, the
congenital nevus often shows extension of nevus cells
into the deeper levels of the dermis, with “inﬁltration”
of cells between collagen bundles. In addition, con-
genital nevus cells often are seen intermingled with
neurovascular bundles in the reticular dermis and sur-
rounding normal adnexal skin structures (e.g., hair fol-
licles, sebaceous glands). Large congenital melanocytic
nevi may show extension of nevus cells into the subcu-
taneous fat.
TREATMENT AND PROGNOSIS
Many congenital melanocytic nevi are excised for aes-
thetic purposes. In addition, 3% to 15% of large con-
genital nevi may undergo malignant transformation
into melanoma. Therefore, whenever feasible, these
lesions should be removed completely by conservative
surgical excision. Close follow-up is required for lesions
not removed. Patients with multiple large congenital
nevi also are at risk for developing neurocutaneous
Fig. 10-51 Congenital melanocytic nevus. Pigmented
lesion of the skin showing hypertrichosis.
Fig. 10-52 Congenital melanocytic nevus. Deeply
pigmented lesion of the lingual mandibular gingiva in a 3-
year-old child. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

386 ORAL AND MAXILLOFACIAL PATHOLOGY
melanosis, a rare congenital syndrome in which
patients may develop melanotic neoplasms of the
central nervous system (CNS), including meningeal
melanosis or melanoma. Unfortunately, no effective
therapy is currently available for patients with symp-
tomatic neurocutaneous melanosis.
HALO NEVUS
Halo nevus is a melanocytic nevus with a pale hypopig-
mented border or “halo” of the surrounding epithe-
lium, apparently as a result of nevus cell destruction by
the immune system. The halo develops because the
immune cells also attack the melanocytes adjacent to
the nevus. The cause of the immune attack is unknown,
but regression of the nevus usually results. Interest-
ingly, the development of multiple halo nevi has been
seen in patients who have had a recent excision of a
melanoma.
CLINICAL FEATURES
The halo nevus is typically an isolated phenomenon
associated with a preexisting acquired melanocytic
nevus. It is most common on the skin of the trunk
during the second decade of life. The lesion typically
appears as a central pigmented papule or macule, sur-
rounded by a uniform, 2- to 3-mm zone of hypopig-
mentation (Fig. 10-53). Sometimes this peripheral
zone is much wider.
HISTOPATHOLOGIC FEATURES
Histopathologically, the halo nevus differs from the
routine acquired melanocytic nevus only in the
presence of an intense chronic inﬂammatory cell
inﬁltrate, which surrounds and inﬁltrates the nevus
cell population.
TREATMENT AND PROGNOSIS
Usually, treatment is not required for halo nevus
because it eventually will regress entirely. If treatment
is elected, then conservative surgical removal is cura-
tive and recurrence is unlikely.
SPITZ NEVUS (BENIGN JUVENILE
MELANOMA; SPINDLE AND EPITHELIOID
CELL NEVUS)
Spitz nevus is an uncommon type of melanocytic nevus
that shares many histopathologic features with mela-
noma. It was, in fact, ﬁrst described as a juvenile mela-
noma. The distinctly benign biologic behavior of the
lesion was ﬁrst emphasized by Spitz in 1948. The ﬁrst
oral example was not reported until 1990.
CLINICAL FEATURES
The Spitz nevus typically develops on the skin of the
extremities or the face during childhood. It appears as
a solitary, dome-shaped, pink to reddish-brown papule,
usually smaller than 6 mm in greatest diameter. The
young age at presentation and the relatively small size
of the Spitz nevus are useful features to help distin-
guish it from melanoma.
HISTOPATHOLOGIC FEATURES
The Spitz nevus has the overall microscopic architec-
ture of a compound nevus, showing a zonal differentia-
tion from the superﬁcial to deep aspects of the lesion
and good symmetry. Lesional cells are either spindle
shaped or plump (epithelioid), and the two types often
are intermixed. The epithelioid cells may be multinu-
cleated and appear somewhat bizarre, often lacking
cell cohesiveness. Mitotic ﬁgures, all normal in appear-
ance, may be seen in the superﬁcial aspects of the
lesion. Ectatic superﬁcial blood vessels, which probably
impart much of the reddish color of some lesions, are
seen frequently. The nevocellular nature of the lesional
cells is demonstrated by immunohistochemical reac-
tivity for S-100 protein and neuron-speciﬁc enolase.
TREATMENT AND PROGNOSIS
Conservative surgical excision is the treatment of
choice for a Spitz nevus. There is little chance of recur-
rence after the nevus is removed.
BLUE NEVUS (DERMAL MELANOCYTOMA;
JADASSOHN-TIÈCHE NEVUS)
Blue nevus is an uncommon, benign proliferation
of dermal melanocytes, usually deep within subepithe-
lial connective tissue. Two major types of blue nevus
Fig. 10-53 Halo nevus. Elevated brown lesion of the skin
showing surrounding depigmentation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 387
are recognized: (1) the common blue nevus and (2)
the cellular blue nevus. The common blue nevus is
the second most frequent melanocytic nevus encoun-
tered in the mouth. The blue color of this melanin-
producing lesion can be explained by the Tyndall
effect, which relates to the interaction of light
with particles in a colloidal suspension. In the case of
a blue nevus, the melanin particles are deep to the
surface, so that the light reﬂected back has to pass
through the overlying tissue. Colors with long wave-
lengths (reds and yellows) tend to be more readily
absorbed by the tissues; the shorter-wavelength blue
light is more likely to be reﬂected back to the observer’s
eyes.
CLINICAL FEATURES
The common blue nevus may affect any cutaneous or
mucosal site, but it has a predilection for the dorsa of
the hands and feet, the scalp, and the face. Mucosal
lesions may involve the oral mucosa, conjunctiva, and,
rarely, sinonasal mucosa. Oral lesions are found almost
always on the palate. The lesion usually occurs in chil-
dren and young adults, and a female predilection is
seen. It appears as a macular or dome-shaped, blue
or blue-black lesion smaller than 1 cm in diameter
(Fig. 10-54).
The cellular blue nevus is much less common and
usually develops during the second to fourth decades
of life, but it may be congenital. More than 50% of cel-
lular blue nevi arise in the sacrococcygeal or buttock
region, although they may be seen on other cutaneous
or mucosal surfaces. Clinically, this nevus appears as a
slow-growing, blue-black papule or nodule that some-
times attains a size of 2 cm or more. Occasional lesions
remain macular.
HISTOPATHOLOGIC FEATURES
Histopathologically, the common blue nevus consists
of a collection of elongated, slender melanocytes with
branching dendritic extensions and numerous melanin
globules. These cells are located deep within the dermis
or lamina propria (Fig. 10-55) and usually align them-
selves parallel to the surface epithelium. The cellular
blue nevus appears as a well-circumscribed, highly
cellular aggregation of plump, melanin-producing
spindle cells within the dermis or submucosa. More
typical pigmented dendritic spindle cells are seen at
the periphery of the lesional tissue. Occasionally, a blue
nevus is found in conjunction with an overlying mela-
nocytic nevus, in which case the term combined nevus
is used.
TREATMENT AND PROGNOSIS
If clinically indicated, conservative surgical excision is
the treatment of choice for the blue nevus of the skin.
Recurrence is minimal with this treatment. Malignant
Fig. 10-54 Blue nevus. A well-circumscribed, deep-blue
macular lesion is seen on palatal mucosa.
Fig. 10-55 Blue nevus. A, Abundant melanin is seen
within spindle-shaped melanocytes located relatively deep
within the lamina propria and parallel to the surface
epithelium. B, High-power view showing heavily pigmented
spindle-shaped cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

388 ORAL AND MAXILLOFACIAL PATHOLOGY
transformation to melanoma is rare but has been
reported. However, because an oral blue nevus clini-
cally can mimic an early melanoma, it is usually advis-
able to perform a biopsy of intraoral pigmented lesions,
especially because of the extremely poor prognosis for
oral melanoma (see page 433).
LEUKOPLAKIA (LEUKOKERATOSIS;
ERYTHROLEUKOPLAKIA)
Oral leukoplakia (leuko = white; plakia = patch) is
deﬁned by the World Health Organization (WHO) as
“a white patch or plaque that cannot be characterized
clinically or pathologically as any other disease.” The
term is strictly a clinical one and does not imply a spe-
ciﬁc histopathologic tissue alteration.
The deﬁnition of leukoplakia is unusual in that it
makes the diagnosis dependent not so much on deﬁn-
able appearances as on the exclusion of other entities
that appear as oral white plaques. Such lesions as
lichen planus, morsicatio (chronic cheek nibbling),
frictional keratosis, tobacco pouch keratosis, nicotine
stomatitis, leukoedema, and white sponge nevus must
be ruled out before a clinical diagnosis of leukoplakia
can be made. As with most oral white lesions, the clini-
cal color results from a thickened surface keratin layer,
which appears white when wet, or a thickened spinous
layer, which masks the normal vascularity (redness) of
the underlying connective tissue.
Although leukoplakia is not associated with a spe-
ciﬁc histopathologic diagnosis, it is typically considered
to be a precancerous or premalignant lesion. When the
outcome of a large number of leukoplakic lesions is
reviewed, the frequency of transformation into malig-
nancy is greater than the risk associated with normal
or unaltered mucosa. Because there is considerable
misunderstanding of this concept, Box 10-3 provides
deﬁnitions that are used throughout the chapter.
INCIDENCE AND PREVALENCE
Although leukoplakia is considered a premalignant
lesion, the use of the clinical term in no way suggests
that histopathologic features of epithelial dysplasia are
present in all lesions. Dysplastic epithelium or frankly
invasive carcinoma is, in fact, found in only 5% to 25%
of biopsy samples of leukoplakia. The precancerous
nature of leukoplakia has been established, not so
much on the basis of this association or on the fact that
more than one third of oral carcinomas have leukopla-
kia in close proximity, as on the results derived from
clinical investigations that monitored numerous leuko-
plakic lesions for long periods. The latter studies suggest
a malignant transformation potential of 4% (estimated
lifetime risk). Speciﬁc clinical subtypes or phases, men-
tioned later, are associated with potential rates as high
as 47%. These ﬁgures may be artiﬁcially low because
many lesions are surgically removed at the beginning
of follow-up.
Leukoplakia is by far the most common oral precan-
cer, representing 85% of such lesions. Based on pooled,
weighted data from previously reported studies, the
worldwide prevalence of leukoplakia has been esti-
mated to fall within a range of 1.5% to 4.3%. There is a
strong male predilection (70%), except in regional
populations in which women use tobacco products
more than men. A slight decrease in the proportion of
affected males, however, has been noted over the past
half century. The disease is diagnosed more frequently
now than in the past, probably because of an enhanced
awareness on the part of health professionals (rather
than because of a real increase in frequency).
CAUSE
The cause of leukoplakia remains unknown, although
hypotheses abound.
TOBACCO
The habit of tobacco smoking appears most closely
associated with leukoplakia development. More than
80% of patients with leukoplakia are smokers. When
large groups of adults are examined, smokers are much
more likely to have leukoplakia than nonsmokers.
Heavier smokers have greater numbers of lesions and
Box 10-3
Precancer Terminology Used in This Text
●Precancerous lesion (precancer, premalignancy). A
benign, morphologically altered tissue that has a
greater than normal risk of malignant transformation.
●Precancerous condition. A disease or patient habit
that does not necessarily alter the clinical appear-
ance of local tissue but is associated with a greater
than normal risk of precancerous lesion or cancer
development in that tissue.
●Malignant transformation potential. The risk of
cancer being present in a precancerous lesion or
condition, either at initial diagnosis or in the future
(usually expressed in percentages). The potential for
mucosa without precancerous lesions or conditions
is called normal.
●Relative risk. A speciﬁc epidemiologic measure of
the association between exposure to a particular
factor and the risk of acquiring a disease, expressed
as a ratio of the incidence or prevalence of a disease
among those exposed and those not exposed to the
factor. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 389
larger lesions than do light smokers, especially after
many years of tobacco use. In addition, a large propor-
tion of leukoplakias in persons who stop smoking either
disappear or become smaller within the ﬁrst year of
habit cessation.
The smokeless tobacco habit produces a somewhat
different result. It often leads to a clinically distinctive
white oral plaque called tobacco pouch keratosis
(see page 398). This lesion probably is not a true
leukoplakia.
ALCOHOL
Alcohol, which seems to have a strong synergistic effect
with tobacco relative to oral cancer production, has not
been associated with leukoplakia. People who exces-
sively use mouth rinses with an alcohol content greater
than 25% may have grayish buccal mucosal plaques,
but these are not considered true leukoplakia.
SANGUINARIA
Persons who use toothpaste or mouth rinses containing
the herbal extract, sanguinaria, may develop a true
leukoplakia. This type of leukoplakia (sanguinaria-
associated keratosis) is usually located in the maxil-
lary vestibule or on the alveolar mucosa of the maxilla
(Fig. 10-56). More than 80% of individuals with vestib-
ular or maxillary alveolar leukoplakia have a history of
using products that contain sanguinaria, compared
with 3% of the normal population.
The affected epithelium may demonstrate dysplasia
identical to that seen in other leukoplakias, although
the potential for the development of cancer is uncer-
tain. The leukoplakic plaque may not disappear even
after the patient stops using the product; some lesions
have persisted for years afterwards.
ULTRAVIOLET RADIATION
Ultraviolet radiation is accepted as a causative factor
for leukoplakia of the lower lip vermilion. This is usually
associated with actinic cheilosis (see page 405). Immu-
nocompromised persons, especially transplant patients,
are especially prone to the development of leuko-
plakia and squamous cell carcinoma of the lower lip
vermilion.
MICROORGANISMS
Several microorganisms have been implicated in the
cause of leukoplakia. Treponema pallidum, for example,
produces glossitis in the late stage of syphilis, with or
without the arsenic therapy in popular use before the
advent of modern antibiotics. The tongue is stiff and
frequently has extensive dorsal leukoplakia.
Tertiary syphilis is rare today, but oral infections
by another microorganism, Candida albicans, are not.
Candida organisms can colonize the superﬁcial epithe-
lial layers of the oral mucosa, often producing a thick,
granular plaque with a mixed white and red coloration
(Fig. 10-57). The terms candidal leukoplakia and
Fig. 10-56 Sanguinaria-associated keratosis. Thin white
plaque on the maxillary alveolar mucosa.
Fig. 10-57 Candidal leukoplakia. A, Well-circumscribed
red and white plaque on the anterior ﬂoor of mouth, which
showed candidal infestation on cytology smears. B, After
antifungal therapy, the erythematous component resolved,
resulting in a homogeneous white plaque. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

390 ORAL AND MAXILLOFACIAL PATHOLOGY
candidal hyperplasia have been used to describe
such a lesion, and biopsy may show dysplastic or
hyperplastic histopathologic changes. It is not known
whether this yeast produces dysplasia or secondarily
infects previously altered epithelium, but some of these
lesions disappear or become less extensive, even less
severely dysplastic, after antifungal therapy. Tobacco
smoking may cause the leukoplakia and also predis-
pose the patient to develop candidiasis.
Human papillomavirus (HPV), in particular sub-
types 16 and 18, has been identiﬁed in some oral leu-
koplakias. These are the same HPV subtypes associated
with uterine cervical carcinoma and a subset of oral
squamous cell carcinomas. Such viruses, unfortunately,
also can be found in normal oral epithelial cells, and
so their presence is perhaps no more than coincidental.
It may be signiﬁcant, however, that HPV-16 has been
shown to induce dysplasia-like changes in normally
differentiating squamous epithelium in an otherwise
sterile in vitro environment.
TRAUMA
Several keratotic lesions, which until recently had been
viewed as variants of leukoplakia, are now considered
not to be precancers. Nicotine stomatitis is a general-
ized white palatal alteration that seems to be a hyper-
keratotic response to the heat generated by tobacco
smoking (usually a pipe), rather than a response to the
carcinogens within the smoke (see page 403). Its malig-
nant transformation potential is so low as to be about
the same as that of normal palatal mucosa.
In addition, chronic mechanical irritation can
produce a white lesion with a roughened keratotic
surface, termed frictional keratosis. Although the
resulting lesion is clinically similar to true leukoplakia,
such a lesion is now thought to be no more than a
normal hyperplastic response (similar to a callus on the
skin). Keratoses of this type are readily reversible after
elimination of the trauma, and obviously traumatic
lesions such as linea alba (see page 285), morsicatio
(see page 286), and toothbrush gingival “abrasion”
have not been documented to have transformed into
malignancy. In addition, the presence of dentures or
broken and missing teeth has not been shown to
increase the cancer risk. Alveolar ridge keratoses (Fig.
10-58)—involving the retromolar pad or crest of an
edentulous alveolar ridge—represent another form of
frictional keratosis caused by masticatory function or
denture trauma. Frictional keratosis should be differ-
entiated from the group of oral precancers.
CLINICAL FEATURES
Leukoplakia usually affects persons older than 40 years
of age. Prevalence increases rapidly with age, espe-
cially for males, and as many as 8% of men older than
70 years of age reportedly are affected (Fig. 10-59).
The average age of affected persons (60 years) is similar
to the average age for patients with oral cancer;
however, in some studies, leukoplakia has been found
to occur about 5 years earlier (on average) than oral
squamous cell carcinoma.
Fig. 10-58 Frictional keratosis. There is a rough,
hyperkeratotic change to the posterior mandibular alveolar
ridge (“alveolar ridge keratosis”), because this area is now
edentulous and becomes traumatized from mastication. Such
frictional keratoses should resolve when the source of
irritation is eliminated and should not be mistaken for true
leukoplakia.
90
80
70
60
50
40
30
20
10
0
15 25 35 45 55 65 75+
Age (in years)
Number of cases per 1000 persons
Males
Females
Fig. 10-59 Leukoplakia. Age-speciﬁc prevalence (number
of new cases per 1000 adults examined at various ages) for
oral leukoplakia demonstrates increasing prevalence with
increasing age, especially for men. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 391
Approximately 70% of oral leukoplakias are found
on the lip vermilion, buccal mucosa, and gingiva.
Lesions on the tongue, lip vermilion, and oral ﬂoor,
however, account for more than 90% of those that show
dysplasia or carcinoma. Individual lesions may have a
varied clinical appearance and tend to change over
time. Early and mild lesions appear as slightly elevated
gray or gray-white plaques, which may appear some-
what translucent, ﬁssured, or wrinkled and are typi-
cally soft and ﬂat (Fig. 10-60). They usually have sharply
demarcated borders but occasionally blend gradually
into normal mucosa.
Mild or thin leukoplakia, which seldom shows dys-
plasia on biopsy, may disappear or continue unchanged.
For tobacco smokers who do not reduce their habit, as
many as two thirds of such lesions slowly extend later-
ally, become thicker, and acquire a distinctly white
appearance. The affected mucosa may become leath-
ery to palpation, and ﬁssures may deepen and become
more numerous. At this stage or phase, the lesion is
often called a homogeneous or thick leukoplakia
(Figs. 10-61 and 10-62). Most thick, smooth lesions
remain indeﬁnitely at this stage. Some, perhaps as
many as one third, regress or disappear; a few become
even more severe, develop increased surface irregu-
larities, and are then called granular or nodular leu-
koplakia (Figs. 10-63 and 10-64). Some lesions
demonstrate sharp or blunt projections and have
been called verrucous or verruciform leukoplakia
(Fig. 10-65).
A special high-risk form of leukoplakia, prolifera-
tive verrucous leukoplakia (PVL), is characterized by
the development of multiple keratotic plaques with
roughened surface projections (Fig. 10-66). The rela-
tionship of PVL to cases described as verrucous leukopla-
kia is uncertain. The multiple PVL plaques tend to
Fig. 10-60 Early or thin leukoplakia. This early lesion of
the ventral tongue is smooth, white, and well demarcated
from the surrounding normal mucosa.
Fig. 10-61 Homogeneous or thick leukoplakia. A diffuse,
corrugated white patch on the right ventral surface of the
tongue and ﬂoor of mouth.
Fig. 10-62 Homogeneous or thick leukoplakia. Extensive
buccal mucosa lesion with an uneven whiteness and ﬁssures.
Moderate epithelial dysplasia was noted on histopathologic
evaluation, and squamous cell carcinoma later developed in
this area.
Fig. 10-63 Granular leukoplakia. Focal leukoplakic lesion
with a rough, granular surface on the posterior lateral border
of the tongue. Biopsy of the lesion revealed an early invasive
squamous cell carcinoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

392 ORAL AND MAXILLOFACIAL PATHOLOGY
slowly spread and involve additional oral mucosal sites.
The gingiva frequently is involved, although other sites
may be affected as well. Although the lesions typically
begin as simple, ﬂat hyperkeratoses that are indistin-
guishable from ordinary leukoplakic lesions, PVL
exhibits persistent growth, eventually becoming exo-
phytic and verrucous in nature. As the lesions progress,
they may go through a stage indistinguishable from
verrucous carcinoma (see page 422), but they later
usually develop dysplastic changes and transform into
full-ﬂedged squamous cell carcinoma (usually within
8 years of initial PVL diagnosis). These lesions rarely
regress despite therapy. PVL is unusual among the leu-
koplakia variants in having a strong female predilec-
tion (1:4 male-to-female ratio) and minimal association
with tobacco use.
Leukoplakia may become dysplastic, even invasive,
with no change in its clinical appearance. However,
some lesions eventually demonstrate scattered patches
of redness, called erythroplakia (see page 397). Such
areas usually represent sites in which epithelial cells
are so immature or atrophic that they can no longer
produce keratin. This intermixed red-and-white lesion,
called erythroleukoplakia or speckled leukoplakia,
represents a pattern of leukoplakia that frequently
reveals advanced dysplasia on biopsy (Fig. 10-67).
Of course, many leukoplakic lesions are a mixture
of the previously mentioned phases or subtypes.
Because it is important to perform a biopsy of the
lesional site with the greatest potential to contain dys-
plastic cells, Figs. 10-68 and 10-69 provide a clinical
and graphic representation of such a lesion. Biopsy
sites should be taken from areas with clinical lesional
appearances that are most similar to those toward the
right in Fig. 10-69.
Fig. 10-64 Granular leukoplakia. Irregular white patch in
the ﬂoor of the mouth of a heavy smoker. Early invasive
squamous cell carcinoma was found on biopsy.
Fig. 10-65 Verruciform leukoplakia. Exophytic papillary
lesion of the anterior maxillary alveolar ridge. Biopsy revealed
a well-differentiated squamous cell carcinoma.
BA
Fig. 10-66 Proliferative verrucous leukoplakia (PVL). A, Large, diffuse, and corrugated
white lesions of the buccal mucosa and tongue. B, Same patient showing the extensive
thickened and ﬁssured alteration of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 393
article, Alexander, Wright, and Thiebaud support this
approach when they state, “Noninvasive screening
techniques such as cytologic testing (including brush
biopsy) and lesion staining with supravital dyes have
many pitfalls and should not be considered as
substitutes for biopsy when there is concern about
malignancy.”
Fig. 10-67 Erythroleukoplakia. Mixed red-and-white lesion
of the lateral border of the tongue. Biopsy revealed
carcinoma in situ.
Fig. 10-68 Leukoplakia. Extensive ventral and lateral
tongue lesion containing multiple areas representing various
possible phases or clinical appearances (compare with Fig.
10-69).
Normal
mucosa
Thin,
smooth
leukoplakia
Thick,
fissured
leukoplakia
Granular,
verruciform
leukoplakia
Erythroleukoplakia
(speckled leukoplakia)
LEGEND
Normal
epithelium
Dysplastic
epithelial
cells
Lymphocytes
Candida
hyphae
Keratin
layer
• Hyperkeratosis
• Acanthosis
• Lymphocytes
(occasional)
• Hyperkeratosis
• Acanthosis
• Lymphocytes
(occasional)
• Dysplasia
(mild/moderate)
• Irregular hyperkeratosis
(verruciform hyperkeratosis)
• Bulbous rete pegs
• Lymphocytes (moderate numbers)
• Moderate/severe dysplasia
• Congested vessels
• Candida hyphae (maybe)
• Irregular hyperkeratosis
• Bulbous and crowded rete pegs (on left)
• Epithelial atrophy (on right)
• Lymphocytes (moderate to numerous)
• Severe dysplasia (on left)
• Carcinoma in situ (on right)
(top-to-bottom dysplasia, keratin?)
• Congested vessels
Erythroplakia
In recent years, attempts have been made to develop
new techniques to aid in the identiﬁcation and diagno-
sis of premalignant and malignant oral lesions.
However, at the present time, careful clinical evalua-
tion with directed conventional biopsy remains the
best and most accurate means of assessing oral
leukoplakic lesions (see Fig. 10-101). In their excellent
Fig. 10-69 Leukoplakia. Composite representation of the various phases or clinical
appearances of oral leukoplakia, with anticipated underlying histopathologic changes. Lesions
have increasing malignant transformation potentials as their appearances approach those
toward the right. (From Bouquot JE, Gnepp DR: Laryngeal precancer—a review of the literature, commentary and
comparison with oral leukoplakia, Head Neck 13:488-497, 1991.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

394 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Microscopically, leukoplakia is characterized by a
thickened keratin layer of the surface epithelium
(hyperkeratosis), with or without a thickened spinous
layer (acanthosis). Some leukoplakias demonstrate
surface hyperkeratosis but show atrophy or thinning
of the underlying epithelium. Frequently, variable
numbers of chronic inﬂammatory cells are noted
within the subjacent connective tissue.
The keratin layer may consist of parakeratin (hyper-
parakeratosis), orthokeratin (hyperorthokeratosis),
or a combination of both (Fig. 10-70). With parakera-
tin, there is no granular cell layer and the epithelial
nuclei are retained in the keratin layer. With ortho-
keratin, the epithelium demonstrates a granular cell
layer and the nuclei are lost in the keratin layer.
Verrucous leukoplakia has papillary or pointed
surface projections, varying keratin thickness, and
broad, blunted rete ridges. It may be difﬁcult to differ-
entiate it from early verrucous carcinoma.
PVL shows a variable microscopic appearance,
depending on the stage of the lesions. Early PVL
appears as a benign hyperkeratosis that is indistin-
guishable from other simple leukoplakic lesions. With
time, the condition progresses to a papillary, exophytic
proliferation that is similar to localized lesions of ver-
rucous leukoplakia (or what is sometimes termed ver-
rucous hyperplasia). In later stages this papillary
proliferation exhibits downgrowth of well-differenti-
ated squamous epithelium with broad, blunt rete
ridges. This epithelium demonstrates invasion into the
underlying lamina propria; at this stage it is indistin-
guishable from verrucous carcinoma. In the ﬁnal stages
the invading epithelium becomes less differentiated,
transforming into a full-ﬂedged squamous cell carci-
noma. Because of the variable clinical and histopatho-
logic appearance of PVL, careful correlation of the
clinical and microscopic ﬁndings is required for
diagnosis.
Most leukoplakic lesions demonstrate no dysplasia
on biopsy. Evidence of epithelial dysplasia is found in
only 5% to 25% of cases if all oral sites are considered.
When present, these dysplastic changes typically begin
in the basilar and parabasilar portions of the epithe-
lium. The more dysplastic the epithelium becomes, the
more the atypical epithelial changes extend to involve
the entire thickness of the epithelium. The histopatho-
logic alterations of dysplastic epithelial cells are similar
to those of squamous cell carcinoma and may include
the following:
●Enlarged nuclei and cells
●Large and prominent nucleoli
●Increased nuclear-to-cytoplasmic ratio
● Hyperchromatic (excessively dark-staining) nu-
clei
● Pleomorphic (abnormally shaped) nuclei and
cells
●Dyskeratosis (premature keratinization of indi-
vidual cells)
●Increased mitotic activity (excessive numbers of
mitoses)
●Abnormal mitotic ﬁgures (tripolar or star-shaped
mitoses or mitotic ﬁgures above the basal layer)
In addition, histomorphologic alterations of dysplas-
tic epithelium are evident at low-power magniﬁcation,
including the following:
●Bulbous or teardrop-shaped rete ridges
●Loss of polarity (lack of progressive maturation
toward the surface)
●Keratin or epithelial pearls (focal, round collec-
tions of concentrically layered keratinized cells)
●Loss of typical epithelial cell cohesiveness
When epithelial dysplasia is present, the pathologist
provides a descriptive adjective relating to its “severity”
or intensity. Mild epithelial dysplasia refers to altera-
tions limited principally to the basal and parabasal
layers (Fig. 10-71). Moderate epithelial dysplasia
demonstrates involvement from the basal layer to the
midportion of the spinous layer (Fig. 10-72). Severe
epithelial dysplasia demonstrates alterations from
the basal layer to a level above the midpoint of the
epithelium (Fig. 10-73). Sometimes dysplasia will be
seen to extend down the duct of a minor salivary
gland, especially in lesions of the ﬂoor of the mouth
(Fig. 10-74).
When the entire thickness of the epithelium is
involved, the term carcinoma in situ is used. Carci-
noma in situ is deﬁned as dysplastic epithelial cells that
extend from the basal layer to the surface of the mucosa
Fig. 10-70 Hyperorthokeratosis. This medium-power
photomicrograph demonstrates hyperorthokeratosis with a
well-deﬁned granular cell layer on the left side. The right side
shows normal parakeratinized epithelium without a granular
cell layer. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 395
(“top-to-bottom” change) (Fig. 10-75). There may or
may not be a thin layer of keratin on the surface. The
epithelium may be hyperplastic or atrophic. Some
authorities consider this entity to be a precancerous
lesion; others believe that it represents a genuine malig-
nancy discovered before invasion. Regardless of the
concept preferred, the important feature of carcinoma
in situ is that no invasion has occurred, despite the fact
that the atypical epithelial cells look exactly like those
of squamous cell carcinoma (see page 419). Without
invasion, the most serious aspect of malignant transfor-
mation, metastasis, cannot occur. In this light, it should
be mentioned that keratin pearl formation is rare in
carcinoma in situ and may indicate the presence of a
focus of invasive squamous cell carcinoma in the adja-
cent tissue.
Sometimes dysplasia will be seen extending down
the ducts of the minor salivary glands, especially in
lesions in the ﬂoor of the mouth. When ductal dyspla-
sia occurs in a precancerous surface dysplasia, the
Fig. 10-71 Mild epithelial dysplasia. Hyperchromatic and
slightly pleomorphic nuclei are noted in the basal and
parabasal cell layers of this stratiﬁed squamous epithelium.
Fig. 10-72 Moderate epithelial dysplasia. Dysplastic
changes extend to the midpoint of the epithelium and are
characterized by nuclear hyperchromatism, pleomorphism,
and cellular crowding.
Fig. 10-73 Severe epithelial dysplasia. Epithelium
exhibiting marked pleomorphism, hyperchromatism, and
scattered mitotic ﬁgures. Atypical cells involve most of the
epithelial thickness.
Fig. 10-74 Ductal dysplasia. Salivary gland duct exhibiting
squamous metaplasia and dysplasia that originated from an
overlying surface epithelial dysplasia.
Fig. 10-75 Carcinoma in situ. Dysplastic changes extend
throughout the entire thickness of the epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

396 ORAL AND MAXILLOFACIAL PATHOLOGY
recurrence rate is increased. The depth of ductal dys-
plasia does not appear to be a signiﬁcant factor.
TREATMENT AND PROGNOSIS
Because leukoplakia represents a clinical term only,
the ﬁrst step in treatment is to arrive at a deﬁnitive
histopathologic diagnosis. Therefore, a biopsy is man-
datory and will guide the course of treatment. Tissue
obtained for biopsy, moreover, should be taken from
the clinically most “severe” areas of involvement
(with features toward the right side of Fig. 10-69).
Multiple biopsies of large or multiple lesions may be
required.
Leukoplakia exhibiting moderate epithelial dyspla-
sia or worse warrants complete destruction or removal,
if feasible. The management of leukoplakia exhibiting
less severe change is guided by the size of the lesion
and the response to more conservative measures, such
as smoking cessation.
Complete removal can be accomplished with equal
effectiveness by surgical excision, electrocautery, cryo-
surgery, or laser ablation. Long-term follow-up after
removal is extremely important because recurrences
are frequent and because additional leukoplakias may
develop. This is especially true for the verruciform or
granular types, 83% of which recur and require addi-
tional removal or destruction. Leukoplakia not exhibit-
ing dysplasia often is not excised, but clinical evaluation
every 6 months is recommended because of the possi-
bility of progression toward epithelial dysplasia. Addi-
tional biopsies are recommended if smoking continues
or if the clinical changes increase in severity.
Overall, 4% of oral leukoplakias become squamous
cell carcinoma after diagnosis, according to follow-up
studies. As previously stated, this ﬁgure, and those
mentioned later, may be artiﬁcially low because so
many monitored cases are treated early in an investiga-
tion. Not to do so, of course, raises certain ethical ques-
tions; hence, more accurate data may never become
available. Other confounding features of leukoplakia
follow-up investigations include variations in diagnos-
tic deﬁnitions and periods of observation. Typically, the
latter extend for 5 to 10 years, but several studies have
observed patients with lesions for more than 20 years—
one study for more than half a century.
With these caveats in mind, follow-up investigations
have demonstrated that carcinomatous transformation
usually occurs 2 to 4 years after the onset of the white
plaque, but it may occur within months or after decades.
Transformation does not appear to depend on the age
of the affected patient.
Although dysplasia may be present in any leukopla-
kia, each clinical appearance or phase of leukoplakia
has a different malignant transformation potential.
Thin leukoplakia seldom becomes malignant without
demonstrating a clinical change. Homogeneous, thick
leukoplakia undergoes malignant transformation in 1%
to 7% of cases. Once the surface becomes granular or
verruciform, the malignant transformation potential
becomes 4% to 15%. Erythroleukoplakia carries an
average transformation potential of 28%, but the
rates have varied from 18% to 47% in different
investigations.
The increased frequency of transformation of the
different phases of leukoplakia is related closely to the
degree of dysplasia present. The greater the clinical
severity, the greater the chance of signiﬁcant dysplasia
and malignant transformation. Estimates of the malig-
nant potential for histopathologically proven dysplastic
lesions are, unfortunately, open to question because so
many are excised completely. Thus their true biologic
behavior in an unaltered state may not be appreciated
fully. With this understanding, however, lesions diag-
nosed as moderate and severe dysplasia reportedly
have malignant transformation potentials of 4% to 11%
and 20% to 35%, respectively. Cancers from dysplastic
lesions usually develop within 3 years of the dysplasia
diagnosis, but they can occur much later. Additionally,
one in three dysplasias will recur after complete
removal.
In addition to the clinical and histopathologic ap-
pearance at diagnosis, several factors may increase the
risk for cancer in leukoplakic lesions. These include
persistence over several years, occurrence in a female
patient, occurrence in a nonsmoker, and occurrence
on the oral ﬂoor or ventral tongue. Leukoplakia of the
latter two locations has shown malignant transforma-
tion in 16% to 39% of all cases and 47% of those occur-
ring in females.
There is much interest in the identiﬁcation of chro-
mosomal, genetic, and molecular alterations that may
aid in predicting the risk of malignant transformation
for oral leukoplakia. Cytogenetic studies have sug-
gested that loss of heterozygosity (LOH) of chromo-
some arms 3p and 9p is associated with increased risk
of malignant transformation, and additional LOH at
4q, 8p, 11q, 13q, and 17p further increases this risk.
Additional alterations such as microsatellite instabil-
ity (insertion or deletion of base pairs in repetitive
stretches of short DNA sequences), increased telomer-
ase activity (important for cellular longevity), and
changes in expression of various molecular markers
(e.g., p53 and other markers of apoptosis, p16 and
other markers of cell cycle regulation, epidermal
growth factor receptor [EGFR], matrix metalloprotein-
ases, vascular endothelial growth factor) have been
found to correlate with histopathologic progression in
oral premalignant lesions. Despite these interesting
observations, many of the previously discussed analy- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 397
ses require fresh tissue or labor-intensive techniques
that are not widely available, which limits their use in
routine clinical practice. Thus histopathologic grading
of dysplasia remains the standard method for predict-
ing the risk of progression to malignancy.
Some smoking-related leukoplakias with no or
minimal dysplasia may disappear or diminish in size
within 3 months after the patient stops smoking. Thus
habit cessation is recommended. Chemoprevention
also may be useful, but it remains primarily experimen-
tal. Isotretinoin (13-cis-retinoic acid, a form of vitamin
A)—alone or in combination with betacarotene—has
been reported to reduce or eliminate some leukoplakic
lesions in short-term studies. Toxic reactions to sys-
temic retinoid agents are frequent, however, as is lesion
recurrence after the conclusion of therapy. Agents such
as bleomycin, lycopene, and cyclooxgenase-2 (COX-2)
inhibitors have been investigated as potential chemo-
preventive agents as well. However, to date there is
insufﬁcient evidence from well-designed clinical trials
to support the effectiveness of such medical therapies
in treating oral dysplasia or preventing the progression
of oral dysplasia to squamous cell carcinoma.
ERYTHROPLAKIA (ERYTHROPLASIA;
ERYTHROPLASIA OF QUEYRAT)
As with leukoplakia, erythroplakia is deﬁned as a red
patch that cannot be clinically or pathologically diag-
nosed as any other condition. Queyrat originally used
the term erythroplasia to describe a precancerous red
lesion that develops on the penis. Oral erythroplakia is
clinically and histopathologically similar to the genital
process. Almost all true erythroplakias demonstrate
signiﬁcant epithelial dysplasia, carcinoma in situ, or
invasive squamous cell carcinoma. The causes of
erythroplakia are unknown, but they are presumed to
be the same as those associated with invasive squa-
mous cell carcinoma of the mouth (see page 409).
The point prevalence rate (number of persons with
active lesions at a given point in time) of oral erythro-
plakia has been estimated as 1 per 2500 adults. The
reported prevalence among several large-scale epide-
miologic surveys—most of which were conducted in
South and Southeast Asia—ranges from 0.02% to 0.83%.
The incidence is not known, but the average annual
incidence for microscopically proven oral carcinoma
in situ, which represents the great majority of erythro-
plakias, has been estimated to be 1.2 per 100,000
population (2.0 in males and 0.5 in females) in the
United States.
Erythroplakia also may occur in conjunction with
leukoplakia (see page 388) and has been found concur-
rently with a large proportion of early invasive oral
carcinomas. Although erythroplakia is less common
than leukoplakia, it has a much greater potential to be
severely dysplastic at the time of biopsy or to develop
invasive malignancy at a later time.
CLINICAL FEATURES
Erythroplakia is predominantly a disease of middle-
aged to older adults with no signiﬁcant gender predi-
lection. In the United States, a peak prevalence of 65
to 74 years has been reported. In India, the peak preva-
lence is in a somewhat younger age range of 45 to 54
years. The ﬂoor of mouth, tongue, and soft palate are
the most common sites of involvement, and multiple
lesions may be present.
The altered mucosa appears as a well-demarcated
erythematous macule or plaque with a soft, velvety
texture (Figs. 10-76 and 10-77). It is usually asymp-
tomatic and may be associated with an adjacent
leukoplakia (erythroleukoplakia) (see Fig. 10-67).
Nonspeciﬁc mucositis, candidiasis, psoriasis, or vascu-
lar lesions may clinically mimic erythroplakia, and
biopsy often is required to distinguish between them.
HISTOPATHOLOGIC FEATURES
According to one large clinicopathologic investigation,
90% of erythroplakic lesions histopathologically repre-
sent severe epithelial dysplasia (see page 394), carci-
noma in situ (see page 394), or superﬁcially invasive
squamous cell carcinoma (see page 419). The epithe-
lium shows a lack of keratin production and often is
atrophic, but it may be hyperplastic. This lack of kera-
tinization, especially when combined with epithelial
thinness, allows the underlying microvasculature to
show through, thereby explaining the red color. The
Fig. 10-76 Erythroplakia. An erythematous macular lesion
is seen on the right ﬂoor of the mouth with no associated
leukoplakia. Biopsy showed early invasive squamous cell
carcinoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

398 ORAL AND MAXILLOFACIAL PATHOLOGY
underlying connective tissue often demonstrates
chronic inﬂammation.
TREATMENT AND PROGNOSIS
Red lesions of the oral mucosa, especially those of the
oral ﬂoor and ventral or lateral tongue, should be
viewed with suspicion, and a biopsy should be per-
formed. If a source of irritation can be identiﬁed and
removed, then biopsy of such a lesion may be delayed
for 2 weeks to allow a clinically similar inﬂammatory
lesion time to regress.
As with leukoplakia, the treatment of erythroplakia
is guided by the deﬁnitive diagnosis obtained by biopsy.
Lesions exhibiting moderate dysplasia or worse must
be removed completely or destroyed by the methods
used for leukoplakia (see page 396). It is best, however,
to preserve most of the specimen for microscopic
examination because of the possibility that a focal inva-
sive carcinoma might be missed in the initial biopsy
material. Recurrence and multifocal oral mucosal
involvement are common with erythroplakia; hence,
long-term follow-up is suggested for treated patients.
SMOKELESS TOBACCO USE
AND SMOKELESS TOBACCO
KERATOSIS (SNUFF POUCH;
SNUFF DIPPER’S LESION;
TOBACCO POUCH KERATOSIS;
SPIT TOBACCO KERATOSIS)
The three main types of smokeless tobacco used in the
United States include chewing tobacco, moist snuff,
and dry snuff. Moist snuff is the most popular, with a
77% increase in sales over the past 15 years, whereas
dry snuff and chewing tobacco have been declining
in popularity. The increase in popularity of moist snuff
may be related in part to the convenience of small,
prepackaged pouches that can be used discreetly.
Chewing tobacco often is used by men in conjunction
with outdoor activities, and dry snuff is used primarily
by women in the southern United States. Smokeless
tobacco use also has been referred to as spit tobacco
use—a term preferred by the U.S. federal government
in its attempt to diminish the appeal of the habit.
As part of its Healthy People 2010 objectives, the
U.S. Department of Health and Human Services has
set a goal to reduce the prevalence of smokeless tobacco
use among U.S. adults from 2.3% to 0.4%. At present,
the proportion of adult men in the United States who
regularly use smokeless tobacco approximates 4.5%.
Among male high school students, the proportion is as
high as 20% to 27% in some Southeastern and Midwest-
ern states. However, over the past few decades, smoke-
less tobacco use has declined, particularly among
young men 18 to 24 years of age. The habit is started
early in life, usually at 8 to 14 years of age, and rarely
is initiated after 20 years of age. A national survey
detected smokeless tobacco lesions of all types in 1.5%
(2.9% in males, 0.1% in females) of U.S. adolescents and
teenagers.
In India, smokeless tobacco may be combined in a
quid with other products, such as betel leaves, areca
nuts, and slaked lime. Oral lesions associated with
betel quid use are described separately (see the discus-
sion of oral submucous ﬁbrosis on page 401).
CLINICAL FEATURES
Several health and addiction hazards may be associ-
ated with the use of smokeless tobacco because of the
ready absorption of nicotine and other molecules
through the oral mucosa. A variety of local oral altera-
tions also are found in chronic users. One of the most
common local changes is a characteristic painless loss
of gingival tissues in the area of tobacco contact (Fig.
10-78). This gingival recession may be accompanied by
destruction of the facial surface of the alveolar bone
and correlates well with the quantity of daily use and
the duration of the smokeless tobacco habit. Although
the association between smokeless tobacco and gingi-
val recession is well known, there is some variability
across studies regarding the association between
smokeless tobacco and periodontal bone loss. Research-
ers have suggested that this variability may be related
to the speciﬁc type of smokeless tobacco used or pos-
sible confounding by concurrent cigarette smoking.
Dental caries also has been reported to be more
prevalent in smokeless tobacco users, perhaps because
of the high sugar content of some brands; other reports
Fig. 10-77 Erythroplakia. Well-circumscribed red patch on
the posterior lateral hard and soft palate. (From Neville BW, Chi
AC, Jeter M: Diagnostic challenge: a red lesion on the palate, J Am Dent
Assoc 137:1537-1538, 2006.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 399
dispute caries susceptibility. Long-term use may lead
to localized or generalized wear of occlusal and incisal
surfaces, especially in those using the product in dusty
environments. A brown-black extrinsic tobacco stain is
typically found on the enamel and cementum surfaces
of the teeth adjacent to the tobacco. In addition, hali-
tosis is a frequent ﬁnding in chronic users.
A characteristic white plaque, the smokeless
tobacco keratosis, also is produced on the mucosa in
direct contact with snuff or chewing tobacco. In
Western cultures, it affects 15% of chewing tobacco
users and 60% of snuff users, if mild examples are
included. The development of this lesion is most
strongly inﬂuenced by habit duration and also by the
brand of tobacco used, early onset of smokeless tobacco
use, total hours of daily use, amount of tobacco con-
sumed daily, and number of sites routinely used for
tobacco placement. Smokeless tobacco keratosis in
many Western cultures is usually noted in young adult
men and in men older than 65 years of age, because
the habit has not been popular among the generation
that is now middle-aged. In some populations, the
prevalence of smokeless tobacco keratosis (and the
smokeless tobacco habit) is most frequent among older
women. Individual lesions begin to develop shortly
after heavy tobacco use begins, and new lesions seldom
arise in persons with a long history of use. The lesion
is conﬁned to areas in direct contact with spit tobacco.
It is typically a thin, gray or gray-white, almost “trans-
lucent,” plaque with a border that blends gradually into
the surrounding mucosa (Fig. 10-79). Sometimes mild
peripheral erythema is present.
The altered mucosa typically has a soft velvety feel to
palpation, and stretching of the mucosa often reveals a
distinct “pouch” (snuff pouch, tobacco pouch) caused
by ﬂaccidity in the chronically stretched tissues in the
area of tobacco placement. Because the tobacco is not
in the mouth during a clinical examination, the usually
stretched mucosa appears ﬁssured or rippled, in a
fashion resembling the sand on a beach after an ebbing
tide. Similar alterations can occur when other bulky
materials are held chronically in the vestibule (e.g., hard
candy, sunﬂower seeds, beef jerky). Induration, ulcer-
ation, and pain are not associated with this lesion.
Smokeless tobacco keratosis usually takes 1 to 5
years to develop. Once it occurs, however, the keratosis
typically remains unchanged indeﬁnitely unless the
daily tobacco contact time is altered. In some cases the
white lesion gradually becomes thickened to the point
of appearing leathery or nodular (Fig. 10-80).
HISTOPATHOLOGIC FEATURES
The histopathologic appearance of smokeless tobacco
keratosis is not speciﬁc. The squamous epithelium is
hyperkeratinized and acanthotic, with or without intra-
cellular vacuolization or “edema” of glycogen-rich
superﬁcial cells. Parakeratin chevrons may be seen as
pointed projections above or within superﬁcial epithe-
lial layers (Fig. 10-81). Increased subepithelial vascu-
larity and vessel engorgement often are seen. In some
cases an unusual deposition of amorphous eosinophilic
material is noted within the subjacent connective tissue
and salivary glands (Fig. 10-82). Epithelial dysplasia is
uncommon in smokeless tobacco keratosis and, when
present, is typically mild. Occasionally, however, sig-
niﬁcant dysplasia or squamous cell carcinoma may be
present.
TREATMENT AND PROGNOSIS
Chronic use of smokeless tobacco in the United States
is considered to be carcinogenic, although the risk is
less than that associated with cigarette smoking and
Fig. 10-78 Smokeless tobacco–related gingival recession.
Extensive recession of the anterior mandibular facial gingiva.
Fig. 10-79 Tobacco pouch keratosis, mild. A soft, ﬁssured,
gray-white lesion of the lower labial mucosa located in the
area of chronic snuff placement. The gingival melanosis is
racial pigmentation and not associated with the keratosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

400 ORAL AND MAXILLOFACIAL PATHOLOGY
alcohol abuse. Fortunately, the clinical appearance of
smokeless tobacco keratosis is distinct enough and the
malignant transformation potential is low enough so
that biopsy is needed for only the more severe lesions
(i.e., those demonstrating an intense whiteness, a gran-
ular or verruciform clinical appearance, ulceration,
mass formation, induration, or hemorrhage). Obvi-
ously, treatment would then depend on the histopatho-
logic diagnosis. Without microscopic evidence of
dysplasia or malignancy, keratoses are not treated.
Alternating the tobacco-chewing sites between the left
and right sides will eliminate or reduce the keratotic
lesion but may result in epithelial alteration or gingival
and periodontal difﬁculties in two sites rather than
one.
Squamous cell carcinoma (see page 410) related to
smokeless tobacco use typically develops after a long
latency period of several decades. In a recent review of
case control studies performed in the United States
and Western Europe, the reported relative risk of
developing oral cancer from chronic smokeless tobacco
use ranged from less than 2 to 26, with lower risk
associated with chewing tobacco and moist snuff and
higher risk associated with dry snuff. Recent studies
from Sweden, however, have failed to show an
increased risk for users of Swedish moist snuff (also
known as snus). Many of the early reports of malignant
Fig. 10-80 Tobacco pouch keratosis, severe. A somewhat
leathery, white, ﬁssured plaque of the posterior mandibular
vestibule, which is located in the area of chronic chewing
tobacco placement.
Fig. 10-81 Tobacco pouch keratosis. Epithelium exhibiting
acanthosis, hyperparakeratosis, and “chevron” formation.
Fig. 10-82 Tobacco pouch keratosis. A, Low-power view
showing mild hyperkeratosis and acanthosis. Note linear
deposition of amorphous, eosinophilic material in the lamina
propria above the minor salivary glands. B, Higher-power
view of the amorphous material. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 401
transformation of snuff-related lesions described
lesions among female dry snuff users in the southern
United States. Only recently have epidemiologic studies
tried to separate the various types of smokeless tobacco
with respect to their carcinogenic potential. Squamous
cell carcinoma is the most common malignancy result-
ing from this habit, but an uncommon low-grade oral
malignancy, verrucous carcinoma (“snuff dipper’s”
cancer), also may be associated with smokeless tobacco
use (see page 422).
Signiﬁcantly, habit cessation leads to a normal
mucosal appearance (usually within 2 weeks) in 98%
of smokeless tobacco keratosis lesions that are not
intensely white (Fig. 10-83). A lesion that remains after
6 weeks without smokeless tobacco contact should be
considered to be a true leukoplakia and should be
sampled for biopsy and managed accordingly.
ORAL SUBMUCOUS FIBROSIS
Oral submucous ﬁbrosis is a chronic, progressive,
scarring, high-risk precancerous condition of the oral
mucosa seen primarily in the Indian subcontinent,
Southeast Asia, Taiwan, southern China, and Papua
New Guinea. It has been linked to the chronic place-
ment in the mouth of a betel quid or paan and is found
in 0.4% of India’s villagers. The quid consists typically of
a nut from the areca palm tree and slaked lime, usually
with tobacco and sometimes with sweeteners and con-
diments, wrapped in a betel leaf. The slaked lime acts
to release alkaloids (arecoline, arecaidine, guvacine,
and guvacoline) from the areca nut, producing a feeling
of euphoria and well-being in the user. Villagers habitu-
ally chew betel quids from an early age, frequently
for 16 to 24 hours daily. Commercial freeze-dried
betel quid substitutes (such as pan masala, gutkha, and
mawa), conveniently packaged in portable sachets, have
become increasingly popular because they have a long
shelf life and do not require preparation before use.
These products contain a higher concentration of areca
nut and appear to cause oral submucous ﬁbrosis more
rapidly than conventionally prepared betel quid.
The condition is characterized by a mucosal rigidity
of varied intensity caused by a ﬁbroelastic hyperplasia
and modiﬁcation of the superﬁcial connective tissue.
The submucosal changes may be a response to the
areca nut, whereas the epithelial alterations and carci-
nogenesis may be the result of tobacco contact.
However, several studies suggest that even betel quid
without tobacco may be carcinogenic, albeit probably
less so than when combined with tobacco. Nutritional
deﬁciency increases the risk and severity of ﬁbrosis,
and some persons seem to have a genetic predisposi-
tion to it. A few individuals have developed the disease
after only a few contacts with areca nut.
The underlying pathogenetic mechanism for oral
submucous ﬁbrosis is hypothesized to involve the role
of the areca nut in disrupting the homeostatic equilib-
rium between synthesis and degradation of the extra-
cellular matrix. Cytokines and growth factors produced
by activated inﬂammatory cells may promote ﬁbrosis
by inducing proliferation of ﬁbroblasts, upregulating
collagen synthesis, and downregulating collagenase
production. In addition, considerable amounts of
copper have been found in areca nut products; copper
may upregulate collagen production by increasing the
A B
Fig. 10-83 Tobacco pouch keratosis. A, Moderately severe lesion of the lower anterior
vestibule and lip in a 15-year-old male subject, which demonstrates a gray-white surface
change and ﬁssuring. The patient had been placing snuff in the area for several years. B, Two
weeks after cessation of the tobacco habit, the mucosa has returned to an almost normal
appearance. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

402 ORAL AND MAXILLOFACIAL PATHOLOGY
activity of the enzyme lysyl oxidase involved in colla-
gen synthesis and cross-linking.
CLINICAL FEATURES
Oral submucous ﬁbrosis often is ﬁrst noted in young
adult betel quid users, whose chief complaint is an
inability to open the mouth (trismus), often accompa-
nied by mucosal pain while eating spicy foods. An
interincisal distance of less than 20 mm is considered
severe; in advanced cases, the jaws may actually be
inseparable. Females are more susceptible to these
changes than males.
Vesicles, petechiae, melanosis, xerostomia, and a
generalized oral burning sensation (stomatopyrosis)
are usually the ﬁrst signs and symptoms. The buccal
mucosa, retromolar area, and soft palate are the most
commonly affected sites. The mucosa in these regions
develops a blotchy, marblelike pallor and a progressive
stiffness of subepithelial tissues (Fig. 10-84). When the
tongue is involved, it becomes rather immobile, is fre-
quently diminished in size, and may be devoid of papil-
lae. Submucosal ﬁbrous bands are palpable on the
buccal mucosa, soft palate, and labial mucosa of fully
developed cases. Involvement may extend beyond the
oral cavity to involve the oropharynx and upper esoph-
agus. Leukoplakia of the surface mucosa often is
noted.
Betel quid chewers also may exhibit a brown-red
discoloration of the mucosa with an irregular surface
that tends to desquamate. This particular change,
known as betel chewer’s mucosa, is not believed to
be precancerous. In addition, some authors have
reported betel quid lichenoid lesions, characterized
by white, parallel, wavy striae resembling oral lichen
planus (see page 782).
HISTOPATHOLOGIC FEATURES
Oral submucous ﬁbrosis is characterized by the sub-
mucosal deposition of dense and hypovascular collag-
enous connective tissue with variable numbers of
chronic inﬂammatory cells (Fig. 10-85). Epithelial
changes include subepithelial vesicles in early lesions
and hyperkeratosis with marked epithelial atrophy in
older lesions. Epithelial dysplasia is found in 10% to
15% of cases submitted for biopsy, and carcinoma is
found in at least 6% of sampled cases.
The lesions of so-called betel chewer’s mucosa are
histopathologically similar to morsicatio buccarum
(see page 286), except that the ragged keratinaceous
surface is covered by encrustations of betel quid
ingredients.
TREATMENT AND PROGNOSIS
Unlike tobacco pouch keratosis, oral submucous ﬁbro-
sis does not regress with habit cessation. Patients with
mild cases may be treated with intralesional corticoste-
roids to reduce the symptoms; surgical splitting or exci-
sion of the ﬁbrous bands may improve mouth opening
and mobility in the later stages of the disease. One
study showed that intralesional injections of inter-
feron-γ improved maximum mouth opening, reduced
mucosal burning, and increased suppleness of the
buccal tissues. Additional agents that have been inves-
tigated for the treatment of oral submucous ﬁbrosis
include lycopene (alone or in combination with intra-
lesional steroid injections) and pentoxifylline.
Frequent evaluation for development of oral squa-
mous cell carcinoma is essential because a 17-year
malignant transformation rate of 8% has been deter-
mined for betel quid users in India. Overall, persons
Fig. 10-84 Oral submucous ﬁbrosis. Pallor and ﬁbrosis of
the soft palate in a betel quid chewer. The uvula has retained
its normal color.
Fig. 10-85 Oral submucous ﬁbrosis. Mucosal biopsy
exhibiting hyperparakeratosis, basilar hyperplasia, and ﬁbrosis
in the lamina propria. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 403
with oral submucous ﬁbrosis are at least 19 times more
likely to develop oral cancer than persons without the
disease.
NICOTINE STOMATITIS (NICOTINE
PALATINUS; SMOKER’S PALATE)
Once a common mucosal change of the hard palate,
nicotine stomatitis has become less common as cigar
and pipe smoking have lost popularity. Although this
lesion is a white keratotic change obviously associated
with tobacco smoking, it does not appear to have a
premalignant nature, perhaps because it develops in
response to heat rather than the chemicals in tobacco
smoke. Because pipe smoking generates more heat on
the palate than other forms of smoking, nicotine stoma-
titis has been associated most often with this habit.
Similar changes can also be produced by the long-term
use of extremely hot beverages.
In some South American and Southeast Asian cul-
tures, hand-rolled cigarettes and cigars are smoked
with the lit end held within the mouth. This “reverse
smoking” habit produces a pronounced palatal kerato-
sis, or reverse smoker’s palate, which has a signiﬁ-
cant potential to develop dysplasia or carcinoma.
CLINICAL FEATURES
Nicotine stomatitis most commonly is found in men
older than 45 years of age. With long-term exposure to
heat, the palatal mucosa becomes diffusely gray or
white; numerous slightly elevated papules are noted,
usually with punctate red centers (Figs. 10-86 and
10-87). Such papules represent inﬂamed minor sali-
vary glands and their ductal oriﬁces. The mucosa that
covers the papules frequently appears whiter than the
surrounding epithelium.
The palatal keratin may become so thickened that a
ﬁssured or “dried mud” appearance is imparted. The
whiteness usually involves marginal gingiva and inter-
dental papillae, and leukoplakia of the buccal mucosa
is occasionally seen. A heavy brown or black tobacco
stain may be present on the teeth.
HISTOPATHOLOGIC FEATURES
Nicotine stomatitis is characterized by hyperkeratosis
and acanthosis of the palatal epithelium and mild,
patchy, chronic inﬂammation of subepithelial connec-
tive tissue and mucous glands (Fig. 10-88). Squamous
metaplasia of the excretory ducts is usually seen, and
an inﬂammatory exudate may be noted within the duct
lumina. In cases with papular elevation, hyperplastic
Fig. 10-86 Nicotine stomatitis. This extensive leathery,
white change of the hard palate in a pipe smoker is sprinkled
throughout with numerous red papules, which represent
inﬂamed salivary duct openings. The gingival mucosa also is
keratotic.
Fig. 10-87 Nicotine stomatitis. Close-up of the inﬂamed
ductal openings of involved salivary glands of the hard palate.
Note the white keratotic ring at the lip of many of the
inﬂamed ducts.
Fig. 10-88 Nicotine stomatitis. There is hyperkeratosis
and acanthosis of the palatal epithelium. Note the squamous
metaplasia of the minor salivary gland ducts. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

404 ORAL AND MAXILLOFACIAL PATHOLOGY
ductal epithelium may be seen near the oriﬁce. The
degree of epithelial hyperplasia and hyperkeratosis
appears to correlate positively with the duration and
the level of heat exposure. Epithelial dysplasia rarely is
seen.
TREATMENT AND PROGNOSIS
Nicotine stomatitis is completely reversible, even when
it has been present for many decades. The palate
returns to normal, usually within 1 to 2 weeks of
smoking cessation. Although this is not a precancerous
lesion and no treatment is needed, the patient never-
theless should be encouraged to stop smoking (and
other high-risk areas should be examined closely). Any
white lesion of the palatal mucosa that persists after 1
month of habit cessation should be considered a true
leukoplakia and managed accordingly (see page 396).
ACTINIC KERATOSIS
(SOLAR KERATOSIS)
Actinic keratosis is a common cutaneous premalig-
nant lesion that is caused by cumulative ultraviolet
(UV) radiation to sun-exposed skin, especially in fair-
skinned people. A similar phenomenon, actinic chei-
losis, is associated with sun damage to the lower lip
vermilion (see page 405). UV light exposure can
produce mutations in the p53 tumor suppressor gene,
an alteration found frequently in this and other precan-
cers and cancers of the head and neck region. Muta-
tions in the telomerase gene represent another early
event in lesion development, resulting in delayed apop-
tosis and immortalization of cells. Although UV light
exposure is the major etiologic factor, additional poten-
tial risk factors include immunosuppression, arsenic
exposure, and certain genetic abnormalities, such as
albinism, Rothmund-Thompson syndrome, Cockayne
syndrome, xeroderma pigmentosum (see page 747),
and Bloom syndrome.
The lesion will develop on the skin of more than 50%
of all white adults with signiﬁcant lifetime sun expo-
sure, and in the U.S. white population the prevalence
rate is 15% for older men and 6% for older women. The
prevalence increases with advancing age. According to
the National Ambulatory Medical Care Survey, more
than 47 million physician ofﬁce visits were conducted
in the United States over a 10-year period for the diag-
nosis of actinic keratosis.
CLINICAL FEATURES
Actinic keratosis seldom is found in persons younger
than 40 years of age. The face and neck, the dorsum of
the hands, the forearms, and the scalp of bald-headed
men are the most common sites of occurrence. Indi-
vidual lesions are irregular scaly plaques, which vary
in color from normal to white, gray, or brown, and may
be superimposed on an erythematous background (Fig.
10-89). The keratotic scale peels off with varying
degrees of difﬁculty. Palpation reveals a “sandpaper,”
roughened texture, and some lesions can be felt more
easily than they can be seen. Typically, a lesion is
smaller than 7 mm in diameter but may reach a size of
2 cm, usually with minimal elevation above the surface
of the skin. Occasional lesions, however, produce so
much keratin that a “horn” may be seen arising from
the central area. Other skin lesions, such as verruca
vulgaris or seborrheic keratosis, also may produce
keratin or cutaneous horns.
HISTOPATHOLOGIC FEATURES
Histopathologically, actinic keratosis is characterized
by hyperparakeratosis and acanthosis (Fig. 10-90).
Teardrop-shaped rete ridges typically extend down
from the epithelium; by deﬁnition, some degree of epi-
thelial dysplasia is present. When full-thickness dyspla-
sia is noted, this is termed bowenoid actinic keratosis.
Suprabasilar acantholysis may be seen, as may melano-
sis and a lichenoid inﬂammatory inﬁltrate. The dermis
exhibits a band of pale basophilic change, which rep-
resents sun-damaged collagen and elastic ﬁbers (solar
elastosis). In this band of sun-damaged connective
tissue, there is a fourfold increase in the amount of
elastic ﬁbers, and band thickness is increased with
increased exposure to actinic rays. Variable numbers
of chronic inﬂammatory cells are typically present.
TREATMENT AND PROGNOSIS
Because of its precancerous nature, it is usually recom-
mended that actinic keratosis be destroyed by liquid
nitrogen cryotherapy, curettage, electrodesiccation, or
Fig. 10-89 Actinic keratosis. A plaque of the skin of the
face with a rough, sandpaper-like surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 405
surgical excision. Alternative treatment methods
include topical agents (including 5-ﬂuorouracil, imiqui-
mod, and diclofenac) and photodynamic therapy.
Recurrence is rare, but additional lesions frequently
arise in adjacent sun-damaged skin. Long-term follow-
up, therefore, is recommended.
Although the exact frequency of malignant transfor-
mation is unknown, it has been estimated that 10% of
actinic keratoses will progress to squamous cell carci-
noma, typically over a period of approximately 2
years.
ACTINIC CHEILOSIS
(ACTINIC CHEILITIS)
Actinic cheilosis is a common premalignant altera-
tion of the lower lip vermilion that results from long-
term or excessive exposure to the ultraviolet component
of sunlight. It is a problem conﬁned predominantly to
light-complexioned people with a tendency to sunburn
easily. Outdoor occupation obviously is associated with
this problem, leading to the popular use of terms such
as farmer’s lip and sailor’s lip. A person with chronic
sunlight exposure and compromised immunity, espe-
cially a transplant recipient, has an elevated risk of
developing a cancer of the lower lip vermilion.
Actinic cheilosis is similar to actinic keratosis of
the skin (see previous topic) in its pathophysiologic and
biologic behavior.
CLINICAL FEATURES
Actinic cheilosis seldom occurs in persons younger
than 45 years of age. It has a strong male predilection,
with a male-to-female ratio as high as 10:1 in some
studies.
The lesion develops so slowly that patients often are
not aware of a change. The earliest clinical changes
include atrophy of the lower lip vermilion border,
characterized by a smooth surface and blotchy pale
areas. Blurring of the margin between the vermilion
zone and the cutaneous portion of the lip is typically
seen (Fig. 10-91). As the lesion progresses, rough, scaly
areas develop on the drier portions of the vermilion.
These areas thicken and may appear as leukoplakic
lesions, especially when they extend near the wet line
of the lip. The patient may report that the scaly material
can be peeled off with some difﬁculty, only to reform
again within a few days.
With further progression, chronic focal ulceration
may develop in one or more sites (Fig. 10-92). Such
ulcerations may last for months and often suggest
progression to early squamous cell carcinoma
(Fig. 10-93).
HISTOPATHOLOGIC FEATURES
Actinic cheilosis is usually characterized by an atrophic
stratiﬁed squamous epithelium, often demonstrating
marked keratin production. Varying degrees of epithe-
Fig. 10-90 Actinic keratosis. A, An extremely excessive
amount of parakeratin is noted on the epidermal surface.
B, High-power view showing hyperchromatism and
pleomorphism of the epidermal cells.
Fig. 10-91 Actinic cheilosis. A blurring of the interface
between the vermilion mucosa and the skin of the lip is
especially noted in this case. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

406 ORAL AND MAXILLOFACIAL PATHOLOGY
lial dysplasia may be encountered. A mild chronic
inﬂammatory cell inﬁltrate commonly is present sub-
jacent to the dysplastic epithelium. The underlying
connective tissue invariably demonstrates a band of
amorphous, acellular, basophilic change known as
solar (actinic) elastosis, an ultraviolet light–induced
alteration of collagen and elastic ﬁbers (Fig. 10-94).
TREATMENT AND PROGNOSIS
Many of the changes associated with actinic cheilosis
are probably irreversible, but patients should be
encouraged to use lip balms with sunscreens to prevent
further damage. Areas of induration, thickening, ulcer-
ation, or leukoplakia should be submitted for biopsy to
rule out carcinoma. In clinically severe cases without
obvious malignant transformation, a lip shave proce-
dure (vermilionectomy) may be performed. The ver-
milion mucosa is removed, and either a portion of the
intraoral labial mucosa is pulled forward or the wound
is allowed to heal by secondary intention. The advan-
tage of this technique is that it provides tissue for his-
topathologic examination should areas of superﬁcially
invasive squamous cell carcinoma be present. Alterna-
tive treatments include CO
2 or erbium:YAG (Er:YAG)
laser ablation, electrodesiccation, topical 5-ﬂuoroura-
cil, topical imiquimod, photodynamic therapy, and
chemoexfoliation (or “chemical peel”) with trichloro-
acetic acid. Long-term follow-up is recommended. Of
course, if a squamous cell carcinoma is identiﬁed, then
the involved lip is treated accordingly.
Squamous cell carcinoma, usually well-differenti-
ated, develops over time in 6% to 10% of actinic cheilo-
sis cases reported from medical centers. Such malignant
transformation seldom occurs before 60 years of age,
with the resulting carcinoma typically enlarging slowly
and metastasizing only at a late stage.
KERATOACANTHOMA
(“SELF-HEALING” CARCINOMA;
PSEUDOCARCINOMA;
KERATOCARCINOMA; SQUAMOUS
CELL CARCINOMA,
KERATOACANTHOMA TYPE)
Keratoacanthoma is a self-limiting, epithelial prolif-
eration with a strong clinical and histopathologic simi-
larity to well-differentiated squamous cell carcinoma.
In fact, some authorities consider it to represent an
extremely well-differentiated form of squamous cell
carcinoma. Cutaneous lesions presumably arise from
the infundibulum of hair follicles. Intraoral lesions
have been reported, but they are rare; in fact, some
authorities do not accept keratoacanthoma as an intra-
oral disease.
Fig. 10-92 Actinic cheilosis. Crusted and ulcerated lesions
of the lower lip vermilion.
Fig. 10-93 Squamous cell carcinoma arising in actinic
cheilosis. Patient with actinic cheilosis of the lower lip, who
developed a small, chronic ulceration. Biopsy revealed early
invasive squamous cell carcinoma.
Fig. 10-94 Actinic cheilosis. Hyperorthokeratosis and
epithelial atrophy. Note the striking underlying solar elastosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 407
The cause of this lesion is unknown, but sun damage
and human papillomavirus (HPV), possibly subtypes
26 or 37, have been proposed. The association with sun
damage is suggested by the fact that most solitary
lesions are found on sun-exposed skin, predominantly
in older adults. Additional potential contributing factors
include tar exposure, immunosuppression, and burns
or other trauma. Keratoacanthoma-like lesions have
been produced in animals by the cutaneous applica-
tion of carcinogens.
There appears to be a hereditary predisposition
for multiple lesions, and the lesions occur with in-
creased frequency in patients with Muir-Torre syn-
drome (sebaceous neoplasms, keratoacanthomas, and
gastrointestinal carcinomas).
A number of studies have examined potential
genetic alterations or immunohistochemical markers
for distinguishing between keratoacanthoma and squa-
mous cell carcinoma. In general, these studies have
shown that squamous cell carcinoma tends to have
different chromosomal abnormalities and a greater
number of genetic aberrations compared with kerato-
acanthoma, suggesting different pathogenetic mecha-
nisms between these two lesions.
CLINICAL FEATURES
Keratoacanthoma rarely occurs in patients before 45
years of age and shows a male predilection. Almost 95%
of solitary lesions are found on sun-exposed skin, and
8% of all cases are found on the outer edge of the ver-
milion border of the lips, with equal frequency on both
the upper and the lower lips.
Keratoacanthoma appears as a ﬁrm, nontender,
well-demarcated, sessile, dome-shaped nodule with a
central plug of keratin (Figs. 10-95 and 10-96), although
lesions reported as intraoral keratoacanthoma usually
have lacked the central plug. The outer portion of the
nodule has a normal texture and color but may be ery-
thematous. The central keratin plug is yellowish, brown,
or black and has an irregular, crusted, often verruci-
form surface.
The evolution of keratoacanthoma can be divided
into three phases: (1) growth phase, (2) stationary
phase, and (3) involution phase. During the growth
phase, rapid enlargement is typical, with the lesion
usually attaining a diameter of 1 to 2 cm within 6
weeks. This critical feature helps to distinguish it from
the more slowly enlarging squamous cell carcinoma.
The lesion stabilizes during the stationary phase, which
usually is of a duration similar to that of the growth
phase. Most lesions regress spontaneously within 6 to
12 months of onset, frequently leaving a depressed
scar in the area (Fig. 10-97). The regression of these
lesions is a curious phenomenon, which some investi-
gators have theorized is related to a cytotoxic immune
response to the tumor.
Occasional patients demonstrate large numbers of
keratoacanthomas. One multiple-lesion variant, the
Ferguson Smith type, manifests in early life and
appears to be hereditary; the lesions are not likely to
involute spontaneously. Another variant manifests as
hundreds of small papules of the skin and upper diges-
tive tract (eruptive Grzybowski type) and may be
associated with internal malignancy.
HISTOPATHOLOGIC FEATURES
Keratoacanthoma of the skin and lip vermilion war-
rants excisional or large incisional biopsy with inclu-
sion of adjacent, clinically normal epithelium for
proper histopathologic interpretation; this is because
the overall pattern of the tumor is diagnostically more
important than the appearance of individual cells. The
Fig. 10-95 Keratoacanthoma. A nontender, well-
demarcated nodule of the skin of the nose in an older
woman. The nodule demonstrates a central keratin plug.
Fig. 10-96 Keratoacanthoma. This lesion, which is located
at the outer edge of the vermilion border of the lip,
demonstrates a prominent core or plug of keratin. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

408 ORAL AND MAXILLOFACIAL PATHOLOGY
cells appear mature, although considerable dyskerato-
sis (abnormal or premature keratin production) is typi-
cally seen in the form of deeply located individually
keratinizing lesional cells and keratin pearls similar
to those found in well-differentiated squamous cell
carcinoma.
The surface epithelium at the lateral edge of the
tumor appears normal; at the lip of the central crater,
however, a characteristic acute angle (or “buttress”) is
formed between the overlying epithelium and the
lesion. The crater is ﬁlled with keratin, and the epithe-
lium at the base of the crater proliferates downward
(Fig. 10-98). This action often elicits a pronounced
chronic inﬂammatory cell response. Downward prolif-
eration does not extend below the level of the sweat
glands in skin lesions or into underlying muscle in ver-
milion lesions. Late-stage lesions show considerably
more keratinization of the deeper aspects of the tumor
than do early lesions.
TREATMENT AND PROGNOSIS
Despite the propensity of keratoacanthoma to involute
of its own accord, surgical excision of large lesions is
indicated for optimal aesthetic appearance because
signiﬁcant scarring may otherwise occur. After exci-
sion, 4% to 8% of treated patients experience recur-
rence. Although surgical excision is the preferred
treatment, alternative therapies include cryosurgery
(reserved for small early lesions), intralesional injec-
tion of chemotherapeutic agents (such as 5-ﬂuoroura-
cil, bleomycin, methotrexate, or interferon α-2a), and
topical imiquimod. Systemic chemotherapy, often
combined with cryotherapy, may be used to treat
patients with multiple lesions of the Ferguson Smith or
eruptive Grzybowski type.
Aggressive behavior and malignant transformation
into carcinoma have been reported in a small propor-
tion of keratoacanthomas—particularly those occurring
in the setting of immunosuppression. However, the
close histopathologic similarities between this lesion
and squamous cell carcinoma sometimes make it dif-
ﬁcult to rule out the possibility of misinterpretation of
the microscopic section.
A
B
C
Fig. 10-97 Keratoacanthoma. A, Appearance on initial
presentation. Note small, central keratin-ﬁlled invagination.
B, Same lesion 1 week later showing slight enlargement.
C, Same lesion showing further growth 3 weeks after initial
presentation. All three photographs were taken at the same
magniﬁcation. (Courtesy of Dr. John Lovas.)
Fig. 10-98 Keratoacanthoma. Low-power microscopic
view showing extensive epidermal proliferation with a central
keratin plug. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 409
SQUAMOUS CELL CARCINOMA
In approximately one of every three Americans now
living, a malignancy will develop at some point. It is
estimated that in 2007, more than 1,444,000 cancer
cases will be diagnosed in the United States, in addition
to more than 1 million nonmelanoma skin cancers.
Although 66% of affected persons now survive their
disease, cancer still causes more than 559,000 deaths
each year in the United States and accounts for more
than 20% of all deaths. In addition, the current annual
death rate from nondermal cancers (186 per 100,000
persons) has increased by 30% since 1930, partially
because of a considerable increase in the incidence of
lung cancer and partially because people are now less
likely to die at an early age of other common disorders,
such as cardiovascular disease and infection. From the
1990s through the present, however, this trend has
reversed, and the average annual incidence and mor-
tality rates for all cancers combined (excluding non-
melanoma skin cancers) have been declining.
Oral cancer accounts for less than 3% of all cancers
in the United States, but it is the eighth most common
cancer in males and the ﬁfteenth most common in
females. It is the eleventh most common cancer world-
wide, with an especially high incidence reported in the
Indian subcontinent, Australia, France, Brazil, and
southern Africa. Approximately 94% of all oral malig-
nancies are squamous cell carcinoma. In the United
States, approximately 22,000 new cases of oral squa-
mous cell carcinoma are diagnosed annually, and slightly
more than 5300 individuals die of this disease each
year. The average annual incidence and mortality rates,
however, vary considerably between different races,
genders, and age groups.
As with so many carcinomas, the risk of intraoral
cancer increases with increasing age, especially for
males. The annual incidence rate (the number of newly
diagnosed cases per 100,000 persons each year) for
this disease is 5 per 100,000 in the United States,
although many texts report an 11 to 15 per 100,000
rate because of the inadvertent inclusion of pharyngeal
and vermilion cancers with the intraoral cases. In the
United States, white men have a higher risk of intraoral
cancer after 65 years of age than does any other group.
However, the highest annual incidence rate in middle
age is seen in American men of African ancestry (Fig.
10-99). Although the annual incidence rate for intra-
oral cancer in black males has been decreasing slowly
since the middle to late 1980s, marked disparities in
survival and mortality rates between black and white
males persist. Females, whether white or nonwhite,
have a much lower annual incidence rate than males
at all age levels. The overall male-to-female ratio is
3:1.
Carcinoma of the lip vermilion is somewhat differ-
ent from intraoral carcinoma. It has a pathophysiology
more akin to squamous cell carcinoma of the sun-
exposed skin. The average annual incidence rate for
white males in the United States is 4 per 100,000, but
the rate increases dramatically with age, to almost 30
per 100,000 for men older than 75 years of age. Once
the most common oral cancer, the cumulative lifetime
risk for developing lip cancer today is only 0.15% for
men and 0.07% for women. There was a considerable
decrease in the annual incidence rate of this cancer in
white males in the United States during the latter half
of the twentieth century, because fewer and fewer of
them held outdoor occupations. Few women or non-
white men develop lip carcinoma; there has been little
change in the incidence over time for these groups.
Outside the United States, exceptionally wide differ-
ences in annual incidence and mortality rates for oral
carcinoma are found. These rates vary by as much as
twentyfold among different countries. Many of these
differences are undoubtedly caused by differing popu-
lation habits, life expectancies, preventive education,
and the quality of medical records in various countries.
Despite the difﬁculties involved in interpreting such
data, however, the data have been helpful in identify-
ing potential causative factors.
ETIOLOGY OF ORAL CANCER
The cause of oral squamous cell carcinoma is multifac-
torial. No single causative agent or factor (carcinogen)
has been clearly deﬁned or accepted, but both extrinsic
and intrinsic factors may be at work. It is likely that
more than a single factor is needed to produce such a
malignancy (cocarcinogenesis). Extrinsic factors include
80
70
60
50
40
30
20
10
0
15 25 35 45 55 65 75 85
Age (in years)
Number of cases per 100,000 persons
Black males
White males
Black females
White females
Fig. 10-99 Oral carcinoma. Age-speciﬁc incidence rates
for intraoral squamous cell carcinoma (number of new cases
diagnosed per 100,000 persons each year). Separate rates
are provided for white and black men and women in the
United States. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

410 ORAL AND MAXILLOFACIAL PATHOLOGY
such external agents as tobacco smoke, alcohol, syphi-
lis, and (for vermilion cancers only) sunlight. Intrinsic
factors include systemic or generalized states, such as
general malnutrition or iron-deﬁciency anemia. Hered-
ity does not appear to play a major causative role in
oral carcinoma. Many oral squamous cell carcinomas
have been documented to be associated with or pre-
ceded by a precancerous lesion, especially leukopla-
kia (Table 10-1).
TOBACCO SMOKING
Tobacco smoking reached its greatest popularity in the
United States during the 1940s, when at least 65% of
white men smoked and other population subgroups
were beginning to smoke in large numbers. Today less
than 21% of U.S. adults, men and women alike, smoke
cigarettes. Unfortunately, the remaining smokers
appear to be the heavier users; therefore, the effects on
the mouth may be even greater than the typical effects
noted in the past.
Much indirect clinical evidence implicates the habit
of tobacco smoking in the development of oral squa-
mous cell carcinoma. The proportion of smokers (80%)
among patients with oral carcinoma is two to three
times greater than the general population. The risk for
a second primary carcinoma of the upper aerodigestive
tract is two to six times greater for treated patients with
oral cancer who continue to smoke than for those who
quit after diagnosis.
In addition, case control studies have shown that
pipe and cigar smoking carries a greater oral cancer risk
than does cigarette smoking, and that the relative risk
(smoker’s risk for oral cancer compared with that of a
nonsmoker) is dose dependent for cigarette smokers.
It is at least ﬁve for persons who smoke 40 cigarettes
daily, but increases to as much as 17 for persons who
smoke 80 or more cigarettes daily. The risk, further-
more, increases the longer the person smokes.
The greatest risk of all probably is found in certain
isolated Indian and South American cultures in which
the practice of reverse smoking is popular, especially
among women. In reverse smoking, the burning end of
a handmade cigar or cigarette is held inside the mouth.
This habit considerably elevates one’s risk for oral
cancer. Where reverse smoking is practiced, as many
as 50% of all oral malignancies are found on the hard
palate, a site usually spared by this disease.
It should be mentioned that there may be distinct
differences between head and neck cancers that
develop in smokers compared with those that develop
in nonsmokers, although these differences do not
appear to affect survival. Tumors in nonsmokers
contain a lower frequency of common genetic altera-
tions and have certain clinical differences. For example,
affected nonsmokers are more likely to be female, to
have oral (especially tongue) rather than pharyngeal or
laryngeal disease, to be very young, and to demonstrate
mutations of the p53 and other tumor suppressor
genes.
SMOKELESS TOBACCO
Smokeless tobacco use in Western cultures may in-
crease a chronic user’s risk for oral carcinoma by a
factor ranging from less than two to as high as 26. This
variation in relative risk reported by different epide-
miologic case control studies may be inﬂuenced by
Table 10-1 Precancerous Lesions of the Oral, Pharyngeal, and Laryngeal Mucosa
(Clinical Terms Only)
Disease Name Malignant Transformation Potential
Proliferative verrucous leukoplakia (PVL)* ★★★★★★
Nicotine palatinus in reverse smokers
†
★★★★★
Erythroplakia ★★★★★
Oral submucous ﬁbrosis ★★★★★
Erythroleukoplakia ★★★★
Granular leukoplakia ★★★★
Laryngeal keratosis ★★★
Actinic cheilosis ★★★
Smooth, thick leukoplakia ★★
Smooth, red tongue of Plummer-Vinson syndrome ★★
Smokeless tobacco keratosis ★
Lichen planus (erosive forms)
‡
★?
Smooth, thin leukoplakia +/−
From Speight PM, Farthing PM, Bouquot JE: The pathology of oral cancer and precancer, Curr Diag Pathol 3:165-176, 1997.
*PVL: High-risk, high-recurrence form of oral leukoplakia affecting multiple sites.
†Reverse smoking: smoking with the lit end of the cigarette in one’s mouth.
‡Precancer character is controversial. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 411
the type of smokeless tobacco used, with some studies
suggesting a lower risk associated with wet snuff and
chewing tobacco and a higher risk associated with dry
snuff. This apparent increased risk is supported by
clinicopathologic investigations that have found an
abnormal male-to-female sex ratio for oral carcinoma
(>1.0:1.5) in geographic areas where the habit is more
popular among women than among men. These geo-
graphic areas are typically in the southern United States,
where women use dry snuff. In addition, approximately
50% of all oral cancers in smokeless tobacco users occur
at the site where the tobacco is habitually placed.
BETEL QUID (PAAN)
The betel quid or paan is a compound of natural sub-
stances (i.e., areca palm nuts, betel leaf, slaked lime,
perhaps tobacco leaf) chewed for their psychostimulat-
ing effects. Among betel quid users in Asia, the lifetime
risk of developing oral cancer is a remarkable 8%. This
habit is also associated with signiﬁcant development of
precancers, such as leukoplakia. More than 600 million
persons worldwide chew these quids on a regular
basis.
ALCOHOL
Excessive alcohol consumption has been implicated
in oral cancer development. It is uncertain whether
alcohol alone can initiate carcinogenesis, although it is
well established that alcohol in combination with
tobacco is a signiﬁcant risk factor for oral cancer
development.
Case control studies have concluded that the risk is
dose dependent and time dependent, and the combi-
nation of alcohol and tobacco abuse over long periods
may increase a person’s risk for oral cancer by a factor
of 15 or more (relative risk is 15). In this light, it may
be signiﬁcant that the lowest annual oral cancer inci-
dence rate in the United States is found in Utah, where
75% of the population follows Mormon doctrines that
forbid the use of tobacco and alcohol.
Indirect evidence for alcohol’s role in oral cancer
production includes the fact that approximately one
third of male patients with oral cancer are heavy
alcohol users; less than 10% of the general population
can be classiﬁed as such. Cirrhosis of the liver, likewise,
is found in at least 20% of male patients with oral
cancer. Nutritional deﬁciencies associated with heavy
alcohol consumption also may contribute to an
increased risk of oral cancer development.
PHENOLIC AGENTS
Recent evidence has pointed to an increased oral
cancer risk for workers in the wood products industry
chronically exposed to certain chemicals, such as phe-
noxyacetic acids. Moreover, it has long been known
that these workers are at increased risk for nasal and
nasopharyngeal carcinoma.
RADIATION
The effects of ultraviolet (UV) radiation on the lips
are discussed elsewhere (actinic cheilosis, see page
405), but it is well known that another form of radia-
tion, x-irradiation, decreases immune reactivity and
produces abnormalities in chromosomal material. It
should not seem surprising, then, that radiotherapy to
the head and neck area increases the risk of the later
development of a new primary oral malignancy, either
a carcinoma or a sarcoma. This effect is dose depen-
dent, but even low-dose radiotherapy for benign enti-
ties may increase the local risk to some extent. However,
the small amount of radiation from routine diagnostic
dental radiographs has not been associated with oral
mucosal carcinomas.
IRON DEFICIENCY
Iron deﬁciency, especially the severe, chronic form
known as the Plummer-Vinson or Paterson-Kelly
syndrome (see page 828), is associated with an
elevated risk for squamous cell carcinoma of the
esophagus, oropharynx, and posterior mouth. Malig-
nancies develop at an earlier age than in patients
without iron deﬁciency anemia. People who are deﬁ-
cient in iron tend to have impaired cell-mediated
immunity, and iron is essential to the normal function-
ing of epithelial cells of the upper digestive tract. In
deﬁciency states, these epithelial cells turn over more
rapidly and produce an atrophic or immature mucosa.
Intertwining ﬁbrous bands of scar tissue also may
develop within the esophagus of severely affected
patients (esophageal webs). Patients with such esoph-
ageal webbing seem to be especially susceptible to
malignant transformation.
VITAMIN-A DEFICIENCY
Vitamin-A deﬁciency produces excessive keratiniza-
tion of the skin and mucous membranes, and research-
ers have suggested that the vitamin may play a
protective or preventive role in oral precancer and
cancer. Some believe that blood levels of retinol and
the amount of dietary betacarotene ingested are
inversely proportional to the risk of oral squamous cell
carcinoma and leukoplakia. Long-term therapy with
retinoic acids and betacarotene also has been associ-
ated with a regression of at least some leukoplakic
lesions and a concomitant reduction in the severity of
dysplasia within such lesions.
SYPHILIS
Syphilis (tertiary stage) has long been accepted as
having a strong association with the development of `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

412 ORAL AND MAXILLOFACIAL PATHOLOGY
dorsal tongue carcinoma. The relative risk ratio approx-
imates four. Conversely, a person with a lingual carci-
noma is ﬁve times more likely to have a positive serology
test for syphilis than someone without such a cancer.
The arsenical agents and heavy metals that were used
to treat syphilis before the advent of modern antibiotic
therapy have carcinogenic properties themselves and
may have been responsible for some of the earlier
cancer development in this disease. Regardless of the
pathophysiologic mechanism at work, however, syphi-
lis-associated oral malignancies are rare today because
the infection is typically diagnosed and treated before
the onset of the tertiary stage.
CANDIDAL INFECTION
Hyperplastic candidiasis (see page 217) frequently is
cited as an oral precancerous condition. Because this
lesion appears as a white plaque that cannot be rubbed
off, it also has been called candidal leukoplakia. Unfortu-
nately, it is difﬁcult both clinically and histopathologi-
cally to distinguish between a true hyperplastic
candidiasis and a preexisting leukoplakia with super-
imposed candidiasis. Experimentally, some strains of
Candida albicans have produced hyperkeratotic lesions
of the dorsal rat tongue without any other contributing
factor. In other studies, certain strains have been shown
to produce nitrosamines, chemicals that have been
implicated in carcinogenesis. Some candidal strains
may have the potential to promote the development of
oral cancer; to date, however, the evidence to suggest
this role is largely circumstantial.
ONCOGENIC VIRUSES
Oncogenic (tumor producing) viruses may play a major
role in a wide variety of cancers, although no virus has
deﬁnitively been proven to cause oral cancer so far.
Viral agents capable of integration into the host’s
genetic material may be particularly dangerous and
potentially could commandeer the host’s ability to reg-
ulate normal growth and proliferation of the infected
cell. The oncogenic viruses may immortalize the host
cell, thereby facilitating malignant transformation. In
the past, retroviruses, adenoviruses, herpes simplex
viruses (HSVs), and human papillomaviruses (HPVs)
all have been suggested as playing a role in the devel-
opment of oral carcinoma. It appears, however, that
HPV is the only one still implicated, not only in oral
cancer but also in carcinoma of the pharyngeal tonsil,
larynx, esophagus, uterine cervix, vulva, and penis.
HPV subtypes 16, 18, 31, and 33 are the strains most
closely associated with dysplasia and squamous cell
carcinoma. The underlying mechanisms by which
HPV is believed to contribute to oral carcinogenesis
primarily involve two virally encoded proteins: (1) E6
(which promotes degradation of the p53 tumor sup-
pressor gene product) and (2) E7 (which promotes
degradation of the pRb [retinoblastoma protein] tumor
suppressor gene product).
HSV, especially type 2, once was thought to produce
a large proportion of cancers of the uterine cervix, and
it has been suggested as a causative factor in oral carci-
noma. Evidence now suggests that it may be no more
than a common companion infection in persons with
HPV infections, and that the latter virus plays a much
more important carcinogenic role than does HSV. Cur-
rently, the evidence gathered to prove a causal relation-
ship between HSV and oral carcinoma is insufﬁcient.
IMMUNOSUPPRESSION
Immunosuppression may play a role in the develop-
ment of at least some malignancies of the upper
aerodigestive tract. Without effective immunologic
surveillance and attack, it is thought that newly created
malignant cells cannot be recognized and destroyed at
an early stage. Persons with AIDS and those who are
undergoing immunosuppressive therapy for malig-
nancy or organ transplantation are at increased risk for
oral squamous cell carcinoma and other head and
neck malignancies, especially when tobacco smoking
and alcohol abuse are present.
ONCOGENES AND TUMOR
SUPPRESSOR GENES
Oncogenes and tumor suppressor genes are chromo-
somal components capable of being acted on by a
variety of causative agents. Normal genes, or proto-
oncogenes, are transformed into activated oncogenes
in certain malignancies through the actions of viruses,
irradiation, or chemical carcinogens. Once oncogenes
are activated, they may stimulate the production of an
excessive amount of new genetic material through
ampliﬁcation or overexpression of the involved gene.
Oncogenes probably are involved in the initiation and
progression of a wide variety of neoplasms, including
oral squamous cell carcinoma.
Tumor suppressor genes, on the other hand, allow
tumor production indirectly when they become inacti-
vated or mutated. Genetic aberrations commonly iden-
tiﬁed in oral squamous cell carcinomas include
abnormalities of the ras, myc, and EGFR (epidermal
growth factor receptor; also known as c-erbB1) onco-
genes, and the p53, pRb, p16, and E-cadherin tumor
suppressor genes. Most authorities feel that an accu-
mulation of several of these various genetic aberrations
is necessary before the affected cell expresses a malig-
nant phenotype.
CLINICAL AND RADIOGRAPHIC
FEATURES
Persons with oral squamous cell carcinoma are
most often older men who have been aware of an
alteration in an oral cancer site for 4 to 8 months `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 413
before seeking professional help (8 to 24 months
among lower socioeconomic groups). There is mini-
mal pain during the early growth phase, and this
may explain the delay in seeking professional care.
If the health care professional does not have a
high index of suspicion, then an additional several
weeks or months may elapse before a biopsy is
performed.
Oral squamous cell carcinoma has a varied clinical
presentation, including the following:
● Exophytic (mass forming; fungating, papillary,
verruciform)
●Endophytic (invasive, burrowing, ulcerated)
●Leukoplakic (white patch) (Fig. 10-100)
●Erythroplakic (red patch)
●Erythroleukoplakic (combined red-and-white
patch) (Fig. 10-101)
The leukoplakic and erythroplakic examples are prob-
ably early cases that have not yet produced a mass or
ulceration, and the clinical features are identical to
those described for premalignant leukoplakia and
erythroplakia (see pages 388 and 397). These mucosal
surface changes typically are destroyed by the develop-
ing exophytic or endophytic carcinoma, but many cases
are diagnosed before their complete destruction and
show residual precancerous lesions involving adjacent
mucosa.
An exophytic lesion typically has a surface that is
irregular, fungating, papillary, or verruciform, and its
color may vary from normal to red to white, depending
on the amount of keratin and vascularity (Figs. 10-102
and 10-103). The surface is often ulcerated, and
the tumor feels hard (indurated) on palpation
(Fig. 10-104).
Fig. 10-100 Squamous cell carcinoma. Leukoplakic lesion
on the right ventrolateral surface of the tongue.
Fig. 10-101 Squamous cell carcinoma. Speckled
erythroplakia of the left posterior buccal mucosa. Brush
sampling had been reported to be negative for epithelial
abnormality, but incisional biopsy revealed invasive
squamous cell carcinoma. (From Chi AC, Ravenel MC: AAOMP case
challenge: a “speckled” lesion, J Contemp Dent Pract 6:168-172, 2005.)
Fig. 10-102 Squamous cell carcinoma. An exophytic
lesion of the posterior lateral tongue demonstrates surface
nodularity and minimal surface keratin production. It is
painless and indurated.
Fig. 10-103 Squamous cell carcinoma. An exophytic
buccal lesion shows a roughened and irregular surface with
areas of erythema admixed with small areas of white
keratosis. Surface ulceration is evident. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

414 ORAL AND MAXILLOFACIAL PATHOLOGY
The endophytic growth pattern has a depressed,
irregularly shaped, ulcerated, central area with a sur-
rounding “rolled” border of normal, red or white
mucosa (Fig. 10-105). The rolled border results from
invasion of the tumor downward and laterally under
adjacent epithelium. This appearance is not unique to
oral carcinoma because granulomatous lesions, such
as deep fungal infections, tuberculosis, tertiary syphi-
lis, oral lesions of Wegener’s granulomatosis or
Crohn’s disease, and chronic traumatic ulcers, may
look similar.
Destruction of underlying bone, when present, may
be painful or completely painless, and it appears on
radiographs as a “moth-eaten” radiolucency with ill-
deﬁned or ragged margins (an appearance similar to
osteomyelitis) (Fig. 10-106). Carcinoma also can extend
for many centimeters along a nerve (perineural inva-
sion) without breaking away to form a true
metastasis.
LIP VERMILION CARCINOMA
Carcinoma of the lip vermilion is typically found in
light-skinned persons with either long-term exposure
to UV radiation from sunlight or a history of acute sun
damage (sunburn) early in life. Seventy percent of
affected individuals have outdoor occupations. It is
usually associated with actinic cheilosis (see page
405) and may arise at the site where the patient holds
a cigarette, cigar, or pipe stem. Almost 90% of lesions
are located on the lower lip.
The typical vermilion carcinoma is a crusted, oozing,
nontender, indurated ulceration that is usually less
than 1 cm in greatest diameter when discovered (Figs.
10-107 and 10-108). The tumor is characterized by a
slow growth rate, and most patients have been aware
Fig. 10-104 Squamous cell carcinoma. Chronic ulcerated
lesion on the right ventral surface of the tongue. The rolled
anterior margin felt indurated on palpation.
Fig. 10-105 Squamous cell carcinoma. An ulcerated or
endophytic lesion of the hard palate demonstrates rolled
borders and a necrotic ulcer bed. This cancer was painless,
although it had partially destroyed underlying palatal bone.
Fig. 10-106 Squamous cell carcinoma. Bone involvement
is characterized by an irregular, “moth-eaten” radiolucency
with ragged margins—an appearance similar to that of
osteomyelitis.
Fig. 10-107 Squamous cell carcinoma. Small, crusted
ulcer of the lower lip vermilion. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 415
of a “problem” in the area for 12 to 16 months before
a formal diagnosis is made. Metastasis is a late event;
at diagnosis, fewer than 2% of patients have metastati-
cally involved lymph nodes, usually in the submental
region. Perineural invasion may result in extension of
the tumor into the mandible through the mental
foramen. Although this tumor is typically diagnosed
and treated at an early stage, patient neglect can result
in considerable destruction of normal tissue (Fig.
10-109).
INTRAORAL CARCINOMA
The most common site for intraoral carcinoma is the
tongue, usually the posterior lateral and ventral sur-
faces. The oral ﬂoor is affected almost as frequently in
men but is involved much less commonly in women.
Other sites of involvement (in descending order of fre-
quency) are the soft palate, gingiva, buccal mucosa,
labial mucosa, and hard palate.
Carcinoma of the tongue accounts for more than
50% of intraoral cancers in population studies in the
United States (Figs. 10-110 and 10-111). Two thirds of
lingual carcinomas appear as painless, indurated
masses or ulcers of the posterior lateral border; 20%
occur on anterior lateral or ventral surfaces, and only
4% occur on the dorsum. The tongue especially is the
site of involvement in young patients and, in fact, is the
site of the only congenital oral squamous cell carci-
noma reported.
Carcinoma of the oral ﬂoor represents 35% of all
intraoral cancers in epidemiologic surveys and appears
to be increasing in frequency among females. It occurs
a decade earlier in women than in men but is still
usually a disease of older adults. Of all intraoral carci-
nomas, ﬂoor of mouth lesions are the most likely to
Fig. 10-108 Squamous cell carcinoma. Ulcerated mass of
the lower lip vermilion.
Fig. 10-109 Squamous cell carcinoma. Patient neglect
can result in extensive involvement, even in a readily visible
site such as the lip vermilion. This ulcerating lesion of the
lower lip had been present for more than 1 year before
diagnosis.
Fig. 10-110 Squamous cell carcinoma. Ulcerated lesion
with surrounding leukoplakia on the posterior lateral and
ventral tongue.
Fig. 10-111 Squamous cell carcinoma. Ulcerated,
exophytic mass of the posterior lateral border of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

416 ORAL AND MAXILLOFACIAL PATHOLOGY
arise from a preexisting leukoplakia or erythroplakia
(Fig. 10-112). It is also the oral cancer site most often
associated with the development of a second primary
malignancy of another aerodigestive tract location or
of a distant organ. The most common site of involve-
ment is the midline near the frenum.
Gingival and alveolar carcinomas are usually pain-
less and most frequently arise from keratinized mucosa
in a posterior mandibular site. This tumor has a special
propensity to mimic the benign inﬂammatory and
reactive lesions, such as pyogenic granuloma, that are
so common to the gingiva. When the cancer develops
in an edentulous area, it may give rise to a mass that
“wraps around” a denture ﬂange and superﬁcially
resembles inﬂammatory ﬁbrous hyperplasia (epulis ﬁs-
suratum) (Fig. 10-113). Tumors of the maxillary alveo-
lar ridge may extend onto the hard palate (Fig. 10-114).
If the tumor is adjacent to a tooth (Fig. 10-115), then
it may mimic periodontal disease or a pyogenic granu-
loma. Gingival carcinoma often destroys the underly-
ing bone structure, causing tooth mobility. This lesion
may not become clinically evident until after tooth
extraction, when it proliferates out of the socket to
mimic the hyperplastic granulation tissue of epulis
granulomatosa. Of all the intraoral carcinomas, this
one is least associated with tobacco smoking and has
the greatest predilection for females.
OROPHARYNGEAL CARCINOMA
Carcinoma of the soft palate and oropharyngeal mucosa
has the same basic clinical appearance as more ante-
rior carcinomas, except that, in this posterior location,
the patient often is unaware of its presence and the
diagnosis may be delayed. Tumor size is typically
greater than that of more anterior carcinomas, and the
proportion of cases with cervical and distant metastasis
Fig. 10-112 Squamous cell carcinoma. Granular red and
white lesion in the anterior ﬂoor of mouth.
Fig. 10-113 Squamous cell carcinoma. An exophytic
lesion with an irregular and pebbled surface has a linear
indentation along its facial aspect resulting from pressure
from the patient’s lower denture. Underlying alveolar bone
was extensively destroyed.
Fig. 10-114 Squamous cell carcinoma. Large fungating
tumor of the maxillary alveolar ridge and hard palate.
Fig. 10-115 Squamous cell carcinoma. An innocuous
pebbled-surface change of the attached and marginal gingiva
was interpreted as an inﬂammatory change until multifocal
white keratoses occurred. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 417
at diagnosis is higher (Fig. 10-116). Three of every four
oropharyngeal carcinomas arise from the tonsillar area
or soft palate; most of the others originate on the base
of the tongue. The initial symptoms are usually pain or
difﬁculty in swallowing (dysphagia). The pain may be
dull or sharp and frequently is referred to the ear.
As a general rule, the more posterior or inferior the
oropharyngeal tumor location is, the larger is the lesion
and the greater is the chance for lymphatic spread by
the time of diagnosis. A soft palate lesion may present
as a localized tumor, but 80% of posterior oropharyn-
geal wall lesions have metastasized or extensively
involved surrounding structures by the time of
diagnosis.
METASTASIS
The metastatic spread of oral squamous cell carcinoma
is largely through the lymphatics to the ipsilateral cer-
vical lymph nodes (Fig. 10-117). A cervical lymph
node that contains a metastatic deposit of carcinoma is
usually ﬁrm to stony hard, nontender, and enlarged
(Fig. 10-118). If the malignant cells have perforated
the capsule of the node and invaded into surrounding
tissues, then the node will feel “ﬁxed,” or not easily
movable. Extracapsular spread (extension of metastatic
deposits outside of the lymph node capsule) is a micro-
scopic feature associated with poor prognosis, includ-
ing increased risk of locoregional recurrence, distant
metastasis, and lower survival rates.
Occasionally, contralateral or bilateral metastatic
deposits are seen, and at least 2% of patients have
distant (“below the clavicles”) metastasis at diagnosis;
in some studies this ﬁgure is as high as 22%. The most
common sites of distant metastasis are the lungs, liver,
and bones, but any part of the body may be affected.
Carcinoma of the lower lip and oral ﬂoor tends to
travel to the submental nodes; tumors from the poste-
rior portions of the mouth travel to the superior jugular
and digastric nodes. Lymphatic drainage from the oro-
pharynx leads to the jugulodigastric chain of lymph
nodes or to the retropharyngeal nodes, and metastatic
deposits from oropharyngeal carcinoma are usually
found there.
Metastasis is not an early event for carcinomas of the
oral cavity proper. However, because of delay in the
diagnosis, approximately 21% of patients have cervical
metastases at diagnosis (60% in reports from tertiary
care medical centers). In contrast, tumors that arise
more posteriorly in the oropharynx are prone to early
metastasis. More than 50% of all affected persons in
Fig. 10-116 Squamous cell carcinoma. Large, ulcerated
lesion of the right lateral soft palate.
Fig. 10-117 Squamous cell carcinoma, metastatic
spread. Diagram demonstrating potential sites for metastatic
spread of oral carcinoma to regional lymph nodes.
Preauricular
Jugulo-digastric
Submandibular
Submental
Mid jugular
Low jugular
Tail of parotid
High jugular
Spinal accessory
Transverse cervical
Fig. 10-118 Squamous cell carcinoma. Metastatic
deposits within cervical lymph nodes present as ﬁrm, painless
enlargements as seen in this patient with metastasis to a
superior jugular node from a posterior lateral tongue
carcinoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

418 ORAL AND MAXILLOFACIAL PATHOLOGY
population studies have positive cervical nodes at diag-
nosis, and one in 10 already have distant metastasis by
that time.
STAGING
Tumor size and the extent of metastatic spread of oral
squamous cell carcinoma are the best indicators of
the patient’s prognosis. Quantifying these clinical
parameters is called staging the disease. Table 10-2
summarizes the most popular staging protocol, the
tumor-node-metastasis (TNM) system. Individualized
TNM classiﬁcations are used for most human cancers,
with each system pertaining exclusively to a speciﬁc
anatomic site and a speciﬁc tumor type. This staging
protocol depends on three basic clinical features:
1. T—Size of the primary tumor, in centimeters
2. N—Involvement of local lymph nodes
3. M—Distant metastasis
Once the three parameters are determined, they are
tallied together to determine the appropriate stage.
The higher the stage classiﬁcation, the worse the prog-
nosis (Table 10-3). In other words, a stage IV lesion is
associated with a much worse prognosis than a stage I
lesion. Most head and neck staging protocols do not
use histopathologic or immunohistochemical ﬁndings
beyond those needed for a determination of the
diagnosis.
Table 10-2 Tumor-Node-Metastasis (TNM) Staging System for Oral Carcinoma
Primary Tumor Size (T)
TX No available information on primary tumor
T0 No evidence of primary tumor
Tis Only carcinoma in situ at primary site
T1 Tumor 2 cm or less in greatest diameter
T2 Tumor more than 2 cm but not more than 4 cm in greatest diameter
T3 Tumor more than 4 cm in greatest diameter
T4a (Lip) Tumor invades through cortical bone, inferior alveolar nerve, ﬂoor
of mouth, or skin of face (i.e., chin, nose)
Tumor is resectable
T4a (Oral cavity) Tumor invades through cortical bone, into deep extrinsic
tongue muscles (genioglossus, hyoglossus, palatoglossus, and
styloglossus), maxillary sinus, or skin of face
Tumor is resectable
T4b Tumor involves masticator space, pterygoid plates, or skull base and/or
encases internal carotid artery
Tumor is unresectable
REGIONAL LYMPH NODE INVOLVEMENT (N)
NX Nodes could not be or were not assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral node 3 cm or less in greatest diameter
N2 Metastasis in a single ipsilateral node more than 3 cm but not greater
than 6 cm in greatest diameter; multiple ipsilateral nodes, none
more than 6 cm in greatest diameter; or bilateral or contralateral
nodes, none more than 6 cm in greatest diameter
N2a
N2b
N2c
Metastasis in a single ipsilateral node more than 3 cm but not greater
than 6 cm in greatest diameter
Metastasis in multiple ipsilateral nodes, none more than 6 cm in
greatest diameter
Metastasis in bilateral or contralateral nodes, none more than 6 cm in
greatest diameter
N3 Metastasis in a node more than 6 cm in greatest diameter
Involvement by Distant Metastases (M)
MX Distant metastasis was not assessed
MO No evidence of distant metastasis
M1 Distant metastasis is present
From Tumor-node-metastasis (TNM) staging system for oral carcinoma. In Greene FL, Page DL, Fleming ID et al, editors, AJCC cancer staging manual, ed
4, New York, 2002, Springer. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 419
HISTOPATHOLOGIC FEATURES
Squamous cell carcinoma arises from dysplastic sur-
face epithelium and is characterized histopathologi-
cally by invasive islands and cords of malignant
squamous epithelial cells. When the tumor is sampled
fortuitously at the earliest moment of invasion, the
adjectives superﬁcially invasive or microinvasive often are
used. The features of epithelial dysplasia are discussed
in more detail in the section pertaining to leukoplakia
(see page 394).
Invasion is represented by irregular extension of
lesional epithelium through the basement membrane
and into subepithelial connective tissue. Individual
squamous cells and sheets or islands of cells are seen
to be thriving as independent entities within the con-
nective tissues, without attachment to the surface epi-
thelium. Invading cells and cell masses may extend
deeply into underlying adipose tissue, muscle, or bone,
destroying the original tissue as they progress. Lesional
cells may surround and destroy blood vessels and may
invade into the lumina of veins or lymphatics. There is
often a strong inﬂammatory or immune cell response
to invading epithelium, and focal areas of necrosis may
be present. The lesional epithelium is capable of induc-
ing the formation of new small blood vessels (angio-
genesis) and, occasionally, dense ﬁbrosis (desmopla-
sia or scirrhous change).
Whether the tumor is superﬁcially or deeply inva-
sive, lesional cells generally show abundant eosino-
philic cytoplasm with large, often darkly staining
(hyperchromatic) nuclei and an increased nuclear-
to-cytoplasmic ratio. Varying degrees of cellular and
nuclear pleomorphism are seen. The normal product of
squamous epithelium is keratin, and keratin pearls (a
round focus of concentrically layered keratinized cells)
may be produced within lesional epithelium. Single
cells also may undergo individual cell keratinization.
Histopathologic evaluation of the degree to which
these tumors resemble their parent tissue (squamous
epithelium) and produce their normal product (keratin)
is called grading. Lesions are graded on a 3-point
(grades I to III) or a 4-point (grades I to IV) scale. The
less differentiated tumors receive the higher numerals.
The histopathologic grade of a tumor is related some-
what to its biologic behavior. In other words, a tumor
that is mature enough to closely resemble its tissue of
origin seems to grow at a slightly slower pace and to
metastasize later in its course. Such a tumor is called
low-grade, grade I, or well-differentiated squamous cell
carcinoma (Fig. 10-119). In contrast, a tumor with
much cellular and nuclear pleomorphism and with
little or no keratin production may be so immature that
it becomes difﬁcult to identify the tissue of origin. Such
a tumor often enlarges rapidly, metastasizes early in its
course, and is termed high-grade, grade III/IV, poorly
differentiated, or anaplastic (Fig. 10-120). A tumor with
a microscopic appearance somewhere between these
two extremes is labeled a “moderately differentiated”
carcinoma (Fig. 10-121).
To a certain extent, the grading of squamous cell
carcinoma is a subjective process, depending on the
area of the tumor sampled and the individual patholo-
gist’s criteria for evaluation. Moreover, clinical staging
seems to correlate much better with the prognosis
than microscopic grading. Over the past several
decades, investigators have proposed various multi-
parameter histopathologic assessment systems in an
attempt to provide more objective criteria that corre-
late with prognosis. Variables such as pattern of
invasion, tumor thickness, degree of keratinization,
nuclear pleomorphism, lymphocytic response, and
mitotic rate have been included in such grading
systems. However, widespread agreement regarding
the use of such methods is lacking.
The diagnosis of squamous cell carcinoma almost
always is made with routine light microscopy. Special
studies that use monoclonal antibodies directed against
cytokeratins may, however, be needed to distinguish
Table 10-3 TNM Clinical Staging Categories for Oral Squamous Cell Carcinoma
FIVE-YEAR RELATIVE SURVIVAL RATE
Stage TNM Classiﬁcation Oral Cavity Lip
Stage I T1 N0 M0 68% 83%
Stage II T2 N0 M0 53% 73%
Stage III T3 N0 M0, or T1, T2, or T3 N1 M0 41% 62%
Stage IV
IVA
IVB
IVC
T4a N0 or N1 M0, or T1, T2, T3, or T4a N2 M0
Any T N3 M0, or T4b any N M0
Any M1 lesion
27% 47% `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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420 ORAL AND MAXILLOFACIAL PATHOLOGY
high-grade or poorly differentiated squamous cell car-
cinoma from other malignancies.
TREATMENT AND PROGNOSIS
Carcinoma of the vermilion zone of the lip is usually
treated by surgical excision, typically a wedge resec-
tion, with excellent results. Only 8% recur, and 5-year
survival rates are 95% to 100%. In one study that evalu-
ated all vermilion cancers diagnosed in a population
over six decades, not one patient died of his or her
disease. Squamous cell carcinomas of the upper lip
vermilion appear to have a different biologic behavior
than do those of the lower lip. The 5-year survival rate
is only 58%, and 25% of lesions recur after treatment.
Fortunately, upper lip carcinoma is considerably less
common than lower lip carcinoma.
The clinical stage of the disease guides the treatment
of intraoral squamous cell carcinoma, which consists
of wide (radical) surgical excision, radiation therapy, or
a combination of surgery and radiation therapy. The
tumor’s location may inﬂuence the treatment plan.
Fig. 10-119 Well-differentiated squamous cell
carcinoma. A, Low-power photomicrograph showing islands
of malignant squamous epithelium invading into the lamina
propria. B, High-power view showing dysplastic epithelial
cells with keratin pearl formation.
Fig. 10-120 Poorly differentiated squamous cell
carcinoma. The numerous pleomorphic cells within the
lamina propria represent anaplastic carcinoma.
Oropharyngeal lesions usually receive radiation
therapy. Additional indications for radiation therapy
include the presence of close or positive resection
margins, regional metastasis, high-grade histopatho-
logic features, and perineural or angiolymphatic inva-
sion. A variety of chemotherapeutic agents are used as
adjunctive therapy. Chemotherapy typically is admin-
istered concurrently with radiation, as induction che-
motherapy followed by concurrent chemoradiation, or
as palliative therapy. Commonly used agents include
platinum-containing compounds (e.g., cisplatin, carbo-
platin), 5-ﬂuorouracil, and taxanes (e.g., paclitaxel,
docetaxel). In addition, clinical trials evaluating mono-
clonal antibodies or small molecule inhibitors directed
against EGFR have shown promise, and molecular-
based targeted therapies are anticipated to become
important treatment strategies in the future. Although
chemotherapeutic agents may reduce the size of a
Fig. 10-121 Moderately differentiated squamous cell
carcinoma. Although no keratinization is seen in this
medium-power view, these malignant cells are still easily
recognizable as being of squamous epithelial origin. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 421
tumor mass temporarily, none has improved survival
rates signiﬁcantly.
For the small intraoral carcinoma, a single treat-
ment modality is usually chosen. Patients with larger
lesions or lesions with clinically palpable lymph nodes
typically require combined therapy. In addition,
patients with early-stage (clinically T1/T2 and N0) but
deeply invasive (tumor thickness >3 or 4 mm) tongue
carcinomas are at increased risk for subclinical nodal
metastasis and thus may receive either postoperative
neck irradiation or elective neck dissection. With sus-
pected local lymph node metastasis, either a radical or
modiﬁed radical neck dissection is performed. Radical
neck dissection is essentially an en bloc removal of all
ﬁbrofatty tissues of the lateral triangle of the neck,
including the superior, middle, and inferior jugular
nodes, the supraclavicular group of nodes, and variable
portions of the surrounding musculature. The use of
sentinel-node biopsy (biopsy of the ﬁrst lymph node in
the lymphatic basin to receive drainage from the tumor)
to identify patients with occult neck metastasis has
shown promise but remains investigational for patients
with oral cancer.
The prognosis for survival from oral cancer depends
on tumor stage (see Table 10-3). The 5-year relative
survival rate for intraoral carcinoma is 53% to 68% if
the tumor is relatively small (<4 cm) and metastasis has
not occurred by the time of diagnosis (stage I and II);
41% when the tumor is α4 cm and either without
metastasis or with metastasis in a single ipsilateral
regional lymph β3 cm (stage III); and only 27% when
the tumor has invaded adjacent structures, has metas-
tasized to a distant site, or is associated with regional
metastasis of multiple nodes, a single ipsilateral node
>3 cm and β6 cm, or a node >6 cm (stage IV). Although
some patients die of their disease as many as 10 years
after initial treatment, the great majority of deaths
occur within the ﬁrst 5 years.
The various molecular markers associated with car-
cinoma, such as mutation of the p53 tumor suppressor
gene, have shown equivocal results as prognostic indi-
cators. The relationship between HPV tumor status
and prognosis is unclear. Some studies have suggested
that HPV-positive tumors are associated with improved
treatment response and prolonged survival; however,
other studies have reported no signiﬁcant difference in
survival between patients with HPV-positive and HPV-
negative tumors.
The overall 5-year survival rate for intraoral carci-
noma in whites in the United States and Europe has
increased from 40% in the 1950s to 59% today. During
the same period, however, the rate for black Americans
has increased only slightly from 36% to 39%. Research-
ers believe that this disparity in survival results from
differences in access to health care services; in addi-
tion, some have hypothesized that lifestyle habits (e.g.,
tobacco and alcohol use, nutrition), cultural differ-
ences, and the presence of comorbid conditions may
be contributing factors.
Despite advances in treatment and in the under-
standing of the underlying molecular pathogenesis of
oral cancer, survival rates over the last several decades
have not improved signiﬁcantly and have remained in
the range of 50% to 59%. Therefore, early diagnosis and
prevention are essential for improving patient out-
comes. In addition, there is much interest in the devel-
opment of chemoprevention strategies for preventing
the malignant transformation of oral dysplastic lesions
or preventing the development of second primary or
recurrent tumors in patients with a history of oral squa-
mous cell carcinoma.
MULTIPLE CARCINOMAS
Patients with one carcinoma of the mouth or throat are
at increased risk for additional concurrent (synchro-
nous) or later (metachronous) primary surface epithe-
lial malignancies of the upper aerodigestive tract, the
esophagus, the stomach, the lungs, and other sites. This
risk has been estimated to be as low as 6% and as high
as 44% in affected individuals. The highest ﬁgures are
associated with male patients who continue to smoke
and abuse alcohol after therapy. Overall, in 9% to 25%
of patients with oral carcinoma, additional mouth or
throat malignancies develop.
In patients with more than one upper aerodigestive
tract malignancy, approximately one third of the
tumors arise simultaneously. Of the rest, the second
lesion usually develops within 3 years after the initial
cancer. This tendency toward the development of mul-
tiple mucosal cancers, sometimes called ﬁeld canceriza-
tion, may reﬂect diffuse exposure to local carcinogens,
a process that increases the malignant transformation
potential of all exposed epithelial cells. Molecular
analyses of various markers, including loss of heterozy-
gosity (LOH), microsatellite alterations, p53 tumor
suppressor gene mutations, and X-chromosome inacti-
vation, have identiﬁed genetic alterations shared
between tumor tissue and adjacent clinically normal-
appearing tissue in one third to one half of cases exam-
ined. In addition, investigators have shown that a
signiﬁcant proportion of second primary tumors
develop from the same preneoplastic precursor lesion
or “ﬁeld,” with the remaining cases representing tumors
that develop independently. Furthermore, researchers
have proposed that patches of clonal cells can progress
to develop additional mutations and give rise to sub-
clones in a process known as clonal divergence, which
would account for the genetic heterogeneity typically
seen among these tumors. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

422 ORAL AND MAXILLOFACIAL PATHOLOGY
VERRUCOUS CARCINOMA
(SNUFF DIPPER’S CANCER;
ACKERMAN’S TUMOR)
Verrucous carcinoma is a low-grade variant of oral
squamous cell carcinoma. In 1948, Ackerman
described this lesion in detail, although the term verru-
cous carcinoma had been used in 1944 in a series of
cases reported by Burford, Ackerman, and Robinson.
Ackerman postulated that some of these lesions might
be associated with the use of smokeless tobacco,
because 11 of his 31 patients were “tobacco chewers.”
However, there was no mention of the type of smoke-
less tobacco used and no mention of whether any of
these patients also had smoked tobacco. In addition to
the oral mucosa, verrucous carcinoma has been identi-
ﬁed at several extraoral sites, including laryngeal, vul-
vovaginal, penile, anorectal, sinonasal, and esophageal
mucosa, as well as the skin of the breast, axilla, ear
canal, and soles of the feet. Tumors at anatomic sites
other than the mouth are unrelated to tobacco use.
Several investigators have identiﬁed human papillo-
mavirus (HPV) subtypes 16 and 18 in a minority of oral
verrucous carcinomas, but the signiﬁcance of this is
unclear because this virus often is associated with
otherwise normal oral mucosa.
Verrucous carcinoma represents less than 1% to 10%
of all oral squamous cell carcinomas, depending on the
local popularity of smokeless tobacco use. The only
epidemiologic assessment of this tumor in a Western
culture reported an average annual incidence rate of
one to three oral lesions per 1 million population each
year. Among 411,534 cases of head and neck carci-
noma recorded in the National Cancer Database from
1985 to 1996, only 0.6% of cases were diagnosed as
verrucous carcinoma.
Some verrucous carcinomas arise from the oral
mucosa in people who chronically use chewing to-
bacco or snuff, typically in the area where the tobacco
is habitually placed. Cases also occur in nonusers, but
the exact ﬁgure is difﬁcult to assess because patients
will often deny the tobacco habit. In smokeless tobacco
users, conventional squamous cell carcinoma is much
more likely to develop than this low-grade variant.
CLINICAL FEATURES
Verrucous carcinoma is found predominantly in men
older than 55 years of age (average age, 65 to 70 years).
In areas where women are frequent users of dry snuff,
however, older females may predominate. The most
common sites of oral mucosal involvement include the
mandibular vestibule, gingiva, buccal mucosa, tongue,
and hard palate. The site of occurrence often corre-
sponds to the site of chronic tobacco placement. In
cultural groups who keep the tobacco in the maxillary
vestibule or under the tongue, these locations are the
most commonly involved sites.
Oral verrucous carcinoma is usually extensive by
the time of diagnosis, and it is not unusual for a tumor
to be present in the mouth for 2 to 3 years before
deﬁnitive diagnosis. The lesion appears as a diffuse,
well-demarcated, painless, thick plaque with papillary
or verruciform surface projections (Figs. 10-122 and
10-123). Lesions are typically white but also may
appear erythematous or pink. The color depends on
the amount of keratin produced and the degree of host
inﬂammatory response to the tumor. If left untreated,
then lesions may destroy underlying structures, such as
bone, cartilage, muscle, and salivary glands. Enlarged
cervical lymph nodes in patients with verrucous carci-
noma usually represent inﬂammatory reactive changes
rather than nodal metastasis.
Leukoplakia or tobacco pouch keratosis may be
seen on adjacent mucosal surfaces, and verrucous car-
cinoma is a lesion that may develop from the high-risk
Fig. 10-122 Verrucous carcinoma. Extensive papillary,
white lesion of the maxillary vestibule.
Fig. 10-123 Verrucous carcinoma. Large, exophytic,
papillary mass of the maxillary alveolar ridge. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 423
precancer, proliferative verucous leukoplakia (PVL)
(see page 391). PVL and verrucous carcinoma may
have been reported in the past by the name oral ﬂorid
papillomatosis.
HISTOPATHOLOGIC FEATURES
Verrucous carcinoma has a deceptively benign micro-
scopic appearance; it is characterized by wide and
elongated rete ridges that appear to “push” into the
underlying connective tissue (Fig. 10-124). Lesions
usually show abundant keratin (usually parakeratin)
production and a papillary or verruciform surface.
Parakeratin typically ﬁlls the numerous clefts or crypts
(parakeratin plugs) between the surface projections.
These projections may be long and pointed or short
and blunted. The lesional epithelial cells generally
show a normal maturation pattern with no signiﬁcant
degree of cellular atypia. There is frequently an intense
inﬁltrate of chronic inﬂammatory cells in the subjacent
connective tissue.
The histopathologic diagnosis of verrucous carci-
noma requires an adequate incisional biopsy. Because
the individual cells are not very dysplastic, the patholo-
gist must evaluate the overall histomorphologic con-
ﬁguration of the lesion to arrive at an appropriate
diagnosis. Adequate sampling also is important because
as many as 20% of these lesions have a routine squa-
mous cell carcinoma developing concurrently within
the verrucous carcinoma.
TREATMENT AND PROGNOSIS
Because metastasis is an extremely rare event in ver-
rucous carcinoma, the treatment of choice is surgical
excision without radical neck dissection. The surgery
generally need not be as extensive as that required for
routine squamous cell carcinoma of a similar size.
With this treatment, 90% of patients are disease free
after 5 years, although some patients will require at
least one additional surgical procedure during that
time. The treatment failures usually occur in patients
with the most extensive involvement or in those unable
to tolerate extensive surgery because of unrelated sys-
temic diseases. An additional cause of treatment failure
is the initial inability to identify a focal squamous cell
carcinoma arising concurrently within the less aggres-
sive lesion. Verrucous carcinomas containing foci of
conventional squamous cell carcinoma should be
treated as conventional squamous cell carcinomas.
Radiotherapy is an alternative primary treatment
modality but provides poorer local control and thus is
considered less effective than surgery. In addition,
radiotherapy has been unpopular because of published
reports of poorly differentiated or anaplastic carcinoma
developing within the lesion after treatment. However,
more recent analysis suggests that this threat is seri-
ously overexaggerated. Chemotherapy may temporar-
ily reduce the size of verrucous carcinoma and may be
an option for inoperable cases, but it is not considered
a deﬁnitive, stand-alone treatment. In a limited number
of cases, tumor regression after radiochemotherapy or
photodynamic therapy has been reported, although
these treatment alternatives require further study.
SPINDLE CELL CARCINOMA
(SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS
CELL CARCINOMA)
Spindle cell carcinoma is a rare variant of squamous
cell carcinoma characterized by dysplastic surface
squamous epithelium in conjunction with an invasive
spindle cell element. It may be indistinguishable from
connective tissue sarcomas or other spindle cell malig-
nancies at the level of the light microscope.
In the past, this biphasic lesion was thought to be a
“collision” tumor between a carcinoma and sarcoma,
but most authorities now consider the spindle cells to
Fig. 10-124 Verrucous carcinoma. A, Low-power
photomicrograph showing marked epithelial hyperplasia with
a rough, papillary surface and keratin plugging. B, High-
power view showing bulbous rete ridges without signiﬁcant
dysplasia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

424 ORAL AND MAXILLOFACIAL PATHOLOGY
be simply an anaplastic type of carcinoma cell. Elec-
tron microscopy and immunohistochemical analysis
support the concept that these lesional cells are of epi-
thelial origin, with the ability to produce mesenchymal
intermediate ﬁlaments. Based on immunohistochemi-
cal studies, some investigators have hypothesized that
a dysfunctional cadherin-catenin complex important
for intercellular adhesion causes the tumor cells to
shift from a squamous to a spindled type, with increased
inﬁltrative behavior. More than one third of all mucosal
cases develop as recurrences after radiotherapy for a
more differentiated squamous cell carcinoma, a phe-
nomenon known as dedifferentiation.
CLINICAL FEATURES
The mean age at diagnosis for spindle cell carcinoma
is 57 years (range: 29 to 93 years). There is no sex
predilection. The neoplasm occurs predominantly in
the upper aerodigestive tract, especially the larynx, oral
cavity, and esophagus. Within the mouth, the lower lip,
lateral posterior tongue, and alveolar ridges are
common sites, but other areas may be involved.
In contrast to other oral cancers, the spindle cell
carcinoma typically appears as a pedunculated, polyp-
oid mass, but it may occasionally appear as a sessile,
nodular or fungating mass or as an ulcer (Fig. 10-125).
Pain and paresthesia are prominent features. The
tumor grows rapidly, tends to metastasize early, and is
typically diagnosed in a late stage (stages III and IV).
Lower lip lesions seem to have a special propensity to
travel along nerves through the mental foramen and
into the mandibular canal.
HISTOPATHOLOGIC FEATURES
The spindle cell carcinoma is composed predomi-
nantly of fascicles of anaplastic spindle-shaped cells
(Fig. 10-126). Some spindle cells may appear as
obvious epithelial elements, but others strongly resem-
ble atypical mesenchymal cells. On rare occasions,
bone, cartilage, or muscle differentiation may be seen.
Numerous mitotic ﬁgures often are present. The overall
picture is similar to that of an anaplastic ﬁbrosarcoma
(see page 553), except for the often-inconspicuous
squamous element.
The squamous component usually consists of carci-
noma in situ of the overlying surface epithelium but
may appear as islands of dysplastic squamous epithe-
lium among the spindle cells. Direct transition be-
tween the two cell types may be seen. Metastatic lesions
may show only spindle cells, only squamous cells, or a
combination of spindle and squamous cells.
Serial sections may be needed to ﬁnd areas of
unequivocal squamous cell carcinoma, and immuno-
histochemical techniques can be particularly useful in
distinguishing this tumor from mesenchymal spindle
cell malignancies. The lesional cells of most mesenchy-
mal tumors typically produce vimentin but not cyto-
keratin. Approximately two thirds of the cases of
spindle cell carcinoma react with antibodies directed
against cytokeratin, and an equivalent number show
vimentin immunoreactivity. Some cases also will be
positive for carcinoembryonic antigen (CEA).
TREATMENT AND PROGNOSIS
The treatment of choice for spindle cell carcinoma is
radical surgery, with neck dissection when clinically
positive nodes are present. Most authors agree that
radiotherapy and chemotherapy are ineffective.
However, adjuvant radiation therapy may be of beneﬁt
in cases where surgical margins are positive for tumor.
The 5-year disease-free survival rate is approximately
30% for oral lesions, with most deaths occurring within
Fig. 10-125 Spindle cell carcinoma. Large polypoid mass
arising from the right lateral tongue.
Fig. 10-126 Spindle cell carcinoma. Streaming fascicles of
pleomorphic spindle cells that represent anaplastic epithelial
cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 425
1 year of diagnosis. This is somewhat worse than the
prognosis for the tumor when it occurs in other ana-
tomic sites, but it is similar to the prognosis for high-
grade oral squamous cell carcinoma. Surprisingly,
tumor size seems to have little effect on the prognosis,
although there is some evidence that the microscopic
depth of invasion is a strong prognostic indicator in
oral lesions, with superﬁcial tumors demonstrating a
better prognosis.
ADENOSQUAMOUS CARCINOMA
Adenosquamous carcinoma is a rare variant of squa-
mous cell carcinoma that is characterized histopatho-
logically by a combination of adenocarcinoma and
squamous cell carcinoma. The adenoid (glandular)
pattern, which includes mucus production, has been
demonstrated clearly in metastatic deposits. Some
authorities consider this carcinoma to be merely a
high-grade mucoepidermoid carcinoma (see page
487). The cause is unknown.
CLINICAL FEATURES
Cases of adenosquamous carcinoma have been
reported from the tongue, oral ﬂoor, and other mucosal
surfaces, usually in older adults. There is a slight male
predilection. The clinical appearance is that of a
nodular, broad-based, variably painful mass with or
without surface ulceration. Eighty percent of patients
have metastatic deposits within the neck nodes at
diagnosis.
HISTOPATHOLOGIC FEATURES
Adenosquamous carcinoma appears as an admixture
of a surface squamous cell carcinoma and an underly-
ing ductal adenocarcinoma. The glandular component
tends to be most prominent in deeper portions of the
tumor. Intracytoplasmic mucin is noted by mucicar-
mine staining in most cases, making differentiation
from mucoepidermoid carcinoma difﬁcult but helping
to distinguish adenosquamous carcinoma from forms
of squamous cell carcinoma that exhibit a pseudoglan-
dular pattern of degeneration. Both squamous and
glandular components immunoreact with antibodies
directed against high molecular–weight cytokeratin
(KL1).
TREATMENT AND PROGNOSIS
Radical surgical excision, with or without radiation
therapy, is the treatment of choice for patients with
adenosquamous carcinoma. The prognosis is poor;
among previously reported cases involving the upper
aerodigestive tract, the overall 5-year survival rate is
13%, with 42% of patients dying of disease after a mean
period of 2 years after their diagnosis. Cervical lymph
node metastasis develops in approximately 65% of
patients, and distant metastasis develops in approxi-
mately 23% of patients, with the lung being the most
common site of dissemination.
BASALOID SQUAMOUS
CARCINOMA (BASALOID
SQUAMOUS CELL CARCINOMA)
Basaloid squamous carcinoma is a lesion found pri-
marily in the upper aerodigestive tract mucosa and
represents the most recently described variant of squa-
mous cell carcinoma. It has a tendency to develop in
the hypopharynx, but dozens of oral lesions have been
reported.
CLINICAL FEATURES
Basaloid squamous carcinoma of the head and neck
occurs predominantly in men, although no signiﬁcant
gender predilection exists among previously reported
oral cases. The neoplasm tends to occur in persons 40
to 85 years of age and in abusers of alcohol and smoked
tobacco. It most commonly involves the larynx, pyri-
form sinus, and tongue base, but any region of the
upper aerodigestive tract may be affected. The indi-
vidual lesion clinically appears as a fungating mass or
ulcer and may be painful or interfere with swallowing
(dysphagia). Almost 80% of patients have cervical
metastases at the time of diagnosis of this high-grade,
aggressive cancer.
HISTOPATHOLOGIC FEATURES
As its name connotes, basaloid squamous carcinoma
has two microscopic components. The ﬁrst is a super-
ﬁcial, well-differentiated or moderately differentiated
squamous cell carcinoma, often with surface ulcer-
ation, multifocal origin, and areas of carcinoma in situ.
The second, deeper component is an invasive basaloid
epithelium arranged in islands, cords, and glandlike
lobules. This deeper tumor often shows palisading of
peripheral cells, necrosis of central regions, and occa-
sional squamous differentiation (Fig. 10-127). This
component appears similar to basal cell carcinoma,
adenoid cystic carcinoma, basal cell adenocarcinoma,
or neuroendocrine carcinoma. The interface between
the two components is typically sharp and distinct, but
transition from squamous to basaloid cells may occa-
sionally be seen. Basaloid cells and islands of cells often
are surrounded by mucoid stroma (basal lamina mate- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

426 ORAL AND MAXILLOFACIAL PATHOLOGY
rial). Microcystic spaces ﬁlled with PAS-positive basal
lamina material may be interspersed among the tumor
islands as well.
TREATMENT AND PROGNOSIS
Basaloid squamous carcinoma is an aggressive malig-
nancy. Affected patients have a mean survival time of
only 23 months. Although somewhat controversial,
several recent studies have suggested that basaloid
squamous cell carcinoma may have a similar outcome
compared with conventional squamous cell carcinoma
when cases are matched by clinical stage and anatomic
location. Therefore, the poor prognosis for basaloid
squamous cell carcinoma simply might be caused by a
tendency for these patients to be diagnosed with late-
stage disease. Surgery followed by radiotherapy is the
recommended treatment, usually with adjuvant che-
motherapy for the distant metastases.
CARCINOMA OF THE
MAXILLARY SINUS
Carcinoma of the maxillary sinus or antrum is an
uncommon malignancy of largely unknown cause. It
does not appear to be related to sinusitis or nasal polyps.
Unlike squamous cell carcinomas in other head and
neck sites, squamous cell carcinomas of the paranasal
sinuses have been associated only weakly with tobacco
use. A strong causal relationship to occupational wood
and leather dust exposure has been established for the
rarely occurring sinonasal intestinal type of adenocar-
cinoma. Maxillary sinus carcinomas comprise only 3%
of all head and neck carcinomas; however, among
paranasal sinus carcinomas, the maxillary sinus is the
most common site (accounting for 80% of lesions). Most
lesions remain asymptomatic or mimic sinusitis for
long periods while the tumor grows to ﬁll the sinus.
Therefore, the diagnosis may not be made until the
lesion has perforated through the surrounding bone.
The majority of maxillary sinus carcinomas are clas-
siﬁed as squamous cell carcinomas. However, additional
carcinomas that may arise in this location include sino-
nasal adenocarcinoma, sinonasal undifferentiated
carcinoma (SNUC) (see next section), neuroendocrine
(small cell undifferentiated) carcinoma, and salivary
gland type of adenocarcinoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Typically, carcinoma of the maxillary sinus is a disease
of older adults. There is a slight predilection for males.
More than 80% of cases are advanced (stage III or stage
IV) at the time of diagnosis. Affected patients generally
complain of a chronic unilateral nasal stufﬁness or
notice an ulceration or mass of the hard palate or alveo-
lar bone (Fig. 10-128). When the second division of the
trigeminal nerve is involved, intense pain or paresthesia
of the midface or maxilla may occur, perhaps simulating
a toothache. Teeth in the area of the tumor may become
loosened, and dental radiographs often reveal a “moth-
eaten” destruction of the lamina dura and surrounding
bone. A panoramic radiograph shows a cloudy sinus
with destruction of its bony wall; however, the extent of
the tumor is best visualized by computed tomography
(CT) or magnetic resonance imaging (MRI).
If the tumor perforates the lateral wall of the sinus,
unilateral facial swelling and pain are usually present.
If the extension is medial, then nasal obstruction or
hemorrhage usually occurs. Extension superiorly
results in displacement or protrusion of the eyeball.
Approximately 4% of patients have cervical or subman-
dibular lymph node metastasis at the time of diagnosis.
Fig. 10-127 Basaloid squamous carcinoma. Sheets of
basaloid squamous epithelium exhibiting a high mitotic index
and tumor necrosis.
Fig. 10-128 Carcinoma of the maxillary sinus. The tumor
has produced a bulge of the posterior maxillary alveolar ridge
and is beginning to ulcerate through the surface mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 427
Distant metastasis is quite uncommon until late in the
progression of disease.
HISTOPATHOLOGIC FEATURES
Although the antrum is lined by respiratory epithe-
lium, the great majority of maxillary sinus carcinomas
are squamous cell carcinomas, usually moderately
or poorly differentiated.
TREATMENT AND PROGNOSIS
Carcinoma conﬁned within the maxillary sinus usually
is treated by hemimaxillectomy; those that have perfo-
rated through the surrounding bone are treated by
radiotherapy or combined radical surgery and radio-
therapy. However, even with radical treatment the
prognosis is poor, with a 5-year survival rate of approxi-
mately 40%. The presence of metastatic deposits in
local lymph nodes reduces the survival rate to less than
8%, as does involvement of the pterygopalatine fossa.
With or without cervical node involvement, death
usually occurs from local destruction and the inability
to control the primary disease.
SINONASAL UNDIFFERENTIATED
CARCINOMA
Sinonasal undifferentiated carcinoma (SNUC) is a
rare, highly aggressive, and clinicopathologically dis-
tinctive neoplasm of the nasal cavity and paranasal
sinuses. The tumor was ﬁrst described in 1986, and
since then fewer than 100 cases have been reported. In
the earlier literature, tumors of this type were probably
reported as anaplastic or undifferentiated carcinomas.
The histogenesis is uncertain; some investigators
have theorized that the cell of origin may be related to
the schneiderian membrane or olfactory epithelium.
The pathogenesis of SNUC is poorly understood. A few
cases have been associated with a history of smoking
or the presence of Epstein-Barr virus (EBV), although
a strong correlation with these factors has not been
established. In some instances, patients have devel-
oped SNUC secondary to radiation therapy for naso-
pharyngeal carcinoma or retinoblastoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although a broad age range (third through ninth
decades) has been reported, there is a tendency for
older patients to be affected, with a median age at pre-
sentation in the sixth decade. Men are affected more
commonly than women, with a male-to-female ratio of
approximately 2:1 to 3:1.
SNUC is well known for rapid development of
locally extensive disease. The neoplasm typically
appears as a large tumor mass that can involve multiple
regions of the sinonasal tract, usually including the
nasal cavity, maxillary sinus, and ethmoid sinuses. In
addition, extension into contiguous sites—such as the
nasopharynx, orbit, and cranial cavity—is common.
Inferior penetration into the oral cavity is possible as
well. There is usually relatively rapid development of
multiple sinonasal symptoms, including nasal obstruc-
tion or discharge, epistaxis, swelling, and pain. Orbital
involvement may lead to proptosis, periorbital swell-
ing, diplopia, and vision loss. Cranial nerve palsies are
a common ﬁnding as well.
Radiographic assessment is best performed by CT
or MRI, which typically reveals a large, expansile sino-
nasal mass with bony destruction and invasion of adja-
cent structures (Fig. 10-129).
HISTOPATHOLOGIC FEATURES
Sinonasal undifferentiated carcinoma is characterized
by trabeculae, ribbons, sheets, and nests of polygonal
cells with minimal cytoplasm and pleomorphic, hyper-
chromatic to vesicular nuclei. No squamous or glandu-
lar differentiation should be observed. Mitotic ﬁgures
are numerous. Tumor necrosis, apoptosis, and lympho-
vascular invasion usually are prominent. The surface
Fig. 10-129 Sinonasal undifferentiated carcinoma
(SNUC). T1-weighted magnetic resonance image (MRI)
showing a large destructive mass ﬁlling the right maxillary
sinus with extension into the orbital region and nasal cavity.
(Courtesy of Dr. Zoran Rumboldt.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

428 ORAL AND MAXILLOFACIAL PATHOLOGY
epithelium overlying the tumor may exhibit dysplasia
or carcinoma in situ. Immunohistochemical staining for
cytokeratin or epithelial membrane antigen typically is
positive.
TREATMENT AND PROGNOSIS
The standard approach has been aggressive multi-
modal therapy, including complete surgical resection
when feasible followed by adjuvant radiation and/or
chemotherapy. The prognosis for this lesion is extremely
poor, with an overall 5-year survival rate of less than
20%. However, a few centers recently have reported
promising results with induction chemotherapy fol-
lowed by radiation and surgical resection of any
remaining disease. This newer treatment approach has
been associated with 2-year survival rates of 64% to
75%. High-dose chemotherapy and bone marrow trans-
plantation may extend the life of the patient. Local
recurrence is common and is the major cause of mor-
bidity and mortality. Metastasis is possible, usually to
cervical lymph nodes, bone, liver, or brain.
NASOPHARYNGEAL CARCINOMA
Nasopharyngeal carcinoma refers to a group of
malignancies that arise from the lining epithelium of
the lymphoid tissue–rich nasopharynx; similar tumors
are found in the palatine tonsil and base of tongue.
These three anatomic sites are collectively called
Waldeyer’s tonsillar tissue or Waldeyer’s ring.
Nasopharyngeal carcinoma is rare in most areas of
the world. The average annual incidence rate in the
United States is less than 1 case per 100,000 persons.
In southern Chinese men, however, the rate is a star-
tling 20 to 55 cases per 100,000. Among southern
Chinese men who migrate to the United States, the rate
is intermediate, which suggests an environmental caus-
ative agent. Intermediate rates also are observed among
many indigenous people of Southeast Asia (including
Thais, Vietnamese, Malays, and Filipinos), Inuits of
Alaska and Greenland, and Arabs of North Africa.
Infection with Epstein-Barr virus, diets deﬁcient in
vitamin C, and consumption of salt ﬁsh that contains
potentially carcinogenic N-nitrosamines have been
implicated as contributory factors. Tobacco also has
been implicated as a risk factor; however, the magni-
tude of risk for carcinoma development for a given
level of tobacco exposure is lower in the nasopharynx
than in other parts of the upper aerodigestive tract.
CLINICAL FEATURES
Nasopharyngeal carcinoma occurs in all age groups,
but most commonly affects those who are 40 to 60
years old. It also occurs three times more commonly in
men than in women. The primary lesion, which usually
arises from the lateral nasopharyngeal wall, often is
small and difﬁcult to detect, even when the area is
examined endoscopically. The ﬁrst sign of disease for
50% to 60% of patients is an enlarged, ﬁrm to hard,
cervical lymph node, which represents metastatic
tumor (Fig. 10-130). Symptoms related to the ear are
described by slightly less than half of these patients. If
the tumor arises near the eustachian tube, then unilat-
eral serous otitis media, otalgia, or hearing loss from
obstruction may be the presenting complaint.
Epistaxis, nasal obstruction, and pharyngeal pain
may be present. The tumor may invade through the
foramen lacerum into the brain, producing CNS symp-
toms, or it may involve cranial nerves in the area,
causing speciﬁc symptoms related to those nerves. Sig-
niﬁcantly, 5% to 10% of patients also have distant metas-
tasis at the time of diagnosis.
HISTOPATHOLOGIC FEATURES
The surgeon often has difﬁculty ﬁnding the primary
lesion of nasopharyngeal carcinoma clinically, and
multiple, systematic biopsy samples of the nasopharyn-
geal mucosa may be necessary for tumor identiﬁcation
Fig. 10-130 Nasopharyngeal carcinoma. This patient
initially appeared with metastatic carcinoma in the left
lateral neck. Further evaluation revealed a primary tumor of
the nasopharynx. (Courtesy of Dr. D. E. Kenady.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 429
and diagnosis. Microscopic examination of a nasopha-
ryngeal carcinoma typically shows one of three histo-
pathologic patterns:
1.Squamous cell carcinoma (keratinizing squa-
mous cell carcinoma)
2.Differentiated nonkeratinizing carcinoma (non-
keratinizing squamous cell carcinoma)
3.Undifferentiated nonkeratinizing carcinoma
(poorly differentiated carcinoma, anaplastic car-
cinoma, lymphoepithelioma)
More than one histopathologic type may be present in
the same biopsy sample, in which case the tumor is clas-
siﬁed according to the predominant histologic type.
The histopathologic features of the keratinizing
squamous cell carcinoma are identical to those of
squamous cell carcinoma of other head and neck
regions (see page 419). Evidence of keratinization must
be seen at the light microscopic level.
The lesional cells of differentiated nonkeratiniz-
ing carcinoma are relatively mature and somewhat
squamous in nature, but they produce no keratin.
Broad interconnecting bands of oval or round cells are
organized in plexiform and papillary patterns.
Undifferentiated nonkeratinizing carcinoma
consists of sheets of lesional cells with less distinct
margins that show virtually no differentiation in most
instances (Fig. 10-131). They have very little cytoplasm
and large vesicular nuclei. These tumor cells are often
intermixed with the lymphoid cells normally found at
this anatomic site. The term lymphoepithelioma has
been used to describe this lesion because it was once
thought to be a malignancy that originated from both
epithelial and lymphoid tissues. This terminology
should be discouraged, however, because the lymphoid
tissue is not part of the neoplastic process. Such undif-
ferentiated tumors may be difﬁcult to distinguish from
lymphoma by light microscopy alone, and immunohis-
tochemical studies often are used to demonstrate
cytokeratins within the carcinoma cells. Some of these
undifferentiated tumors currently are classiﬁed as sino-
nasal undifferentiated carcinomas (SNUC). Occasional
neoplasms show neuroendocrine differentiation.
The less-differentiated lesions tend to occur in
younger individuals. In fact, virtually all nasopharyn-
geal carcinomas in people younger than 40 years of
age are poorly differentiated. Among southern Chinese
patients, the vast majority (95%) of cases are classiﬁed
as undifferentiated nonkeratinizing carcinomas, where-
as in nonendemic areas, 30% to 50% of cases are kera-
tinizing squamous cell carcinomas.
TREATMENT AND PROGNOSIS
Because of the inaccessibility of the nasopharynx and
the high frequency of metastasis at diagnosis, nasopha-
ryngeal carcinoma is treated most frequently with
radiotherapy to the nasopharynx and neck. Although
there has been some controversy regarding the beneﬁt
of adding chemotherapy to radiation therapy, emerg-
ing evidence favors concurrent chemoradiation over
radiation alone for improved survival among patients
with locally advanced disease.
The prognosis ranges from good to poor, depending
on the stage of the disease. The overall 5-year disease-
free survival rate reported in one large series of cases
in the United States was 45.5%. For stage I patients, a
100% 5-year survival rate has been demonstrated.
Stage II is associated with a 67% 5-year survival rate;
stage III, 44%; and stage IV, 34%. Patients with two or
more clinical symptoms tend to have a worse progno-
sis. When treated with radiation therapy, the differen-
tiated and undifferentiated nonkeratinizing types
exhibit a higher local control rate but a greater risk of
distant metastasis compared with the keratinizing type.
In the United States, higher survival rates have been
observed among Chinese-American patients compared
with other ethnic groups. This trend traditionally has
been attributed to the prevalence of the more radiosen-
sitive undifferentiated nonkeratinizing type among
Chinese-American patients; however, for reasons
unclear, Chinese ethnicity has been shown to be a
favorable prognostic factor even independent of histo-
pathologic type. Persons treated for nasopharyngeal
carcinoma are also at increased risk of developing a
second primary malignancy of the head and neck
mucosa.
BASAL CELL CARCINOMA (BASAL CELL
EPITHELIOMA; RODENT ULCER)
Basal cell carcinoma, the most common skin cancer
(and the most common of all cancers), is a locally inva-
sive, slowly spreading, primary epithelial malignancy
that arises from the basal cell layer of the skin and its
Fig. 10-131 Nasopharyngeal carcinoma. Poorly
differentiated tumor exhibiting sheets of rounded tumor cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

430 ORAL AND MAXILLOFACIAL PATHOLOGY
appendages. About 80% are found on the skin of the
head and neck. More than 800,000 new cases of basal
cell carcinoma are diagnosed annually in the United
States, representing 80% of all skin cancers. The world-
wide incidence is increasing by about 10% per year.
Incidence generally increases with age, although a
recent study suggests a disproportionate increase
among young adults (particularly women) as well.
This cancer mainly results from chronic exposure to
ultraviolet radiation. Frequent sunburns and tendency
for freckling in childhood are associated with an
increased risk, whereas occupational sun exposure and
sunburns as an adult do not seem to be risk factors.
Lesser risk factors include exposure to signiﬁcant ion-
izing radiation, ingestion of arsenic, immunosuppres-
sive therapy, and psoralen and ultraviolet A (PUVA)
treatment (often used for psoriasis). In addition, several
genodermatoses are associated with basal cell carci-
noma development, including the nevoid basal
cell carcinoma syndrome (see page 688), xeroderma
pigmentosum (see page 747), albinism, Rasmussen
syndrome, Rombo syndrome, and Bazex-Christol-
Dupré syndrome.
Recent molecular genetic studies have shown that
dysregulation of the hedgehog signaling pathway is a
critical early event in the development of basal cell
carcinoma. Inactivating mutations in the patched
(PTCH) gene on chromosome 9q22 have been identi-
ﬁed in both sporadic cases and patients with the nevoid
basal cell carcinoma syndrome. Mutations in other
genes participating in this pathway (e.g., smoothened
[SMO]) occasionally may be found in sporadic cases as
well. These mutations lead to constitutive activation of
hedgehog signaling and enhanced cellular prolifera-
tion. In addition, mutations in p53 are found in more
than 50% of sporadic basal cell carcinomas and may
represent a later event in tumor development.
Oral lesions have been reported but are usually con-
sidered to be cases of misdiagnosed salivary or odon-
togenic neoplasms.
CLINICAL FEATURES
Basal cell carcinoma is a disease of adult whites, espe-
cially those with fair complexions. Although most
patients are older than 40 years of age at the time of
diagnosis, some lesions are detected as early as the
second decade of life, particularly in patients with red
or blonde hair and blue or green eyes. Approximately
80% of lesions occur on the head and neck, with the
remainder involving the trunk and limbs.
The most common form of this lesion, the nodular
(noduloulcerative) basal cell carcinoma, begins as a
ﬁrm, painless papule that slowly enlarges and gradu-
ally develops a central depression and an umbilicated
appearance. One or more telangiectatic blood vessels
are usually seen coursing over the rolled border sur-
rounding the central depression (Figs. 10-132 and
10-133). When the lesion is pressed, a characteristic
pearly opalescent quality is discerned. Expanding
ulceration often develops in the central depressed area,
and the patient may give a history of intermittent bleed-
ing followed by healing. Untreated lesions continue to
enlarge slowly over months and years, with ulceration
and destruction of underlying structures, hence their
historical name, rodent ulcer. Destruction of underly-
ing bone or cartilage may occur, but metastasis is
extremely rare.
Several other clinicopathologic varieties of this
tumor have also been described. Pigmented basal
cell carcinoma is seen occasionally and represents a
noduloulcerative tumor colonized by benign melano-
Fig. 10-132 Basal cell carcinoma. Early noduloulcerative
basal cell carcinoma of the forehead showing raised, rolled
borders and focal ulceration. Fine, telangiectatic blood vessels
can be seen on the surface.
Fig. 10-133 Basal cell carcinoma. Noduloulcerative lesion
of the upper lip demonstrating telangiectasia and small
ulceration. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 431
cytes (Fig. 10-134). The melanin production imparts a
tan, brown, black, or even bluish color to the lesion,
and usually the pigment is not distributed uniformly,
as it would be in a melanocytic nevus (see page 382).
Sclerosing (morpheaform) basal cell carcinoma
is an insidious lesion that often mimics scar tissue. The
overlying skin appears pale and atrophic, and the lesion
is ﬁrm to palpation with poorly demarcated borders. A
slight elevation may be noted at the edges of the tumor.
Often a great deal of invasion has occurred before the
patient becomes aware of a problem.
The superﬁcial basal cell carcinoma occurs pri-
marily on the skin of the trunk. Often, lesions are mul-
tiple and appear as well-demarcated, erythematous,
scaly patches that may be mistaken clinically for pso-
riasis. A ﬁne, elevated, “threadlike” border is seen at
the margins.
Some investigators believe that the basal cell carci-
noma associated with the nevoid basal cell carci-
noma syndrome (see page 688) should be placed in
a separate category. These lesions develop in both sun-
exposed and protected areas of the skin and may
number in the hundreds on a single patient. The tumors
associated with this syndrome usually do not produce
a signiﬁcant degree of tissue destruction.
HISTOPATHOLOGIC FEATURES
The basal cell carcinoma displays a considerable diver-
sity of appearances under the microscope: nodulocys-
tic (noduloulcerative), superﬁcial, adenoid, pigmented,
inﬁltrative, morpheaform, and keratotic. The noduloul-
cerative, pigmented, and syndrome-related basal cell
carcinomas are comprised of uniform ovoid, dark-
staining basaloid cells with moderate-sized nuclei and
relatively little cytoplasm (Fig. 10-135). The cells are
arranged into well-demarcated islands and strands,
which appear to arise from the basal cell layer of the
overlying epidermis and invade into the underlying
dermal connective tissue. Epithelial islands typically
demonstrate palisading of the peripheral cells; fre-
quently, a clear zone of artifactual retraction is seen
between the epithelial islands and the connective
tissue. Although most of these neoplasms show no dif-
ferentiation, some exhibit areas of keratin production,
sebaceous differentiation, or interlacing strands of
lesional cells that resemble duct formation (“adenoid”).
Necrosis of epithelial islands may produce a cystic
appearance. Actinic damage in the form of solar elas-
tosis almost always is seen in adjacent stroma.
Pigmented basal cell carcinoma demonstrates
dendritic melanocytes within tumor islands, and
melanophages may be seen in the surrounding stroma.
Sclerosing basal cell carcinoma is characterized by
inﬁltrating thin strands of basaloid tumor cells set in a
densely collagenous background. Superﬁcial basal cell
carcinoma includes lobules of tumor cells that drop
from the epidermis in a multifocal pattern. Occasion-
ally, basal cell carcinoma is seen admixed with an inde-
pendent primary squamous cell carcinoma of the skin.
The resulting “collision” tumor is called basosqua-
mous carcinoma. Some authorities consider the baso-
squamous carcinoma to be a simple basal cell carcinoma
with abundant squamous metaplasia.
TREATMENT AND PROGNOSIS
The treatment of basal cell carcinoma often depends
on the size and site of the lesion. Small lesions (<1 cm)
are treated by routine surgical excision, laser ablation,
or electrodesiccation and curettage, with 3- to 5-mm
Fig. 10-134 Basal cell carcinoma. Pigmented basal cell
carcinoma of the cheek.
Fig. 10-135 Basal cell carcinoma. Low-power
photomicrograph showing ulceration of the epidermal
surface associated with an invading tumor of hyperchromatic
epithelial cells. Inset demonstrates islands of basophilic
epithelium with peripheral palisading. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

432 ORAL AND MAXILLOFACIAL PATHOLOGY
margins of clinically normal-appearing skin beyond
the visible lesion. These methods result in a cure rate
of 95% to 98%. Radical surgical excision and radiation
therapy are recommended for large or aggressive
lesions. For sclerosing type of lesions, recurrent lesions,
or lesions situated near embryonic planes of fusion
(along which these tumor cells tend to invade), a pro-
cedure called Mohs micrographic surgery should be
used. This technique essentially uses frozen-section
evaluation of specially mapped and marked surgical
specimens to determine whether tumor tissue has
been left behind. If it has, then the surgeon can return
immediately to that particular area and remove more
tissue, repeating the process until the patient is free of
disease.
Topical treatments have shown promise as an alter-
native for certain variants of basal cell carcinoma,
although long-term follow-up data for these alternative
therapies are lacking. Photodynamic therapy is effec-
tive for superﬁcial basal cell carcinomas, with good
cosmetic outcomes reported. Additional topical treat-
ments include 5% ﬂuorouracil cream for the manage-
ment of multiple superﬁcial basal cell carcinomas on
the trunk and limbs and 5% imiquimod cream for
superﬁcial basal cell carcinomas on the trunk, neck, or
limbs.
Recurrence of a properly treated basal cell carci-
noma is uncommon, and metastasis is exceptionally
rare. In patients with uncontrollable disease, death is
usually the result of local invasion into vital structures.
However, with early detection and the advent of Mohs
surgery, such an outcome is unusual today.
Patients with a history of basal cell carcinoma must
be evaluated periodically. There is a 30% chance of a
second basal cell carcinoma and a 6% chance of a cuta-
neous squamous cell carcinoma developing within 3
years of treatment of the initial tumor.
MERKEL CELL CARCINOMA (MERKEL
CELL TUMOR; NEUROENDOCRINE
CARCINOMA OF SKIN; SMALL CELL
CARCINOMA OF SKIN; TRABECULAR
CARCINOMA OF SKIN)
The Merkel cell carcinoma, ﬁrst described in 1972, is
a rare, aggressive primary malignancy with neuroendo-
crine features. It occurs primarily on the skin of the
head and neck region. As with other skin malignancies,
ultraviolet (UV) light exposure is a major risk factor. In
addition, an increased frequency has been reported
among immunosuppressed individuals, including
transplant recipients, patients with chronic lympho-
cytic leukemia, and patients with HIV infection. Lesional
cells contain cytoplasmic granules that resemble the
neurosecretory granules found within the epidermal
Merkel cells of touch receptor regions. Intraoral and lip
vermilion cases have been reported but are rare.
CLINICAL FEATURES
Merkel cell carcinoma typically appears in older
people, with more than 76% of cases reported in indi-
viduals 65 years or older. The tumor exhibits a predi-
lection for whites and a slight male predominance. It
occurs primarily on the sun-exposed areas of fair-
skinned individuals, most commonly (75%) on the skin
of the face. The vermilion border of the lower lip is also
a susceptible site. Merkel cell carcinoma only rarely
(4.5%) arises from mucosal sites, including the oral,
nasal, pharyngeal, laryngeal, and vaginal mucosa. The
tumor usually appears as a slowly enlarging, dome-
shaped nodule with a smooth surface and prominent
surface vessels (telangiectasias). It is red or violaceous
and ranges in size from 0.5 to 5.0 cm. Ulceration rarely
is seen. Occasional lesions grow rapidly, and 25% dem-
onstrate local metastasis at diagnosis, belying its innoc-
uous clinical appearance.
HISTOPATHOLOGIC FEATURES
Merkel cell carcinoma consists of inﬁltrating sheets
and anastomosing strands of moderately sized, uniform,
undifferentiated basophilic cells in the dermis and sub-
cutaneous fat (Fig. 10-136). Pseudoglandular, trabecu-
lar, cribriform (“Swiss cheese”), and sheetlike patterns
may be seen. The surface epithelium is usually intact
and otherwise unremarkable unless secondarily ulcer-
ated by the tumor. Mitotic ﬁgures are abundant, and
tumor cells have prominent nuclei, scant cytoplasm,
and indistinct cell borders. Intracytoplasmic argyro-
philic granules may be demonstrated by the Grimelius
stain, and lesional cells typically exhibit a “perinuclear
Fig. 10-136 Merkel cell carcinoma. A sheet of
undifferentiated basophilic cells is seen beneath the
epidermal surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 433
dot” immunoreactivity pattern with antibodies directed
against cytokeratin 20 (CK20). Immunopositivity for
markers of neuroendocrine differentiation, such as
chromogranin A, synaptophysin, and neuron-speciﬁc
enolase, also may be helpful in establishing the diagno-
sis. Lack of immunoreactivity for antithyroid transcrip-
tion factor 1 (anti-TTF-1) may help to exclude the
possibility of metastatic small cell carcinoma of the
lung, which may have similar histomorphologic fea-
tures. At times, this entity is difﬁcult to differentiate
histopathologically from amelanotic melanoma, meta-
static esthesioneuroblastoma, metastatic small cell car-
cinoma of the lung, malignant lymphoma, and other
undifferentiated malignancies. In this situation, a panel
of immunohistochemical studies should be used to
exclude these other diagnostic possibilities. Careful
physical examination of the patient also may provide
useful diagnostic information.
TREATMENT AND PROGNOSIS
Merkel cell carcinoma is typically treated by wide local
excision. For small primary skin tumors, removal by
Mohs micrographic surgery with or without adjuvant
radiation has been proven effective and less disﬁguring
than standard surgery. Lymph node dissection is per-
formed when clinically palpable nodes are found. Sen-
tinel lymph node biopsy may be used to determine
whether regional lymph node dissection and/or radia-
tion therapy is indicated in those patients with clini-
cally negative nodes. Some controversy exists regarding
adjuvant therapy in the management of Merkel cell
carcinoma. Although some authors have not found
adjuvant radiation to improve survival, most studies
have shown improved survival and a signiﬁcant
decrease in risk of local recurrence and regional metas-
tasis with postoperative radiation therapy. The role of
adjuvant chemotherapy remains investigational.
Recurrence develops in 55% of cases, most com-
monly within the draining lymph nodes. In a recent
analysis of U.S. Surveillance, Epidemiology, and End
Results (SEER) Program data for a cohort of more than
1000 patients with Merkel cell carcinoma, the 5-year
survival rates for patients with localized, regional, and
distant disease were 75%, 59%, and 25%, respectively.
The overall 5-year disease-speciﬁc survival rate is
approximately 64%. Female sex, localized disease, limb
involvement, and younger age have been found to be
positive predictors of survival. In a few rare cases, com-
plete spontaneous regression of the primary tumor has
been reported, which suggests that immunologic
therapy may be an alternative approach to investigate
in the future.
Approximately 25% of patients with Merkel cell
carcinoma develop additional malignancies (e.g.,
squamous cell carcinomas of the skin, hematologic
malignancies, or adenocarcinomas of the breast or
ovary) before, concurrent with, or after their diagnosis.
Thus these patients should be monitored closely.
MELANOMA (MALIGNANT MELANOMA;
MELANOCARCINOMA)
Melanoma is a malignant neoplasm of melanocytic
origin that arises from a benign melanocytic lesion or
de novo from melanocytes within otherwise normal
skin or mucosa. Although most melanomas occur on
the skin, they may develop at any site where melano-
cytes are present. Damage from UV radiation is con-
sidered a major causative factor, as suggested by the
fact that the incidence of melanoma increases for
light-complexioned populations as they approach the
equator. However, chronic sun exposure does not seem
to be as signiﬁcant as it is for other cutaneous cancers,
such as basal and squamous cell carcinoma. Acute sun
damage may be of greater causative importance than
chronic exposure in melanoma. Lesions of the oral
mucosa, of course, are not related to sun exposure.
The risk of melanoma development is two to eight
times greater when a relative has a history of the cancer.
Additional risk factors include a fair complexion and
light hair, a tendency to sunburn easily, a history of
painful or blistering sunburns in childhood, an indoor
occupation with outdoor recreational habits, a personal
history of melanoma, and a personal history of dysplas-
tic or congenital nevus.
Melanoma is the third most common skin cancer,
but it accounts for only 5% of the total. Most deaths that
are due to skin cancer, however, are caused by mela-
noma. In the United States for the year 2008, it is esti-
mated that 62,480 people will be diagnosed with
cutaneous melanoma and 8420 people will die of the
disease. The age-adjusted incidence rate for skin mela-
noma (23.6 per 100,000 men and 14.9 per 100,000
women) has been increasing dramatically over the past
several decades. Based on U.S. incidence rates from
2002 to 2004, it is estimated that 1 in 58 persons will
be diagnosed with cutaneous melanoma during their
lifetime. Controversy exists regarding this perceived
increase in melanoma incidence. Some investigators
contend that the increase is due to increased numbers
of skin biopsies and improved diagnosis of early-stage
disease, whereas others feel that there is a true increase
in disease rate. Despite increasing incidence, the mor-
tality rate for cutaneous melanoma has remained rela-
tively constant since the 1990s, apparently because a
large proportion of cases are diagnosed at an early
stage. According to the National Cancer Database Report
on Cutaneous and Noncutaneous Melanoma, 91.2% of all
melanomas arise on the skin, whereas ocular, mucosal, `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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434 ORAL AND MAXILLOFACIAL PATHOLOGY
and unknown primaries account for 5.2%, 1.3%, and
2.2% of cases, respectively. Almost 25% of cutaneous
melanomas arise in the head and neck area, 40% occur
on the extremities, and the rest occur on the trunk.
More than half of mucosal melanomas occur in the
head and neck area (including the oral and sinonasal
regions), with the remainder involving the urogenital
and rectal mucosa.
Oral mucosal melanoma is rare in the United States,
where it occurs in only 1 in every 2 million persons
annually and comprises much less than 1% of all mela-
nomas. Several reports suggest it is more frequent in
other countries, such as Japan and Uganda; however,
other investigators have suggested that the true inci-
dence of mucosal melanomas is not greater in these
countries but only appears so because of the compara-
tively low incidence of cutaneous melanomas in these
racial groups. The mucosal melanoma tends to present
at a more advanced stage and is much more aggressive
than its cutaneous counterpart. At least one in three
patients with oral melanoma has a history of a pig-
mented macule in the region of the tumor for some
time before melanoma diagnosis. Melanoma occasion-
ally affects the parotid gland, usually as a metastatic
deposit from a scalp, conjunctival, or paranasal
tumor.
In recent years, there have been many discoveries
regarding recurrent genetic alterations in melanomas,
including those involving the Ras-Raf-ERK, mitogen-
activating protein (MAP) kinase, and phosphatidylino-
sitol 3-kinase (Pl3K) pathways. In particular, a high
proportion (approximately 50% to 70%) of melanomas
possess mutations in the gene encoding BRAF, a protein
kinase involved in the Ras-Raf-ERK signaling pathway.
CLINICAL FEATURES
Most melanomas are seen in white adults. The average
age of affected persons is 50 to 55 years, but cases are
rather evenly distributed over the 30- to 80-year age
bracket. A few melanomas occur in the second and
third decades of life. Four clinicopathologic types of
melanoma have been described:
1. Superﬁcial spreading melanoma
2. Nodular melanoma
3. Lentigo maligna melanoma
4. Acral lentiginous melanoma
Melanomas tend to exhibit two directional patterns
of growth: (1) the radial growth phase and (2) the
vertical growth phase. In the early stages of mela-
noma development, the radial growth phase tends to
predominate in lentigo maligna melanoma, superﬁcial
spreading melanoma, and acral lentiginous melanoma.
In these lesions, the malignant melanocytes have a pro-
pensity to spread horizontally through the basal layer
of the epidermis. Eventually, however, the malignant
cells begin to invade the underlying connective
tissue, thus initiating the vertical growth phase. With
nodular melanoma, the radial growth phase is very
short or nonexistent and the vertical growth phase
predominates.
Because many clinical similarities exist between
melanoma and its benign counterpart, the melanocytic
nevus, an “ABCDE” system of evaluation has been
developed to help distinguish a melanoma clinically
from a melanocytic nevus (Box 10-4).
SUPERFICIAL SPREADING MELANOMA
Superﬁcial spreading melanoma is the most common
form of melanoma, representing 70% of cutaneous
lesions (Fig. 10-137). The most common sites of origin
are the interscapular area of males and the back of the
legs of females. This form of melanoma appears as a
macule with a variety of potential colors (i.e., tan,
Box 10-4
The “ABCDE” Clinical Features
of Melanoma
●Asymmetry (because of its uncontrolled growth
pattern)
●Border irregularity (often with notching)
●Color variegation (which varies from shades of brown
to black, white, red, and blue, depending on the
amount and depth of melanin pigmentation)
●Diameter greater than 6 mm (which is the diameter
of a pencil eraser)
●Evolving (lesions that have changed with respect to
size, shape, color, surface, or symptoms over time)
Fig. 10-137 Superﬁcial spreading melanoma. This lesion
on the neck demonstrates the ABCDE warning signs of
melanoma: Asymmetry, Border irregularity, Color variegation,
Diameter larger than a pencil eraser, and Evolving larger size.
(Courtesy of Dr. Mark Bowden.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 435
brown, gray, black, blue, white, pink). Typically, the
lesion is smaller than 3 cm in greatest diameter at diag-
nosis, but it may be several times that size. Many lesions
are slightly elevated. Clinically, invasion is indicated by
the appearance of surface nodules or induration, and
usually occurs within 1 year of discovery of the precur-
sor macule. Satellite macules or nodules of malignant
cells may develop around the primary lesion.
NODULAR MELANOMA
Nodular melanoma represents 15% of cutaneous mel-
anomas, and one third of such lesions develop in the
head and neck area. Nodular melanoma is thought to
begin almost immediately in the vertical growth phase;
therefore, it typically appears as a nodular elevation
that rapidly invades into the connective tissue. Nodular
melanoma is usually a deeply pigmented exophytic
lesion, although sometimes the melanoma cells are so
poorly differentiated that they no longer can produce
melanin, resulting in a nonpigmented amelanotic
melanoma.
LENTIGO MALIGNA MELANOMA
Lentigo maligna melanoma, which accounts for 5%
to 10% of cutaneous melanomas, develops from a pre-
cursor lesion called lentigo maligna (Hutchinson’s
freckle). Lentigo maligna occurs almost exclusively on
the sun-exposed skin of fair-complexioned older adults,
particularly in the midfacial region, and represents a
melanoma in situ in a purely radial growth phase.
The lesion appears as a large, slowly expanding
macule with irregular borders and a variety of colors,
including tan, brown, black, and even white (Fig.
10-138). Patients usually indicate that the lesion has
been present and has slowly expanded laterally for
years. The average duration of the radial growth phase
is 15 years. The appearance of nodularity within a
lentigo maligna signals the onset of the invasive or ver-
tical growth phase and the transition to lentigo maligna
melanoma.
ACRAL LENTIGINOUS MELANOMA (MUCOSAL
LENTIGINOUS MELANOMA)
Acral lentiginous melanoma is the most common
form of melanoma in blacks, and it is also the most
common form of oral melanoma. It typically develops
on the palms of the hands, soles of the feet, subungual
area, and mucous membranes. It begins as a darkly
pigmented, irregularly marginated macule, which later
develops a nodular invasive growth phase. Recently,
some authorities have separated this lesion into two
entities: (1) acral lentiginous melanoma and (2)
mucosal lentiginous melanoma.
Oral melanoma is often nodular at the time of diag-
nosis, but early lesions may be ﬂat. Affected persons
are usually in their sixth or seventh decade of life. Two
thirds of patients are men. Four of every ﬁve oral mela-
nomas are found on the hard palate or maxillary
alveolus.
An oral lesion typically begins as a brown to black
macule with irregular borders (Figs. 10-139 and
10-140). The macule extends laterally, and a lobulated,
exophytic mass develops once the vertical growth is
initiated (Fig. 10-141). Ulceration may develop early,
but many lesions are dark, lobulated, exophytic masses
without ulceration at the time of diagnosis. More than
20% of oral melanomas contain so little pigment that
they have an essentially normal mucosal tint. Pain is
not a common feature except in ulcerated lesions, and
most lesions remain relatively soft to palpation. Under-
lying or adjacent bone may show radiographic evi-
dence of irregular or “moth-eaten” destruction.
Fig. 10-138 Lentigo maligna melanoma. A slowly
evolving pigmented lesion of the facial skin in an older adult
man.
Fig. 10-139 Oral melanoma. This discrete area of
pigmentation, measuring approximately 5 mm in diameter,
was discovered on the posterior hard palate of a middle-aged
woman during a routine oral examination. Biopsy revealed
melanoma in situ. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

436 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
With cutaneous and oral melanomas, atypical melano-
cytes are initially seen at the epithelial and connective
tissue junction. From here, they have the potential to
proliferate throughout the epithelium, laterally along
the basal cell layer, and downward into the connective
tissue. In the early stages of the neoplasm, atypical
melanocytes are seen either scattered singly among the
basal epithelial cells or as nests within the basal cell
layer. The atypical melanocytes are usually larger than
normal melanocytes and have varying degrees of
nuclear pleomorphism and hyperchromatism.
With superﬁcial spreading melanoma, pagetoid
spread often is seen. Large melanoma cells inﬁltrate
the surface epithelium singly or in nests (Fig. 10-142).
The resulting microscopic pattern is called pagetoid
because it resembles an intraepithelial adenocarci-
noma known as Paget’s disease of skin.
The spreading of the lesional cells along the basal
layer constitutes the radial growth phase of the neo-
plasm. Such lateral spread of cells within the epithe-
lium, which occurs before invasion into the underlying
connective tissue, is characteristically seen in superﬁ-
cial spreading melanoma, lentigo maligna melanoma,
and acral lentiginous melanoma. In acral lentiginous
melanoma, many of the melanocytes have prominent
dendritic processes (Fig. 10-143).
When malignant melanocytes are observed invad-
ing the connective tissue, the vertical growth phase has
taken place. In nodular melanoma, this vertical growth
phase occurs early in the course of the tumor. No radial
growth of cells can be observed in the overlying epithe-
lium beyond the edge of the invasive tumor (Fig.
10-144). The invasive melanoma cells usually appear
either spindle-shaped or epithelioid and inﬁltrate the
connective tissue as loosely aggregated cords or sheets
Fig. 10-140 Oral melanoma. Diffuse, splotchy area of
pigmentation of the lateral hard palate. (Courtesy of Dr. Len
Morrow.)
Fig. 10-141 Oral melanoma. Ulcerated pigmented mass
of the posterior maxillary alveolar ridge.
Fig. 10-142 Superﬁcial spreading melanoma. The radial
growth phase is characterized by the spread of atypical
melanocytes along the basilar portion of the epidermis. Also
note the presence of individual melanocytes invading the
higher levels of the epithelium.
Fig. 10-143 Acral lentiginous melanoma. This palatal
melanoma demonstrates numerous atypical melanocytes in
the basilar portion of the epithelium with invasion into the
superﬁcial lamina propria. This represents the biopsy
specimen from Fig. 10-140. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 437
of pleomorphic cells. Oral lesions tend to show inva-
sion of lymphatic and blood vessels more readily than
skin lesions. Several mucosal melanomas have been
reported to contain unequivocal bone and cartilage, a
feature that may cause diagnostic confusion with pleo-
morphic adenoma, sarcomatoid carcinoma, osteogenic
sarcoma, and mesenchymal chondrosarcoma.
In most instances, the lesional cells of melanoma
contain ﬁne melanin granules, but they may demon-
strate no melanin production (amelanotic melanoma).
A lack of melanin production may cause diagnostic
confusion at the light microscopic level because mela-
noma can mimic a variety of undifferentiated tumors.
Immunohistochemical studies showing S-100 protein,
HMB-45, Melan-A, and Mart-1 reactivity of the lesional
cells are beneﬁcial in distinguishing such melanomas
from other malignancies.
TREATMENT AND PROGNOSIS
Microscopic measurement of the depth of invasion is
an important component of the histopathologic evalu-
ation of cutaneous melanoma because of its correlation
with the prognosis. The Clark system of measurement
assigns a “level” to the lesion that depends on the
deepest anatomic cutaneous region that has been
invaded by tumor cells (Table 10-4). The more recent
Breslow classiﬁcation, however, appears to show a
more accurate correlation with the prognosis and is
based on the actual measurement of the distance from
the top of the granular cell layer to the deepest identiﬁ-
able point of tumor invasion.
Clinical staging for cutaneous melanoma is per-
formed using a TNM classiﬁcation system that takes
into account tumor thickness, ulceration, regional
nodal metastasis, and distant metastasis (Table 10-5).
In this system, tumor thickness as measured by the
Breslow classiﬁcation is an important determinant of
tumor (T) classiﬁcation, and the Clark system is used
only to further subtype T1 lesions (thin melanomas
1 mm). Ulceration is an adverse prognostic factor;
thus patients with stage I to III disease are upstaged
(from A to B) when ulceration is present. Among
patients with stage IV disease, elevated serum lactic
dehydrogenase (LDH) is associated with an especially
poor prognosis.
Although depth of invasion and presence of ulcer-
ation are correlated closely with patient outcome in
cutaneous melanomas, such a close association has not
been found in mucosal melanomas. In general, there
is a marked deterioration in prognosis among patients
with oral mucosal melanomas exceeding a depth of
0.5 mm.
Surgical excision is the mainstay of treatment,
although the extent of the excision is somewhat contro-
versial. Older literature suggests that surgical margins
of 3 to 5 cm around the tumor are necessary to achieve
Fig. 10-144 Nodular melanoma. A, Low-power
photomicrograph showing a nodular mass of malignant
melanocytes invading into the dermis. Note the lack of radial
growth in the adjacent overlying epidermis. B, Higher-power
photomicrograph showing atypical spindle-shaped
melanocytes.
Table 10-4 Clark’s Classiﬁcation in Cutaneous Melanoma
Clark’s Deﬁnition of Level of Tumor Invasion Clark’s Classiﬁcation
Cells conﬁned to epithelium Level I
Cells penetrating papillary dermis Level II
Cells ﬁlling papillary dermis Level III
Cells extending into reticular dermis Level IV
Cells invading subcutaneous fat Level V `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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438 ORAL AND MAXILLOFACIAL PATHOLOGY
Table 10-5 TNM Classiﬁcation System and Stage Groupings for Cutaneous Melanoma
a
T CLASSIFICATION TUMOR THICKNESS
(BRESLOW’S DEPTH OF INVASION)
b
ULCERATION STATUS
T1 ≤1.0 mm a: Without ulceration or Clark’s level II/III
b: With ulceration or Clark’s level IV/V
T2 1.01-2.0 mm a: Without ulceration
b: With ulceration
T3 2.01-4.0 mm a: Without ulceration
b: With ulceration
T4 >4.0 mm a: Without ulceration
b: With ulceration
N CLASSIFICATION NUMBER OF METASTATIC REGIONAL
LYMPH NODES
NODAL METASTATIC MASS
N0 0
N1 One a: Microscopic
c
b: Macroscopic
d
N2 Two to three, or intralymphatic regional metastasis
without nodal metastasis
a: Microscopic
b: Macroscopic
c: In-transit metastasis/satellite(s) without
metastatic nodes
N3 Four or more, or matted nodes, or in-transit
e
metastasis/satellite(s)
f
with metastatic nodes
M CLASSIFICATION SITE OF DISTANT METASTASIS SERUM LACTATE DEHYDROGENASE
M0 No distant metastasis Normal
M1a Distant skin, subcutaneous, or nodal metastasisNormal
M1b Lung metastasis Normal
M1c All other visceral metastases
Any distant metastasis
Normal
Elevated
CLINICAL STAGE
GROUPING
TNM CLASSIFICATION FIVE-YEAR SURVIVAL RATE
g
Stage IA T1a N0 M0 95%
Stage IB T1b N0 M0
T2a N0 M0
91%
89%
Stage IIA T2b N0 M0
T3a N0 M0
77%
79%
Stage IIB T3b N0 M0
T4a N0 M0
63%
67%
Stage IIC T4b N0 M0 45%
Stage III Any T N1 M0
Any T N2 M0
Any T N3 M0
29%-70%
24%-63%
27%
Stage IV Any M1 10%-19%
a
Based on Greene FL, Page DL, Fleming ID et al, editors: AJCC cancer staging manual, ed 6, New York, 2002, Springer.
b
Breslow’s depth is measured from the top of the granular cell layer.
c
Microscopic—clinically occult.
d
Macroscopic—clinically apparent.
e
In-transit—intralymphatic metastases occurring within 2 cm of the primary tumor.
f
Satellite metastasis—intralymphatic metastases occurring >2 cm from the primary tumor but before the ﬁrst echelon of regional lymph nodes.
g
Survival data from Balch CM, Buzaid AC, Soong SJ et al: Final version of the American Joint Committee on Cancer staging system for cutaneous
melanoma, J Clin Oncol 19:3635-3648, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 10 EPITHELIAL PATHOLOGY 439
control, regardless of the site of the lesion. More recent
studies indicate that a 1-cm margin is adequate for
small cutaneous tumors less than 2 mm in thickness.
For larger, more deeply invasive tumors, wide surgical
excision still is recommended.
Lymph node dissection is usually performed on
patients with clinically evident regional metastasis in
the absence of distant metastasis. Elective lymph node
dissection for patients with intermediate thickness (1
to 4 mm) lesions in the absence of clinically palpable
nodes is somewhat controversial. The rationale for this
procedure is that these patients have a high probability
of occult regional nodal disease and low probability of
distant metastasis. However, the reported survival
beneﬁt of this treatment strategy is variable, and signiﬁ-
cant morbidity can be associated with lymph node dis-
section. To address this problem, sentinel-node biopsy
(biopsy of the ﬁrst lymph node in the lymphatic basin
to receive drainage from the tumor) often is used as an
alternative to elective lymph node dissection to identify
patients with occult nodal metastases who would
beneﬁt from total lymphadenectomy.
Although melanomas traditionally are considered to
be radioresistant, several clinical studies have demon-
strated that radiation may be of some beneﬁt as adjunc-
tive—or less commonly primary—therapy for certain
subsets of patients; newer radiotherapy techniques,
such as hypofractionation and neutron beam therapy,
may play a greater role in the future. In addition,
adjunct chemotherapy and immunotherapy are
showing promise. With advances in the understanding
of the molecular pathogenesis of melanoma, rationally
designed targeted therapies (e.g., tyrosine kinase inhib-
itors, farnesyltransferase inhibitors, Pl3K pathway
inhibitors) are being developed as well.
The cutaneous melanoma that is detected early
(β1.0-mm thick with or without ulceration, 1.01- to
2.0-mm thick without ulceration) and removed before
metastasis has developed (stages IA and IB) is associ-
ated with an 89% to 95% 5-year survival rate. Cutane-
ous melanoma that is thicker (1.01 to 2.0 mm with
ulceration, 2.01 to >4 mm with or without ulceration)
but has not yet metastasized at the time of diagnosis
(stages IIA to IIC) is associated with a 45% to 77% 5-
year survival rate. If regional lymph node metastasis is
present at the time of diagnosis (stages IIIA to IIIC),
then 5-year survival rates in the range of 24% to 70%
can be expected. The prognosis for patients with dis-
seminated disease present at the time of diagnosis
(stage IV) is dismal, with a 5-year survival rate of only
7% to 19%. Overall, the 5-year survival rate for cutane-
ous melanoma is 92%, and the 10-year survival rate is
79%. Current survival is much improved over past
decades, primarily as a result of public education. Cur-
rently, the clinical features of cutaneous melanoma are
so widely known that many lesions are discovered and
treated at an early stage.
Other factors may inﬂuence the outcome of the
disease besides the depth of invasion. For reasons that
are unclear, melanomas affecting certain cutaneous
sites seem to carry a worse prognosis than those at
other sites with a similar depth of invasion. The areas
with a worse prognosis are designated BANS (inter-
scapular area of the Back, posterior upper Arm, poste-
rior and lateral Neck, and Scalp). In addition, the
prognosis is better for patients younger than 50 years
of age and for women. Follow-up of patients treated for
melanoma is important not only to monitor for meta-
static disease but also because, in 3% to 5% of these
patients, a second primary melanoma will eventually
develop.
The prognosis for oral melanoma is extremely
poor. Although 5-year survival rates as high as 45%
have been reported, in the majority of studies, 5-year
survival rates are in the range of only 13% to 22%. The
poor prognosis for oral melanoma appears to be related
to difﬁculty in achieving wide resection and a tendency
for early hematogenous metastasis. Younger patients
have a better survival than older ones, and patients
with nonpigmented or amelanotic lesions appear to
have a particularly poor prognosis. Patients usually die
from distant metastasis rather than from the lack of
local control. Radical surgical removal is the treatment
of choice; hemimaxillectomy is done for unilateral
lesions that invade the overlying maxillary bone.
BIBLIOGRAPHY
Squamous Papilloma
Abbey LM, Page DG, Sawyer DR: The clinical and histopatho-
logic features of a series of 464 oral squamous cell papillo-
mas, Oral Surg Oral Med Oral Pathol 49:419-428, 1980.
Bouquot JE, Wrobleski GJ: Papillary (pebbled) masses of the oral
mucosa, so much more than simple papillomas, Pract Peri-
odontics Aesth Dent 8:533-543, 1996.
Carr J, Gyorﬁ T: Human papillomavirus. Epidemiology, trans-
mission, and pathogenesis, Clin Lab Med 20:235-255, 2000.
Freed GL, Derkay CS: Prevention of recurrent respiratory papil-
lomatosis: role of HPV vaccination, Int J Pediatr Otorhinolaryn-
gol 70:1799-1803, 2006.
Kimberlin DW, Malis DJ: Juvenile onset recurrent respiratory
papillomatosis: possibilities for successful antiviral therapy,
Antiviral Res 45:83-93, 2000.
Lee HJ, Smith RJ: Recurrent respiratory papillomatosis: patho-
genesis to treatment, Curr Opin Otolaryngol Head Neck Surg
13:354-359, 2005.
Stamataki S, Nikolopoulos TP, Korres S et al: Juvenile recurrent
respiratory papillomatosis: still a mystery disease with difﬁ-
cult management, Head Neck 29:155-162, 2007.
Summersgill KF, Smith EM, Levy BT et al: Human papillomavi-
rus in the oral cavities of children and adolescents, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 91:62-69, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

440 ORAL AND MAXILLOFACIAL PATHOLOGY
Syrjänen S, Puranen M: Human papillomavirus infections in
children: the potential role of maternal transmission, Crit Rev
Oral Biol Med 11:259-274, 2000.
Terai M, Hashimoto K, Yoda K et al: High prevalence of human
papillomaviruses in the normal oral cavity of adults, Oral
Microbiol Immunol 14:201-205, 1999.
Ward KA, Napier SS, Winter PC et al: Detection of human papil-
loma-virus DNA-sequences in oral squamous-cell papillomas
by the polymerase chain-reaction, Oral Surg Oral Med Oral
Pathol 80:63-66, 1995.
Verruca Vulgaris
Bacelieri R, Johnson SM: Cutaneous warts: an evidence-based
approach to therapy, Am Fam Physician 72:647-652, 2005.
Fazel N, Wilczynski S, Lowe L et al: Clinical, histopathologic, and
molecular aspects of cutaneous human papillomavirus infec-
tions, Dermatol Clin 17:521-536, 1999.
Gibbs S, Harvey I: Topical treatments for cutaneous warts,
Cochrane Database Syst Rev 3:CD001781, 2006.
Green TL, Eversole LR, Leider AS: Oral and labial verruca vul-
garis: clinical, histologic, and immunohistochemical evalua-
tion, Oral Surg Oral Med Oral Pathol 62:410-416, 1986.
Kuykendall-Ivy TD, Johnson SM: Evidence-based review of man-
agement of nongenital cutaneous warts, Cutis 71:213-222,
2003.
Lipke MM: An armamentarium of wart treatments, Clin Med Res
4:273-293, 2006.
Micali G, Dall’Oglio F, Nasca M et al: Management of cutaneous
warts: an evidence-based approach, Am J Clin Dermatol 5:311-
317, 2004.
Plunkett A, Merlin K, Gill D et al: The frequency of common
nonmalignant skin conditions in adults in central Victoria,
Australia, Int J Dermatol 38:901-908, 1999.
Terai M, Takagi M, Matsukura T et al: Oral wart associated with
human papillomavirus type 2, J Oral Pathol Med 28:137-140,
1999.
Condyloma Acuminatum
Anderson KM, Perez-Montiel D, Miles L et al: The histologic dif-
ferentiation of oral condyloma acuminatum from its mimics,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96:420-428,
2003.
Baccaglini L, Atkinson JC, Paton LL et al: Management of oral
lesions in HIV-positive patients, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 103(suppl 1):S50.e1-S50.e23, 2007.
Brodell LA, Mercurio MG, Brodell RT: The diagnosis and treat-
ment of human papillomavirus-mediated genital lesions,
Cutis 79(4 suppl):5-10, 2007.
Brown DR, Schroeder JM, Bryan JT et al: Detection of multiple
papillomavirus types in condylomata acuminata lesions from
otherwise healthy and immunosuppressed patients, J Clin
Microbiol 37:3316-3322,1999.
Giraldo P, Gonçalves AKS, Pereira SAS et al: Human papilloma-
virus in the oral mucosa of women with genital human papil-
lomavirus lesions, Eur J Obstet Gynecol Reprod Biol 126:104-106,
2006.
Gloster HM, Roenigk RK: Risk of acquiring human papillomavi-
rus from the plume produced by the carbon dioxide laser in
the treatment of warts, J Am Acad Dermatol 32:436-441,
1995.
Henley JD, Summerlin DJ, Tomich CE: Condyloma acuminatum
and condyloma-like lesions of the oral cavity: a study of 11
cases with an intraductal component, Histopathology 44:216-
221, 2004.
Kodner CM, Nasraty S: Management of genital warts, Am Fam
Physician 70:2335-2342, 2345-2346, 2004.
Scheinfeld N, Lehman DS: An evidence-based review of medical
and surgical treatments of genital warts, Dermatol Online J
12:5, 2006.
Silverman S Jr, Migliorati CA, Lozada-Nur F et al: Oral ﬁndings
in people with or at high risk for AIDS: a study of 375 homo-
sexual males, J Am Dent Assoc 112:187-192, 1986.
Simon PA: Oral condyloma acuminatum as an indicator of sexual
abuse: dentistry’s role, Quintessence Int 29:455-458, 1998.
Suskind DL, Mirza N, Rosin D et al: Condyloma acuminatum
presenting as a base-of-tongue mass, Otolaryngol Head Neck
Surg 114:487-490, 1996.
Zunt SL, Tomich CE: Oral condyloma acuminatum, J Dermatol
Surg Oncol 15:591-594, 1989.
Multifocal Epithelial Hyperplasia
Aykol A, Anadolu R, Anadolu Y et al: Multifocal papillomavirus
epithelial hyperplasia: successful treatment with CO
2 laser
therapy combined with interferon alpha-2b, Int J Dermatol
42:733-735, 2003.
Benevides dos Santos PJ, Borborema dos Santos CM, Mendonça
RR et al: Human papillomavirus type 13 infecting the con-
junctiva, Diagn Microbiol Infect Dis 53:71-73, 2005.
Borborema-Santos CM, de Castro MM, Benevides dos Santos PJ
et al: Oral focal epithelial hyperplasia: report of ﬁve cases,
Braz Dent J 17:79-82, 2006.
Carlos R, Sedano HO: Multifocal papilloma virus epithelial
hyperplasia, Oral Surg Oral Med Oral Pathol 77:631-635,
1994.
Cuberos V, Perez J, Lopez CJ et al: Molecular and serological
evidence of the epidemiological association of HPV 13 with
focal epithelial hyperplasia: a case-control study, J Clin Virol
37:21-26, 2006.
Garcia-Corona C, Vega-Memije E, Mosqueda-Taylor A et al:
Association of HLA-DR4 (DRB1*0404) with human papillo-
mavirus infection in patients with focal epithelial hyperplasia,
Arch Dermatol 140:1227-1231, 2004.
González LV, Gaviria AM, Sanclemente G et al: Clinical, histo-
pathological and virological ﬁndings in patients with focal
epithelial hyperplasia from Colombia, Int J Dermatol 44:274-
279, 2005.
Harris AM, van Wyk CW: Heck’s disease (focal epithelial hyper-
plasia): a longitudinal study, Community Dent Oral Epidemiol
21:82-85, 1993.
Ledesma-Montes C, Vega-Memije E, Garcés-Ortíz M et al: Mul-
tifocal epithelial hyperplasia. Report of nine cases, Med Oral
Patol Oral Cir Bucal 10:394-401, 2005.
Steinhoff M, Metze D, Stockﬂeth E et al: Successful topical treat-
ment of focal epithelial hyperplasia (Heck’s disease) with
interferon-β, Br J Dermatol 144:1067-1069, 2001.
Tan AK, Tewﬁk TL, Moroz B et al: Focal epithelial hyperplasia,
Otolaryngol Head Neck Surg 112:316-320, 1995.
Viraben R, Aquilina C, Brousset P et al: Focal epithelial hyper-
plasia (Heck disease) associated with AIDS, Dermatology
193:261-262, 1996.
Witkop CJ Jr, Niswander JD: Focal epithelial hyperplasia in
Central and South American Indians and Latinos, Oral Surg
Oral Med Oral Pathol 20:213-217, 1965.
Sinonasal Papillomas
Batsakis JG, Suarez P: Schneiderian papillomas and carcinomas:
a review, Adv Anat Pathol 8:53-64, 2001.
Bawa R, Allen GC, Ramadan HH: Cylindrical cell papilloma of
the nasal septum, Ear Nose Throat J 74:179-181, 1995.
Busquets JM, Hwang PH: Endoscopic resection of sinonasal
inverted papilloma: a meta-analysis, Otolaryngol Head Neck
Surg 134:476-482, 2006. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 441
Califano J, Koch W, Sidransky D et al: Inverted sinonasal papil-
loma: a molecular genetic appraisal of its putative status as a
precursor to squamous cell carcinoma, Am J Pathol 156:333-
337, 2000.
Eggers G, Mühling J, Hassfeld S: Inverted papilloma of paranasal
sinuses, J Craniomaxillofac Surg 35:21-29, 2007.
Holzmann D, Hegyi I, Rajan GP et al: Management of benign
inverted sinonasal papilloma avoiding external approaches,
J Laryngol Otol 121:548-554, 2007.
Hyams VJ: Papillomas of the nasal cavity and paranasal sinuses:
a clinicopathological study of 315 cases, Ann Otol Rhinol Lar-
yngol 80:192-206, 1971.
Kaufman MR, Brandwein MS, William L: Sinonasal papillomas:
clinicopathologic review of 40 patients with inverted and
oncocytic Schneiderian papillomas, Laryngoscope 112:1372-
1377, 2002.
Lane AP, Bolger WE: Endoscopic management of inverted papil-
loma, Curr Opin Otolaryngol Head Neck Surg 14:14-18, 2006.
Lawson W, Kaufman MR, Biller HF: Treatment outcomes in the
management of inverted papilloma: an analysis of 160 cases,
Laryngoscope 113:1548-1556, 2003.
Maitra A, Baskin LB, Lee EL: Malignancies arising in oncocytic
Schneiderian papillomas: a report of 2 cases and review of
the literature, Arch Pathol Lab Med 125:1365-1367, 2001.
Mansell NJ, Bates GJ: The inverted Schneiderian papilloma: a
review and literature report of 43 new cases, Rhinology 38:97-
101, 2000.
Melroy CT, Senior BA: Benign sinonasal neoplasms: a focus on
inverting papilloma, Otolaryngol Clin North Am 39:601-617,
2006.
Minovi A, Kollert M, Draf W et al: Inverted papilloma: feasibility
of endonasal surgery and long-term results of 87 cases, Rhi-
nology 44:205-210, 2006.
Mirza S, Bradley PJ, Acharya A et al: Sinonasal inverted papillo-
mas: recurrence, and synchronous and metachronous malig-
nancy, J Laryngol Otol 1:1-8, 2007.
Pasquini E, Sciaretta V, Farneti G et al: Inverted papilloma:
report of 89 cases, Am J Otolaryngol 25:178-185, 2005.
Sauter A, Matharu R, Hörmann K et al: Current advances in the
basic research and clinical management of sinonasal inverted
papilloma (review), Oncol Rep 17:495-504, 2007.
Sulica RL, Wenig BM, Debo RF et al: Schneiderian papillomas
of the pharynx, Ann Otol Rhinol Laryngol 108:392-397,
1999.
Weiner JS, Sherris D, Kasperbauer J et al: Relationship of human
papillomavirus to Schneiderian papillomas, Laryngoscope
109:21-26, 1999.
Yang YJ, Abraham JL: Undifferentiated carcinoma arising in
oncocytic Schneiderian (cylindrical cell) papilloma, J Oral
Maxillofac Surg 55:289-294, 1997.
Yoskovitch A, Braverman I, Nachtigal D et al: J Sinonasal
schneiderian papilloma, Otolaryngology 27:122-126, 1998.
Molluscum Contagiosum
Braue A, Ross G, Varigos G et al: Epidemiology and impact of
childhood molluscum contagiosum: a case series and critical
review of the literature, Pediatr Dermatol 22:287-294, 2005.
Brown J, Janniger CK, Schwartz RA et al: Childhood molluscum
contagiosum, Int J Dermatol 45:93-99, 2006.
Fornatora ML, Reich RF, Gray RG et al: Intraoral molluscum
contagiosum: report of a case and review of the literature,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92:318-320,
2001.
Smith KJ, Skelton H: Molluscum contagiosum: recent advances
in pathogenic mechanisms and new therapies, Am J Clin Der-
matol 3:535-545, 2002.
Smith KJ, Yeager J, Skelton H: Molluscum contagiosum: its clini-
cal, histopathologic, and immunohistochemical spectrum, Int
J Dermatol 38:664-672, 1999.
van der Wouden JC, Menke J, Gajadin S et al: Interventions for
cutaneous molluscum contagiosum, Cochrane Database Syst
Rev 2:CD004767, 2006.
Watanabe T, Nakamura K, Wakugawa M et al: Antibodies to
molluscum contagiosum virus in the general population and
susceptible patients, Arch Dermatol 136:1518-1522, 2000.
Whitaker SB, Wiegand SE, Budnick SD: Intraoral molluscum
contagiosum, Oral Surg Oral Med Oral Pathol 72:334-336,
1991.
Verruciform Xanthoma
Allen CM, Kapoor N: Verruciform xanthoma in a bone marrow
transplant recipient, Oral Surg Oral Med Oral Pathol 75:591-
594, 1993.
Connolly SB, Lewis EJ, Lindholm JS et al: Management of cutane-
ous verruciform xanthoma, J Am Acad Dermatol 42:343-347,
2000.
Hu H, Li Y, Li S: Verruciform xanthoma of the oral cavity: clini-
copathological study relating to pathogenesis, APMIS
113:629-634, 2005.
Huang JS, Tseng CC, Jin YT et al: Verruciform xanthoma. Case
report and literature review, J Periodontol 67:162-165,
1996.
Neville B: The verruciform xanthoma: a review and report of
eight new cases, Am J Dermatopathol 8:247-253, 1986.
Nowparast B, Howell FV, Rick GM: Verruciform xanthoma: a
clinicopathologic review and report of ﬁfty-four cases, Oral
Surg Oral Med Oral Pathol 51:619-625, 1981.
Oliveira PT, Jaeger RG, Cabral LAG et al: Verruciform xanthoma
of the oral mucosa. Report of four cases and a review of the
literature, Oral Oncol 37:326-331, 2001.
Philipsen HP, Reichart PA, Takata T et al: Verruciform xan-
thoma—biological proﬁle of 282 oral lesions based on a litera-
ture survey with nine new cases from Japan, Oral Oncol
39:325-336, 2003.
Yu CH, Tsai TC, Wang JT et al: Oral verruciform xanthoma: a
clinicopathologic study of 15 cases, J Formos Med Assoc
106:141-147, 2007.
Seborrheic Keratosis
Ellis DL, Yates RA: Sign of Leser-Trélat, Clin Dermatol 11:141-
148, 1993.
Hafner C, Hartmann A, Vogt T: FGFR3 mutations in epidermal
nevi and seborrheic keratoses: lessons from urothelium and
skin, J Invest Dermatol 127:1572-1573, 2007.
Izikson L, Sober AJ, Mihm MC et al: Prevalence of melanoma
clinically resembling seborrheic keratosis: analysis of 9204
cases, Arch Dermatol 138:1562-1566, 2002.
Silver SG, Ho VCY: Seborrheic keratosis. In Freedberg IM, Eisen
AZ, Wolff K et al, editors: Fitzpatrick’s dermatology in general
medicine, ed 6, pp 767-770, New York, 2003, McGraw-Hill.
Wade TR, Ackerman AB: The many faces of seborrheic kerato-
ses, J Dermatol Surg Oncol 5:378-382, 1979.
Wilborn WH, Dismukes DE, Montes IF: Seborrheic keratoses,
J Cutan Pathol 5:373-375, 1978.
Sebaceous Hyperplasia
Daley TD: Intraoral sebaceous hyperplasia: diagnostic criteria,
Oral Surg Oral Med Oral Pathol 75:343-347, 1993.
Dent CD, Hunter WE, Svirsky JA: Sebaceous gland hyperplasia:
case report and literature review, J Oral Maxillofac Surg
53:936-938, 1995.
De Villez RL, Roberts LC: Premature sebaceous gland hyperpla-
sia, J Am Acad Dermatol 6:933-935, 1982. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

442 ORAL AND MAXILLOFACIAL PATHOLOGY
Graham-Brown RAC, McGibbon DH, Sarkany I: A papular
plaque-like eruption on the face due to naevoid sebaceous
gland hyperplasia, Clin Exp Dermatol 8:379-382, 1983.
Richey DF: Aminolevulinic acid photodynamic therapy for seba-
ceous gland hyperplasia, Dermatol Clin 25:59-65, 2007.
Ephelis
Bastiaens M, Hoefnagel J, Westendorp R et al: Solar lentigines
are strongly related to sun exposure in contrast to ephelides,
Pigment Cell Res 17:225-229, 2004.
Bastiaens M, ter Huurne J, Gruis N et al: The melanocortin-1-
receptor gene is the major freckle gene, Human Mol Genet
10:1701-1708, 2001.
Bastiaens MT, Westendorp RG, Vermeer BJ et al: Ephelides are
more related to pigmentary constitutional host factors than
solar lentigines, Pigment Cell Res 12:316-322, 1999.
Bliss JM, Ford D, Swerdlow AJ et al: Risk of cutaneous melanoma
associated with pigmentation characteristics and freckling:
systematic overview of 10 case-control studies, Int J Cancer
62:367-372, 1995.
Actinic Lentigo
Andersen WK, Labadie RR, Bhawan J: Histopathology of solar
lentigines of the face: a quantitative study, J Am Acad Dermatol
36:444-447, 1997.
Beacham BE: Solar-induced epidermal tumors in the elderly, Am
Fam Physician 42:153-160, 1990.
Fleischer AB Jr, Schwartzel EH, Colby SI et al: The combination
of 2% 4-hydroxyanisole (Mequinol) and 0.01% tretinoin is
effective in improving the appearance of solar lentigines and
related hyperpigmented lesions in two double-blind multi-
center clinical studies, J Am Acad Dermatol 42:459-467,
2004.
Holzle E: Pigmented lesions as a sign of photodamage, Br J Der-
matol 127:48-50, 1992.
Jarratt M: Mequinol 2%/tretinoin 0.01% solution: an effective and
safe alternative to hydroquinone 3% in the treatment of solar
lentigines, Cutis 74:319-322, 2004.
Kang S, Goldfarb MT, Weiss JS et al: Assessment of adapalene
gel for the treatment of actinic keratoses and lentigines: a
randomized trial, J Am Acad Dermatol 49:83-90, 2003.
Monestier S, Gaudy C, Gouvernet J et al: Multiple senile lentigos
of the face, a skin ageing pattern resulting from a life excess
of intermittent sun exposure in dark-skinned Caucasians: a
case-control study, Br J Dermatol 154:438-444, 2006.
Ortonne JP, Pandya AG, Lui H et al: Treatment of solar lentigi-
nes, J Am Acad Dermatol 54:S262-S271, 2006.
Rafal ES, Grifﬁths CE, Ditre CM et al: Topical tretinoin (retinoic
acid) treatment for liver spots associated with photodamage,
N Engl J Med 326:368-374, 1992.
Shimbashi T, Kamide R, Hashimoto T: Long-term follow-up in
treatment of solar lentigo and café-au-lait macules with Q-
switch ruby laser, Aesthetic Plast Surg 21:445-448, 1997.
Lentigo Simplex
Buchner A, Merrell PW, Hansen LS et al: Melanocytic hyperpla-
sia of the oral mucosa, Oral Surg Oral Med Oral Pathol 71:58-
62, 1991.
Coleman WP 3rd, Gately LE 3rd, Krementz AB et al: Nevi,
lentigines and melanomas in blacks, Arch Dermatol 116:548-
551, 1980.
Gorlin RJ, Andersen RC, Blaw M: Multiple lentigines syndrome,
Am J Dis Child 117:652-662, 1969.
Grichnik JM, Rhodes AR, Sober AJ: Lentigo simplex. In Freed-
berg IM, Eisen AZ, Wolff K et al, editors: Fitzpatrick’s dermatol-
ogy in general medicine, ed 6, pp 881-882, New York, 2003,
McGraw-Hill.
Melasma
Aloi F, Solaroli C, Giovannini E: Actinic lichen planus simulating
melasma, Dermatology 195:69-70, 1997.
Gupta AK, Gover MD, Nouri K et al: The treatment of melasma:
a review of clinical trials, J Am Acad Dermatol 55:1048-1065,
2006.
Kauh YC, Zachian TF: Melasma, Adv Exp Med Biol 455:491-499,
1999.
Lim JT: Treatment of melasma using kojic acid in a gel containing
hydroquinone and glycolic acid, Dermatol Surg 25:282-284,
1999.
Rendon M, Berneburg M, Arellano I et al: Treatment of melasma,
J Am Acad Dermatol 54:S272-S281, 2006.
Sanchez NP, Pathuk MA, Sato S et al: Melasma: a clinical, light
microscopic, ultrastructural and immunoﬂuorescence study,
J Am Acad Dermatol 4:698-703, 1981.
Victor FC, Gelber J, Rao B: Melasma: a review, J Cutan Med Surg
8:97-102, 2004.
Oral Melanotic Macule
Axéll T: A prevalence study of oral mucosal lesions in an adult
Swedish population, Odontol Revy 27:1-103, 1976.
Bouquot JE: Common oral lesions found during a mass screening
examination, J Am Dent Assoc 112:50-57, 1986.
Bouquot JE, Nikai H: Lesions of the oral cavity. In Gnepp DR,
editor: Diagnostic surgical pathology of the head and neck, pp 141-
238, Philadelphia, 2001, WB Saunders.
Buchner A, Hansen LS: Melanotic macule of the oral mucosa: a
clinicopathologic study of 105 cases, Oral Surg Oral Med Oral
Pathol 48:244-249, 1979.
Buchner A, Merrell PW, Carpenter WM: Relative frequency of
solitary melanocytic lesions of the oral mucosa, J Oral Pathol
Med 33:550-557, 2004.
Dohil MA, Billman G, Pransky S et al: The congenital lingual
melanotic macule, Arch Dermatol 139:767-770, 2003.
Kaugars GE, Heise AP, Riley WT et al: Oral melanotic macules:
a review of 353 cases, Oral Surg Oral Med Oral Pathol 76:
59-61, 1993.
Weathers DR, Corio RL, Crawford BE et al: The labial melanotic
macule, Oral Surg Oral Med Oral Pathol 42:196-205, 1976.
Yeh CJ: Simple cryosurgical treatment of the oral melanotic
macule, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
90:12-13, 2000.
Oral Melanoacanthoma
Andrews BT, Trask DK: Oral melanoacanthoma: a case report, a
review of the literature, and a new treatment option, Ann Otol
Rhinol Laryngol 114:677-680, 2005.
Chandler K, Chaudhry Z, Kumar N et al: Melanoacanthoma: a
rare cause of oral hyperpigmentation, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 84:492-494, 1997.
Contreras E, Carlos R: Oral melanoacanthosis (melanoachan-
toma): report of a case and review of the literature, Med Oral
Patol Oral Cir Bucal 10:9-12, 2005.
Fatahzadeh M, Sirois DA: Multiple intraoral melanoacanthomas:
a case report with unusual ﬁndings, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 94:54-56, 2002.
Fornatora ML, Reich RF, Haber S et al: Oral melanoacanthoma:
a report of 10 cases, review of literature, and immunohisto-
chemical analysis of HMB-45 reactivity, Am J Dermatopathol
25:12-15, 2003.
Heine BT, Drummond JF, Damm DD et al: Bilateral oral mela-
noacanthoma, Gen Dent 44:451-452, 1996.
Landwehr DJ, Halkins LE, Allen CM: A rapidly growing pig-
mented plaque, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 84:332-334, 1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 443
Tomich CE, Zunt SL: Melanoacanthosis (melanoacanthoma) of
the oral mucosa, J Dermatol Surg Oncol 16:231-236, 1990.
Melanocytic Nevus
Allen CM, Pellegrini A: Probable congenital melanocytic nevus
of the oral mucosa: case report, Pediatr Dermatol 12:145-148,
1995.
Barnhill RL: The Spitzoid lesion: the importance of atypical variants
and risk assessment, Am J Dermatopathol 28:75-83, 2006.
Bett BJ: Large or multiple congenital melanocytic nevi: occur-
rence of cutaneous melanoma in 1008 persons, J Am Acad
Dermatol 52:793-797, 2005.
Brener MD, Harrison BD: Intraoral blue nevus: report of a case,
Oral Surg Oral Med Oral Pathol 28:326-330, 1969.
Buchner A, Hansen LS: Pigmented nevi of the oral mucosa: a
clinicopathologic study of 36 new cases and review of 155
cases from the literature. Part I: a clinicopathologic study of
36 new cases, Oral Surg Oral Med Oral Pathol 63:566-572,
1987.
Buchner A, Hansen LS: Pigmented nevi of the oral mucosa: a
clinicopathologic study of 36 new cases and review of 155
cases from the literature. Part II: analysis of 191 cases, Oral
Surg Oral Med Oral Pathol 63:676-682, 1987.
Buchner A, Leider AS, Merrell PW et al: Melanocytic nevi of oral
mucosa: a clinicopathologic study of 130 cases from northern
California, J Oral Pathol Med 19:197-201, 1990.
Casso EM, Grin-Jorgensen CM, Grant-Kels JM: Spitz nevi, J Am
Acad Dermatol 27:901-913, 1992.
Chuang WY, Hao SP, Yeh CJ et al: Blue nevi of the sinonasal
mucosa: a report of two cases and review of the literature,
Laryngoscope 117:371-372, 2007.
Dorji T, Cavazza A, Nappi O et al: Spitz nevus of the tongue with
pseudoepitheliomatous hyperplasia: report of three cases of
a pseudomalignant condition, Am J Surg Pathol 26:774-777,
2002.
Fistarol SK, Itin PH: Plaque-type blue nevus of the oral cavity,
Dermatology 211:224-233, 2005.
Flaitz CM, McCandless G: Palatal blue nevus in a child, Pediatr
Dent 23:354-355, 2001.
Frank SB, Cohen HJ: The halo nevus, Arch Dermatol 89:367-373,
1964.
Hale EK, Stein J, Ben-Porat L et al: Association of melanoma and
neurocutaneous melanocytosis with large congenital melano-
cytic naevi—results from the NYU-LCMN registry, Br J Derma-
tol 152:512-517, 2005.
Laskaris G, Kittas C, Triantafyllou A: Unpigmented intramucosal
nevus of palate. An unusual clinical presentation, Int J Oral
Maxillofac Surg 23:39-40, 1994.
LeBoit P: Spitz nevus: a look back and a look ahead, Adv Dermatol
16:81-109, 2000.
Mader CL, Konzelman JL: Intraoral blue nevus—a review, Cutis
24:165-166, 1979.
Marghoob, AA, Agero ALC, Benvenuto-Andrade C et al: Large
congenital melanocytic nevi, risk of cutaneous melanoma,
and prophylactic surgery, J Am Acad Dermatol 54:868-870,
2006.
Meleti M, Mooi WJ, Casparie MK et al: Melanocytic nevi of the
oral mucosa—no evidence of an increased risk for oral malig-
nant melanoma: an analysis of 119 cases, Oral Oncol 43:
976-981, 2007.
Mones JM, Ackerman AB: “Atypical” Spitz’s nevus, “malignant”
Spitz’s nevus, and “metastasizing” Spitz’s nevus: a critique in
historical perspective of three concepts and ﬂawed fatally,
Am J Dermatopathol 26:310-333, 2004.
Mooi WJ: Spitz nevus and its histologic simulators, Adv Anat
Pathol 9:209-221, 2002.
Nikia H, Miyauchi M, Ogawa I et al: Spitz nevus of the palate.
Report of a case, Oral Surg Oral Med Oral Pathol 69:603-608,
1990.
Pinto A, Raghavendra S, Lee R et al: Epithelioid blue nevus of
the oral mucosa: a rare histologic variant, Oral Surg Oral Med
Oral Pathol 96:429-436, 2003.
Sulit DJ, Guardiano RA, Krivda S: Classic and atypical Spitz nevi:
review of the literature, Cutis 79:141-146, 2007.
Takata M, Saida T: Genetic alterations in melanocytic tumors,
J Dermatol Sci 43:1-10, 2006.
Weedon D, Little JH: Spindle and epithelioid cell nevi in chil-
dren and adults: a review of 211 cases of the Spitz nevus,
Cancer 40:217-225, 1977.
Zembowicz A, Mihm MC: Dermal dendritic melanocytic prolif-
erations: an update, Histopathology 45:433-451, 2004.
Leukoplakia
Alexander RE, Wright JM, Thiebaud S: Evaluating, documenting
and following up oral pathological conditions. A suggested
protocol, J Am Dent Assoc 132:329-335, 2001.
Bagán JV, Jimenez Y, Sanchis JM: Proliferative verrucous leuko-
plakia: high incidence of gingival squamous cell carcinoma,
J Oral Pathol Med 32:379-382, 2003.
Bagán JV, Murillo J, Poveda R et al: Proliferative verrucous leu-
koplakia: unusual locations of oral squamous cell carcinomas,
and ﬁeld cancerization as shown by the appearance of mul-
tiple OSCCs, Oral Oncol 40:440-443, 2004.
Bánóczy J: Follow-up studies in oral leukoplakia, J Maxillofac Surg
5:69-75, 1977.
Barrett AW, Kingsmill VJ, Speight PM: The frequency of fungal
infection in biopsies of oral mucosal lesions, Oral Dis 4:26-31,
1998.
Bernstein ML: Oral mucosal white lesions associated with exces-
sive use of Listerine mouthwash: report of two cases, Oral Surg
Oral Med Oral Pathol 46:781-785, 1978.
Bouquot JE, Gorlin RJ: Leukoplakia, lichen planus and other oral
keratoses in 23,616 white Americans over the age of 35
years, Oral Surg Oral Med Oral Pathol 61:373-381, 1986.
Bouquot J, Kurland L, Weiland L: Leukoplakia of the head and
neck: characteristics of 568 lesions with 6,720 person-years
of follow-up, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
88:202, 1999.
Bouquot JE, Weiland LH, Kurland LT: Leukoplakia and carci-
noma in situ synchronously associated with invasive oral/oro-
pharyngeal carcinoma in Rochester, Minnesota, 1935-1984,
Oral Surg Oral Med Oral Pathol 65:199-207, 1988.
Bouquot JE, Whitaker SB: Oral leukoplakia—rationale for diag-
nosis and prognosis of its clinical subtypes or “phases,” Quin-
tessence Int 25:133-140, 1994.
Brennan M, Migliorati CA, Lockhart PB et al: Management of
oral epithelial dysplasia: a review, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 103 (suppl 1):S19.e1-S19.e12,
2007.
Cabay RJ, Morton TH, Epstein JB: Proliferative verrucous leuko-
plakia and its progression to oral carcinoma: a review of the
literature, J Oral Pathol Med 36:255-261, 2007.
Chi AC, Lambert PR 3rd, Pan Y et al: Is alveolar ridge keratosis
a true leukoplakia? A clinicopathologic comparison of 2,153
lesions, J Am Dent Assoc 138:641-651, 2007.
Cowan CG, Gregg TA, Napier SS et al: Potentially malignant oral
lesions in Northern Ireland: a 20-year population-based per-
spective of malignant transformation, Oral Dis 7:18-24,
2001.
Crissman JD, Zarbo RJ: Dysplasia, in situ carcinoma, and pro-
gression to invasive squamous cell carcinoma of the upper
aerodigestive tract, Am J Surg Pathol 13(suppl 1):5-16, 1989. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

444 ORAL AND MAXILLOFACIAL PATHOLOGY
Daley TD, Lovas JG, Peters E et al: Salivary duct involvement in
oral epithelial dysplasia and squamous cell carcinoma, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 81:186-192,
1996.
Damm DD, Curran A, White DK et al: Leukoplakia of the maxil-
lary vestibule—an association with Viadent? Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 87:61-66, 1999.
Eversole LR, Eversole GM, Kopcik J: Sanguinaria-associated oral
leukoplakia: comparison with other benign and dysplastic
leukoplakic lesions, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 89:455-464, 2000.
Fettig A, Pogrel MA, Silverman S Jr et al: Proliferative verrucous
leukoplakia of the gingiva, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 90:723-730, 2000.
Holmstrup P, Vedtofte P, Reibel J et al: Long-term treatment
outcome of oral premalignant lesions, Oral Oncol 42:461-474,
2006.
Holmstrup P, Vedtofte P, Reibel J et al: Oral premalignant
lesions: is a biopsy reliable? J Oral Pathol Med 36:262-266,
2007.
Hsue SS, Wang WC, Chen CH et al: Malignant transformation
in 1458 patients with potentially malignant oral mucosal dis-
orders: a follow-up study based in a Taiwanese hospital, J Oral
Pathol Med 36:25-29, 2007.
Kaugars GE, Burns JC, Gunsolley JC: Epithelial dysplasia of the
oral cavity and lips, Cancer 62:2166-2170, 1988.
King GN, Healy CM, Glover MT et al: Increased prevalence of
dysplastic and malignant lip lesions in renal-transplant recip-
ients, N Eng J Med 332(16):1052-1057, 1995.
Lee JJ, Hong WK, Hittelman WN et al: Predicting cancer devel-
opment in oral leukoplakia: ten years of translational research,
Clin Cancer Res 6:1702-1710, 2000.
Lee JJ, Hung CH, Cheng SJ et al: Carcinoma and dysplasia in oral
leukoplakias in Taiwan: prevalence and risk factors, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 110:472-480, 2006.
Lodi G, Sardella A, Bez C et al: Systematic review of randomized
trials for the treatment of oral leukoplakia, J Dent Educ 66:896-
902, 2002.
Lodi G, Sardella A, Bez C et al: Interventions for treating oral
leukoplakia, Cochrane Database Syst Rev 4:CD001829, 2006.
Martin IC, Kerawala CJ, Reed M: The application of toluidine
blue as a diagnostic adjunct in the detection of epithelial
dysplasia, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
85:444-446, 1998.
Mascarenhas AK, Allen CM, Moeschberger ML: The association
between Viadent use and oral leukoplakia, Epidemiology
12:741-743, 2001.
Mascarenhas AK, Allen CM, Moeschberger ML: The association
between Viadent use and oral leukoplakia—results of a
matched case-control study, J Public Health Dent 62:158-162,
2002.
Mithani SK, Mydlarz, WK, Grumbine FL et al: Molecular genet-
ics of premalignant oral lesions, Oral Dis 13:126-133, 2007.
Nielson H, Norrild B, Vedtofte P et al: Human papillomavirus in
oral premalignant lesions, Eur J Cancer B Oral Oncol 32B:264-
270, 1996.
Napier SS, Cowan CG, Gregg TA et al: Potentially malignant oral
lesions in Northern Ireland: size (extent) matters, Oral Dis
9:129-137, 2003.
Pandey M, Thomas G, Somanathan T et al: Evaluation of surgical
excision of non-homogeneous oral leukoplakia in a screening
intervention trial, Kerala, India, Oral Oncol 37:103-109,
2001.
Petti S: Pooled estimate of world leukoplakia prevalence: a sys-
tematic review, Oral Oncol 39:770-780, 2003.
Pindborg JJ, Daftary DK, Mehta FS: A follow-up study of sixty-
one oral dysplastic precancerous lesions in Indian villagers,
Oral Surg Oral Med Oral Pathol 43:383-390, 1977.
Reibel J: Prognosis of oral pre-malignant lesions: signiﬁcance of
clinical, histopathological, and molecular biological charac-
teristics, Crit Rev Oral Biol Med 14:47-62, 2003.
Roed-Petersen B: Effect on oral leukoplakia of reducing or
ceasing tobacco smoking, Acta Derm Venereol 62:164-167,
1982.
Rosin MP, Cheng X, Poh C et al: Use of allelic loss to predict
malignant risk for low-grade oral epithelial dysplasia, Clin
Cancer Res 6:357-362, 2000.
Sankaranarayanan R, Mathew B, Varghese C et al: Chemopre-
vention of oral leukoplakia with vitamin A and beta carotene:
an assessment, Oral Oncol 33:231-236, 1997.
Scheifele C, Reichart PA, Dietrich T: Low prevalence of oral
leukoplakia in a representative sample of the US population,
Oral Oncol 39:619-625, 2003.
Schoelch ML, Sekandari N, Regezi JA et al: Laser management
of oral leukoplakias: a follow-up study of 70 patients, Laryn-
goscope 109:949-953, 1999.
Sciubba JJ: Oral leukoplakia, Crit Rev Oral Biol Med 6:147-160,
1995.
Shepman KP, van der Meij EH, Smeele LE et al: Malignant trans-
formation of oral leukoplakia: a follow-up study of a hospital-
based population of 166 patients with oral leukoplakia from
The Netherlands, Oral Oncol 34:270-275, 1998.
Shiu MN, Chen TH, Chang SH et al: Risk factors for leukoplakia
and malignant transformation to oral carcinoma: a leukopla-
kia cohort in Taiwan, Br J Cancer 82:1871-1874, 2000.
Silverman S Jr, Gorsky M: Proliferative verrucous leukoplakia: a
follow-up study of 54 cases, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 84:154-157, 1997.
Silverman S Jr, Gorsky M, Lozada F: Oral leukoplakia and malig-
nant transformation: a follow-up study of 257 patients, Cancer
53:563-568, 1984.
Speight PM, Farthing PM, Bouquot JE: The pathology of oral
cancer and precancer, Curr Diag Pathol 3:165-176, 1997.
Van der Waal I, Axéll T: Oral leukoplakia: a proposal for uniform
reporting, Oral Oncol 38:521-526, 2002.
Van der Waal I, Shepman KP, van der Meij EH et al: Oral leu-
koplakia: a clinicopathologic review, Oral Oncol 33:291-301,
1998.
Waldron CA, Shafer WG: Leukoplakia revisited: a clinicopatho-
logic study of 3256 oral leukoplakias, Cancer 36:1386-1392,
1975.
Zakrzewska JM, Lopes V, Speight P et al: Proliferative verrucous
leukoplakia: a report of ten cases, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 82:396-401, 1996.
Zhang L, Rosin MP: Loss of heterozygosity: a potential tool in
management of oral premalignant lesions? J Oral Pathol Med
30:513-520, 2001.
Erythroplakia
Amagasa T, Yokoo E, Sata K et al: A study of the clinical charac-
teristics and treatment of oral carcinoma in situ, Oral Surg
Oral Med Oral Pathol 60:50-55, 1985
Bouquot JE, Gnepp DR: Epidemiology of carcinoma in situ of the
upper aerodigestive tract, Cancer 61:1685-1690, 1988.
Bouquot JE, Ephros H: Erythroplakia: the dangerous red mucosa,
Pract Periodontics Aesth Dent 7:59-68, 1995.
Bouquot JE, Kurland LT, Weiland LH: Carcinoma in situ of the
upper aerodigestive tract: incidence, time trends, and follow-
up in Rochester, Minnesota, 1935-1984, Cancer 61:1691-
1698, 1988. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 445
Hashibe M, Mathew B, Kuruvilla B et al: Chewing tobacco,
alcohol and the risk of erythroplakia, Cancer Epidemiol Bio-
markers Prev 9:639-645, 2000.
Lumerman H, Freedman P, Kerpel S: Oral epithelial dysplasia
and the development of invasive squamous cell carcinoma,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:321-329,
1995.
Mincer HH, Coleman SA, Hopkins KP: Observations on the
clinical characteristics of oral lesions showing histologic epi-
thelial dysplasia, Oral Surg Oral Med Oral Pathol 33:389-399,
1972.
Reichart PA, Philipsen HP: Oral erythroplakia—a review, Oral
Oncol 41:551-561, 2005.
Shafer WG, Waldron CA: Erythroplakia of the oral cavity, Cancer
36:1021-1028, 1975.
Smokeless Tobacco Keratosis
Axéll T, Mörnstad H, Sundström B: The relation of the clinical
picture to the histopathology of snuff dipper’s lesions in a
Swedish population, J Oral Pathol 5:229-236, 1976.
Bergström J, Keilani H, Lundholm C et al: Smokeless tobacco
(snuff) use and periodontal bone loss, J Clin Periodontol
33:549-554, 2006.
Bouquot JE, Glover ED, Schroeder KL: Leukoplakia and smoke-
less tobacco keratosis are two separate precancers. In Varma
AD: Oral oncology, vol 2, pp 67-69, Delhi, India, 1991,
MacMillan.
Centers for Disease Control and Prevention: Tobacco use among
adults—United States, 2005, MMWR Morb Mortal Wkly Rep
55:1145-1148, 2006.
Centers for Disease Control and Prevention: Youth risk behavior
surveillance—United States, 2005, MMWR Morb Mortal Wkly
Rep 55:1-112, 2006.
Ebbert JO, Carr AB, Dale LC: Smokeless tobacco: an emerging
addiction, Med Clin North Am 88:1593-1605, 2004.
Ebbert JO, Rowland LC, Montori VM et al: Treatments for spit
tobacco use: a quantitative systematic review, Addiction
98:569-583, 2003.
Fisher MA, Taylor GW, Tilashalski KR: Smokeless tobacco and
severe active periodontal disease. NHANES III, J Dent Res
84:705-710, 2005.
Grasser JA, Childers E: Prevalence of smokeless tobacco use and
clinical oral leukoplakia in a military population, Mil Med
162:401-404, 1997.
Gupta PC, Hebert JR, Bhonsle RB et al: Inﬂuence of dietary
factors on oral precancerous lesions in population-based
case-controlled study in Kerala, India, Cancer 85:1885-1893,
1999.
Kaugars GE, Riley WT, Brandt RB et al: The prevalence of oral
lesions in smokeless tobacco users and an evaluation of risk
factors, Cancer 70:2579-2585, 1992.
Lewin F, Norell SE, Johansson H et al: Smoking tobacco, oral
snuff, and alcohol in the etiology of squamous cell carcinoma
of the head and neck. A population-based case-referent study
in Sweden, Cancer 82:1367-1375, 1998.
Martin GC, Brown JP, Eiﬂer CW et al: Oral leukoplakia status
six weeks after cessation of smokeless tobacco use, J Am Dent
Assoc 130:945-954, 1999.
Mumford EA, Levy DT, Gitchell JG et al: Smokeless tobacco use
1992-2002: trends and measurement in the Current Popula-
tion Survey-Tobacco Use Supplements, Tob Control 15:166-
171, 2006.
Nelson DE, Mowery P, Tomar S et al: Trends in smokeless
tobacco use among adults and adolescents in the United
States, Am J Public Health 96:897-905, 2006.
Robertson PB, Walsh MM, Greene JC: Oral effects of smokeless
tobacco use by professional baseball players, Adv Dent Res
11:307-312, 1997.
Rodu B: Smokeless tobacco and oral cancer: a review of the risks
and determinants, Crit Rev Oral Biol Med 15:252-263, 2004.
Schildt E-B, Eriksson M, Hardell L et al: Oral snuff, smoking
habits and alcohol consumption in relation to oral cancer in
a Swedish case-control study, Int J Cancer 77:341-346,
1998.
Stotts RC, Schroeder KL, Burns DM: Smokeless tobacco and health,
NIH publication no. 92-3461, Bethesda, Md, 1992, National
Institutes of Health.
Tomar SL, Winn DM, Swango PA et al: Oral mucosal smokeless
tobacco lesions among adolescents in the United States,
J Dent Res 76:1277-1286, 1997.
Walsh PM, Epstein JB: The oral effects of smokeless tobacco,
J Can Dent Assoc 66:22-25, 2000.
Warnakulasuriya KA, Ralhan R: Clinical, pathological, cellular
and molecular lesions caused by oral smokeless tobacco—a
review, J Oral Pathol Med 36:63-77, 2007.
Oral Submucous Fibrosis
Avon SL: Oral mucosal lesions associated with use of quid, J Can
Dent Assoc 70:244-248, 2004.
Cox SC, Walker DM: Oral submucous ﬁbrosis. A review, Aust
Dent J 41:294-299, 1996.
Hague MF, Meghji S, Nazir R et al: Interferon gamma (IFN-
gamma) may reverse oral submucous ﬁbrosis, J Oral Pathol
Med 30:12-21, 2001.
Hazarey VK, Erlewad DM, Mundhe KA et al: Oral submucous
ﬁbrosis: study of 1000 cases from central India, J Oral Pathol
Med 36:12-17, 2007.
Jacob BJ, Straif K, Thomas G et al: Betel quid without tobacco as
a risk factor for oral precancers, Oral Oncol 40:697-704,
2004.
Kumar A, Bagewadi A, Keluskar V et al: Efﬁcacy of lycopene in
the management of oral submucous ﬁbrosis, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 103:207-213, 2007.
Lai DR, Chen HR, Lin LM et al: Clinical evaluation of different
treatment methods for oral submucous ﬁbrosis. A 10-year
experience with 150 cases, J Oral Pathol Med 24:402-406,
1995.
Maher R, Lee AJ, Warnakulasuriya KA et al: Role of areca nut in
the causation of oral submucous ﬁbrosis: a case-control study
in Pakistan, J Oral Pathol Med 23:65-69, 1994.
Merchant A, Husain SS, Hosain M et al: Paan without tobacco:
an independent risk factor for oral cancer, Int J Cancer 86:128-
131, 2000.
Murti PR, Gupta PC, Bhonsle RB et al: Smokeless tobacco use
in India: effects on oral mucosa. In Stotts RC, Schroeder KL,
Burns DM: Smokeless tobacco and health, NIH publication
no. 92-3461, 1992, Bethesda, Md, National Institutes of
Health.
Nair U, Bartsch H, Nair J: Alert for an epidemic of oral cancer
due to use of the betel quid substitutes gutkha and pan masala:
a review of agents and causative mechanisms, Mutagenesis
19:251-262, 2004.
Norton SA: Betel: consumption and consequences, J Am Acad
Dermatol 38:81-88, 1998.
Rajalallitha P, Vali S: Molecular pathogenesis of oral submucous
ﬁbrosis—a collagen metabolic disorder, J Oral Pathol Med
34:321-328, 2005.
Rajendran R, Vidya R, Saleem S: Pentoxifylline therapy: a new
adjunct in the treatment of oral submucous ﬁbrosis, Indian J
Dent Res 17:190-198, 2006. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

446 ORAL AND MAXILLOFACIAL PATHOLOGY
Ranganathan K, Devi MU, Kirankumar K et al: Oral submucous
ﬁbrosis: a case-control study in Chennai, South India, J Oral
Pathol Med 33:274-277, 2004.
Reichart PA, Philipsen HP: Betel chewer’s mucosa—a review,
J Oral Pathol Med 27:239-242, 1998.
Tilakaratne WM, Klinikowski MF, Saku T et al: Oral submucous
ﬁbrosis: review on aetiology and pathogenesis, Oral Oncol
42:561-568, 2006.
World Health Organization International Agency for Research
on Cancer: IARC monographs on the evaluation and carcinogenic
risks to humans, betel-quid and areca-nut chewing and some areca-
nut-derived nitrosamines, vol 85, Lyon, France, 2004, IARC
Press.
Zheng X, Reichart PA: A review of betel quid chewing, oral
cancer and precancer in Mainland China, Oral Oncol 43:424-
430, 2007.
Nicotine Stomatitis
Ortiz GM, Pierce AM, Wilson DF: Palatal changes associated
with reverse smoking in Filipino women, Oral Dis 2:232-237,
1996.
Rossie KM, Guggenheimer J: Thermally induced “nicotine” sto-
matitis: a case report, Oral Surg Oral Med Oral Pathol 70:597-
599, 1990.
Saunders WH: Nicotine stomatitis of the palate, Ann Otol Rhinol
Laryngol 67:618-627, 1958.
Schwartz DL: Stomatitis nicotina of the palate: report of two
cases, Oral Surg Oral Med Oral Pathol 20:306-315, 1965.
Actinic Keratosis
Alexiades-Armenakas M: Aminolevulinic acid photodynamic
therapy for actinic keratoses/actinic cheilitis/acne: vascular
lasers, Dermatol Clin 25:25-33, 2007.
Fu W, Cockerell CJ: The actinic (solar) keratosis: a 21st-century
perspective, Arch Dermatol 139:66-70, 2003.
Fuchs A, Marmur E: The kinetics of skin cancer: progression of
actinic keratosis to squamous carcinoma, Dermatol Surg
33:1099-1101, 2007.
Gupta AK, Cooper EA, Feldman SR et al: A survey of ofﬁce visits
for actinic keratosis as reported by NAMCS, 1990-1999.
National Ambulatory Medical Care Survey, Cutis 70(suppl
2):8-13, 2002.
Gupta AK, Davey V, Mcphail H: Evaluation of the effectiveness
of imiquimod and 5-ﬂuorouracil for the treatment of actinic
keratosis: critical review and meta-analysis of efﬁcacy studies,
J Cutan Med Surg 9:209-214, 2005.
Hadley G, Derry S, Moore RA: Imiquimod for actinic keratosis:
systematic review and meta-analysis, J Invest Dermatol
126:1251-1255, 2006.
Jorizzo JL: Current and novel treatment options for actinic kera-
tosis, J Cutan Med Surg 8:13-21, 2005.
Lober BA, Fenske NA: Optimum treatment strategies for actinic
keratosis (intraepidermal squamous cell carcinoma), Am J
Clin Dermatol 5:395-401, 2004.
Lober BA, Lober CW: Actinic keratosis is squamous cell carci-
noma, South Med J 93:650-655, 2000.
Marks VJ: Actinic keratosis: a premalignant skin lesion, Otolaryn-
gol Clin North Am 26:23-35, 1993.
Memon AA, Tomenson JA, Bothwell J et al: Prevalence of solar
damage and actinic keratosis in a Merseyside population, Br
J Dermatol 142:1154-1159, 2000.
Tran H, Chen K, Shumack S: Summary of actinic keratosis
studies with imiquimod 5% cream, Br J Dermatol 149(suppl
66):37-39, 2003.
Wade TR, Ackerman AB: The many faces of solar keratoses,
J Dermatol Surg Oncol 4:730-734, 1978.
Actinic Cheilosis
Alexiades-Armenakas M: Aminolevulinic acid photodynamic
therapy for actinic keratoses/actinic cheilitis/acne: vascular
lasers, Dermatol Clin 25:25-33, 2007.
Dufresne RG Jr, Curlin MU: Actinic cheilitis. A treatment review,
Dermatol Surg 23:15-21, 1997.
Huber MA, Terezhalmy GT: The patient with actinic cheilitis,
Gen Dent 54:274-282, 2006.
Kaugars GE, Pillion T, Svirsky JA et al: Actinic cheilitis: a review
of 152 cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
88:181-186, 1999.
Manganaro AM, Will MJ, Poulous E: Actinic cheilitis: a prema-
lignant condition, Gen Dent 5:492-494, 1997.
Markopoulos A, Albanidou-Farmaki E, Kayavis I: Actinic cheili-
tis: clinical and pathologic characteristics in 65 cases, Oral Dis
10:212-216, 2004.
Menta Simonsen Nico M, Rivitti AE, Lourenço SV: Actinic
cheilitis: histologic study of the entire vermilion and
comparison with previous biopsy, J Cutan Pathol 34:309-314,
2007.
Orenstein A, Goldan O, Weissman O et al: A new modality in
the treatment of actinic cheilitis using the Er:YAG laser,
J Cosmet Laser Ther 9:23-25, 2007.
Smith KH, Germain M, Yeager J et al: Topical 5% imiquimod for
the therapy of actinic cheilitis, J Am Acad Dermatol 47:497-
501, 2002.
Keratoacanthoma
Cribier B, Asch P-H, Grosshans E: Differentiating squamous cell
carcinoma from keratoacanthoma using histopathological
criteria. Is it possible? A study of 296 cases, Dermatology
199:208-212, 1999.
Chen YK, Lin LM, Lin CC et al: Keratoacanthoma of the tongue:
a diagnostic problem, Otolaryngol Head Neck Surg 128:581-
582, 2003.
Clausen OPF, Aass HCD, Beigi M: Are keratoacanthomas vari-
ants of squamous cell carcinoma? A comparison of chromo-
somal aberrations by comparative genomic hybridization,
J Invest Dermatol 126:2308-2315, 2006.
de Visscher JG, van der Wal JE, Starink TM et al: Giant kerato-
acanthoma of the lower lip. Report of a case of spontaneous
regression, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
81:193-196, 1996.
Eversole LR, Leider AS, Alexander G: Intraoral and labial kera-
toacanthoma, Oral Surg Oral Med Oral Pathol 54:663-667,
1982.
Grifﬁths RW: Keratoacanthoma observed, Br J Plast Surg 57:485-
501, 2004.
Jaber PW, Cooper PH, Greer ICE: Generalized eruptive kerato-
acanthoma of Grzybowski, J Am Acad Dermatol 29:299-304,
1993.
Janette A, Pecaro B, Lonergan M et al: Solitary intraoral kerato-
acanthoma: report of a case, J Oral Maxillofac Surg 54:1026-
1030, 1996.
Ponti G, Ponz de Leon M: Muir-Torre syndrome, Lancet Oncol
6:980-987, 2005.
Sanchez Yus E, Simon P, Requena L et al: Solitary keratoacan-
thoma: a self-healing proliferation that frequently becomes
malignant, Am J Dermatopathol 22:305-310, 2000.
Schwartz RA: Keratoacanthoma, J Am Acad Dermatol 30:1-19,
1994.
Schwartz RA: Keratoacanthoma: a clinico-pathologic enigma,
Dermatol Surg 30:326-333, 2004.
Weedon D: Keratoacanthoma: a personal perspective, Curr
Diagn Pathol 9:259-265, 2003. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 447
Squamous Cell Carcinoma
American Cancer Society: Cancer facts & ﬁgures—2007, pp 1-56,
Atlanta, Ga, 2007, American Cancer Society.
Anneroth G, Hansen LS, Silverman S Jr: Malignancy grading in
oral squamous cell carcinoma. 1. Squamous cell carcinoma
of the tongue and ﬂoor of mouth: histologic grading in the
clinical evaluation, J Oral Pathol 15:162-168, 1986.
Baker SR, Krause CJ: Carcinoma of the lip, Laryngoscope 90:19-
27, 1980.
Ballantyne AJ, McCarten AB, Ibanez ML: The extension of cancer
of the head and neck through peripheral nerves, Am J Surg
106:657-667, 1963.
Barasch A, Safford M, Eisenberg E: Oral cancer and oral effects
of anticancer therapy, Mt Sinai J Med 65:370-377, 1998.
Black RJ, Gluckman JL, Shumrick DA: Multiple primary tumours
of the upper aerodigestive tract, Clin Otolaryngol 8:277-281,
1983.
Blot WJ, McLaughlin JK, Winn DM et al: Smoking and drinking
in relation to oral and pharyngeal cancer, Cancer Res 48:3282-
3287, 1988.
Bouquot JE: Common oral lesions found during a mass screening
examination, J Am Dent Assoc 112:50-57, 1986.
Bouquot JE: Epidemiology. In Gnepp DR: Pathology of the head
and neck, pp 263-314, New York, 1988, Churchill
Livingstone.
Bouquot JE, Meckstroth RL: Oral cancer in a tobacco-chewing
U.S. population: incidence and mortality, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 86:697-706, 1998.
Bouquot JE, Weiland LH, Kurland LT: Metastases to and from
the upper aerodigestive tract in the population of Rochester,
Minnesota, 1935-1984, Head Neck 11:212-218, 1989.
Braakhuis BJM, Leemans CR, Brakenhoff RH: Expanding ﬁelds
of genetically altered cells in head and neck squamous carci-
nogenesis, Semin Cancer Biol 15:113-120, 2005.
Brandwein-Gensler M, Teixeira MS, Lewis CM et al: Oral squa-
mous cell carcinoma: histologic risk assessment, but not
margin status, is strongly predictive of local disease-free and
overall survival, Am J Surg Pathol 29:167-178, 2005.
Brugere J, Guenel P, Leclerc A et al: Differential effects of tobacco
and alcohol in cancer of the larynx, pharynx, and mouth,
Cancer 57:391-395, 1986.
Bsoul SA, Huber MA, Terezhalmy GT: Squamous cell carcinoma
of the oral tissues: a comprehensive review for oral healthcare
providers, J Contemp Dent Pract 4:001-016, 2005.
Centers for Disease Control and Prevention: Tobacco use among
adults—United States, 2005, MMWR Morb Mortal Wkly Rep
55:1145-1148, 2006.
Chang KW, Chang CS, Lai KS et al: High prevalence of human
papillomavirus infection and possible association with betel
quid chewing and smoking in oral epidermoid carcinomas in
Taiwan, J Med Virol 28:57-61, 1989.
Choi SY, Kahyo H: Effect of cigarette smoking and alcohol con-
sumption in the aetiology of cancer of the oral cavity, pharynx
and larynx, Int J Epidemiol 20:878-885, 1991.
Choong NW, Cohen EEW: Epidermal growth factor receptor
directed therapy in head and neck cancer, Crit Rev Oncol
Hematol 57:25-42, 2006.
Cianfriglia F, Di Gregorio DA, Manieri A: Multiple primary
tumours in patients with oral squamous cell carcinoma, Oral
Oncol 35:157-163, 1999.
Cox MF, Scully C, Maitland N: Viruses in the aetiology of oral
carcinoma? Examination of the evidence, Br J Oral Maxillofac
Surg 29:381-387, 1991.
Davies L, Welch HG: Epidemiology of head and neck cancer in
the United States, Otolaryngol Head Neck Surg 135:451-457,
2006.
de Visscher JG, Schaapveld M, Otter R et al: Epidemiology of
cancer of the lip in the Netherlands, Oral Oncol 34:421-426,
1998.
Dickenson AJ, Currie WJ, Avery BS: Screening for syphilis in
patients with carcinoma of the tongue, Br J Oral Maxillofac
Surg 33:319-320, 1995.
Flaitz CM, Hicks MJ: Molecular piracy: the viral link to carcino-
genesis, Oral Oncol 34:448-453, 1998.
Fukuzawa K, Noguchi Y, Yoshikawa T et al: High incidence of
synchronous cancer of the oral cavity and the upper gastro-
intestinal tract, Cancer Lett 144:145-151, 1999.
Greene FL, Page DL, Fleming ID et al, editors: Lip and oral
cavity. In AJCC cancer staging manual, ed 6, pp 23-32, New
York, 2002, Springer-Verlag.
Ha PK, Califano JA: The molecular biology of mucosal ﬁeld can-
cerization of the head and neck, Crit Rev Oral Biol Med 14:363-
369, 2003.
Ha PK, Califano JA: The role of human papillomavirus in oral
carcinogenesis, Crit Rev Oral Biol Med 15:188-196, 2004.
Hart AK, Karakla DW, Pitman KT et al: Oral and oropharyngeal
squamous cell carcinoma in young adults: a report on 13
cases and review of the literature, Otolaryngol Head Neck Surg
120:828-833, 1999.
Hjortdal O, Naess A, Berner A: Squamous cell carcinomas of the
lower lip, J Craniomaxillofac Surg 23:34-37, 1995.
Jemal A, Siegel R, Ward E et al: Cancer statistics, 2007, CA
Cancer J Clin 57:43-66, 2007.
Kademani D: Oral cancer, Mayo Clin Proc 82:878-887, 2007.
Kalyankrishna S, Grandis JR: Epidermal growth factor receptor
biology in head and neck cancer, J Clin Oncol 24:2666-2672,
2006.
Karja J, Syrjanen S, Usenius T et al: Oral cancer in children under
15 years of age: a clinicopathological and virological study,
Acta Otolaryngol Suppl 449:145-149, 1988.
Kleinman DV, Crossett LS, Gloeckler Ries LA et al: Cancer of the
oral cavity and pharynx: a statistics review monograph, 1973-
1987, NIH Monograph, Bethesda, Md, 1992, National Insti-
tute of Dental Research.
Koch WM, Lango M, Sewell D et al: Head and neck cancer in
nonsmokers: a distinct clinical and molecular entity, Laryngo-
scope 109:1544-1551, 1999.
Kowalski LP, Bagietto R, Lara JR et al: Prognostic signiﬁcance of
the distribution of neck node metastasis from oral carcinoma,
Head Neck 22:207-214, 2000.
Kreimer AR, Clifford GM, Boyle P et al: Human papillomavirus
types in head and neck squamous cell carcinomas world-
wide: a systematic review, Cancer Epidemiol Biomarkers Prev
14:467-475, 2005.
Krogh P, Hald B, Holmstrup P: Possible mycological etiology of
oral mucosal cancer. Catalytic potential of infecting Candida
albicans and other yeasts in production of N-nitrosobenzyl-
methylamine, Carcinogenesis 8:1543-1548, 1987.
Kurumatani N, Kirita T, Zheng Y et al: Time trends in the mortal-
ity rates for tobacco- and alcohol-related cancers within the
oral cavity and pharynx in Japan, 1950-94, J Epidemiol 9:46-
52, 1999.
Lindqvist C, Teppo L: Epidemiological evaluation of sunlight as
a risk factor of lip cancer, Br J Cancer 37:983-989, 1978.
Maserejian NN, Joshipura KJ, Rosner BA et al: Prospective study
of alcohol consumption as risk of oral premalignant lesions
in men, Cancer Epidemiol Biomarkers Prev 15:774-781, 2006.
Mashberg A, Samit AM: Early diagnosis of asymptomatic oral
and oropharyngeal cancer, CA Cancer J Clin 45:328-351,
1995.
Massano J, Regateiro FS, Januário G et al: Oral squamous cell
carcinoma: review of prognostic and predictive factors, Oral `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

448 ORAL AND MAXILLOFACIAL PATHOLOGY
Surg Oral Med Oral Pathol Oral Radiol Endod 102:67-76,
2006.
Mattson ME, Winn DM: Smokeless tobacco: association with increased
cancer risk, NCI Monogr No 8, pp 13-16, Bethesda, Md, 1989,
National Cancer Institute.
McDowell JD: An overview of epidemiology and common risk
factors for oral squamous cell carcinoma, Otolaryngol Clin
North Am 39:277-294, 2006.
Merchant A, Husain SS, Hosain M et al: Paan without tobacco:
an independent risk factor for oral cancer, Int J Cancer 86:128-
131, 2000.
Moreno-Lopez LA, Esparza-Gomez GC, Gonzalez-Navarro A et
al: Risk of oral cancer associated with tobacco smoking,
alcohol consumption and oral hygiene: a case-control study
in Madrid, Spain, Oral Oncol 36:170-174, 2000.
Morse DE, Kerr AR: Disparities in oral and pharyngeal cancer
incidence, mortality and survival among black and white
Americans, J Am Dent Assoc 137:203-212, 2006.
Morse DE, Psoter WJ, Cleveland D et al: Smoking and drinking
in relation to oral cancer and oral epithelial dysplasia, Cancer
Causes Control 18:919-929, 2007.
Nair S, Pillai MR: Human papillomavirus and disease mecha-
nisms: relevance to oral and cervical cancers, Oral Dis 11:350-
359, 2005.
Neville BW, Day TA: Oral cancer and precancerous lesions, CA
Cancer J Clin 52:195-215, 2002.
Niv A, Sion-Vardi N, Gatot A et al: Identiﬁcation and typing of
human papillomavirus (HPV) in squamous cell carcinoma of
the oral cavity and oropharynx, J Laryngol Otol 114:41-46,
2000.
Notani PN, Jayant K: Role of diet in upper aerodigestive tract
cancers, Nutr Cancer 10:103-113, 1987.
Paleri V, Rees G, Arullendran P et al: Sentinel node biopsy in
squamous cell cancer of the oral cavity and oral pharynx: a
diagnostic meta-analysis, Head Neck 27:739-747, 2005.
Partridge M, Kiguwa S, Emilion G et al: New insights into p53
protein stabilisation in oral squamous cell carcinoma, Oral
Oncol 35:45-55, 1999.
Pentenero M, Gandolfo S, Carrozzo M: Importance of tumor
thickness and depth of invasion in nodal involvement and
prognosis of oral squamous cell carcinoma: a review of the
literature, Head Neck 27:1080-1091, 2005.
Prince S, Bailey BM: Squamous cell carcinoma of the tongue:
review, Br J Oral Maxillofac Surg 37:164-174, 1999.
Rodu B: Smokeless tobacco and oral cancer: a review of the risks
and determinants, Crit Rev Oral Biol Med 15:252-263, 2004.
Rodu B, Cole P: Oral cavity and pharynx-throat cancer in the
United States, 1973-2003, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 104:653-658, 2007.
Rothman K, Keller A: The effect of joint exposure to alcohol and
tobacco on risk of cancer of the mouth and pharynx, J Chronic
Dis 25:711-716, 1972.
Sankaranarayanan R: Oral cancer in India: an epidemiologic and
clinical review, Oral Surg Oral Med Oral Pathol 69:325-330,
1990.
Sciubba JJ: Oral cancer: the importance of early diagnosis and
treatment, Am J Clin Dermatol 2:239-251, 2001.
Shaha AR, Patel S, Shasha D et al: Head and neck cancer. In
Lenhard RE, Osteen RT, Gansler T: Clinical oncology, pp 297-
331, Atlanta, Ga, 2000, American Cancer Society.
Shiboski CH, Schmidt BL, Jordan RC: Racial disparity in stage at
diagnosis and survival among adults with oral cancer in the
US, Community Dent Oral Epidemiol 35:233-240, 2007.
Silverman S Jr, Grifﬁth M: Smoking characteristics of patients
with oral carcinoma and the risk for second oral primary
carcinoma, J Am Dent Assoc 85:637-640, 1972.
Specenier PM, Vermorken JB: Neoadjuvant chemotherapy in
head and neck cancer: should it be revisited? Cancer Lett 256:
166-177, 2007.
Speight PM, Farthing PM, Bouquot JE: The pathology of oral
cancer and precancer, Curr Diag Pathol 3:165-176, 1997.
Spiro RH, Guillamondegui O Jr, Paulino AF et al: Pattern of
invasion and margin assessment in patients with oral tongue
cancer, Head Neck 21:408-413, 1999.
Stewart BW, Kleihues P, editors: Head and neck cancer. In
World Cancer Report, pp 232-236, Lyon, France, 2003, IARC
Press.
Syrjänen S: HPV infections and tonsillar carcinoma, J Clin Pathol
57:449-455, 2004.
Syrjänen S: Human papillomavirus (HPV) in head and neck
cancer, J Clin Virol 32S:S59-S66, 2005.
Strome SE, To W, Strawderman M et al: Squamous cell carci-
noma of the buccal mucosa, Otolaryngol Head Neck Surg
120:375-379, 1999.
Tabor MP, Brakenhoff RH, van Houten VMM et al: Persistence
of genetically altered ﬁelds in head and neck cancer patients:
biological and clinical implications, Clin Cancer Res 7:1523-
1532, 2001.
Tralongo V, Rodolico V, Luciani A et al: Prognostic factors in oral
squamous cell carcinoma. A review of the literature, Antican-
cer Res 19:3503-3510, 1999.
van Oijen MG, Leppers VD, Straat FG et al: The origins of mul-
tiple squamous cell carcinomas in the aerodigestive tract,
Cancer 88:884-893, 2000.
Velly AM, Franco EL, Schlecht N et al: Relationship between
dental factors and risk of upper aerodigestive tract cancer,
Oral Oncol 34:284-291, 1998.
Watts JM: The importance of the Plummer-Vinson syndrome in
the etiology of carcinoma of the upper gastrointestinal tract,
Postgrad Med J 37:523-533, 1961.
Winn DM: Smokeless tobacco and cancer: the epidemiologic
evidence, CA Cancer J Clin 38:236-243, 1988.
World Health Organization International Agency for Research
on Cancer: IARC monographs on the evaluation and carcinogenic
risks to humans, Betel-quid and areca-nut chewing and some areca-
nut-derived nitrosamines, vol 85, Lyon, France, 2004, IARC
Press.
Verrucous Carcinoma
Ackerman LV: Verrucous carcinoma of the oral cavity, Surgery
23:670-678, 1948.
Addante RR, McKenna SJ: Verrucous carcinoma, Oral Maxillofac
Surg Clin North Am 18:513-519, 2006.
Bouquot JE: Oral verrucous carcinoma—incidence in two U.S.
populations, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
86:318-324, 1998.
Burford WN, Ackerman LV, Robinson HBG: Ellis Fischel State
Cancer Hospital number: symposium on twenty cases of
benign and malignant lesions of the oral cavity, from the Ellis
Fischel State Cancer Hospital, Columbia, Missouri, Am J
Orthod Oral Surg 30:353-372, 1944.
Jordan RC: Verrucous carcinoma of the mouth, J Can Dent Assoc
61:797-801, 1995.
Kamath VV, Varma RR, Gadewar DR et al: Oral verrucous car-
cinoma: an analysis of 37 cases, J Craniomaxillofac Surg
17:309-314, 1989.
Karthikeya P, Mahima VG, Bhavna G: Sinonasal verrucous car-
cinoma with oral invasion, Indian J Dent Res 17:82-86,
2006.
Koch BB, Trask DK, Hoffman HT et al: National survey of head
and neck verrucous carcinoma: patterns of presentation,
care, and outcome, Cancer 92:110-120, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 449
McCoy JM, Waldron CA: Verrucous carcinoma of the oral cavity:
a review of forty-nine cases, Oral Surg Oral Med Oral Pathol
52:623-629, 1981.
Medina JE, Dichtel W, Luna MA: Verrucous-squamous carcino-
mas of the oral cavity: a clinicopathologic study of 104 cases,
Arch Otolaryngol 110:437-440, 1984.
Ogawa A, Fukua Y, Nakajima T et al: Treatment results of verru-
cous carcinoma and its biological behavior, Oral Oncol
40:793-797, 2004.
Oliveira DT, de Moraes RV, Filho JFF et al: Oral verrucous car-
cinoma: a retrospective study in Sao Paulo Region, Brazil, Clin
Oral Invest 10:205-209, 2006.
Schwartz RA: Verrucous carcinoma of the skin and mucosa, J Am
Acad Dermatol 32:1-24, 1995.
Strojan P, Soba E, Budihna M et al: Radiochemotherapy with
vinblastine, methotrexate, and bleomycin in the treatment of
verrucous carcinoma of the head and neck, J Surg Oncol
92:278-283, 2005.
Tharp II ME, Shidnia H: Radiotherapy in the treatment of ver-
rucous carcinoma of the head and neck, Laryngoscope
105:391-396, 1995.
Spindle Cell Carcinoma
Batsakis JG, Suarez P: Sarcomatoid carcinomas of the upper
aerodigestive tracts, Adv Anat Pathol 7:282-293, 2000.
Benninger MS, Kraus D, Sebek B et al: Head and neck spindle
cell carcinoma: an evaluation of current management, Cleve
Clin J Med 59:479-482, 1992.
Ellis GL, Langloss JM, Heffner DK et al: Spindle-cell carcinoma
of the aerodigestive tract: an immunohistochemical analysis
of 21 cases, Am J Surg Pathol 11:335-342, 1987.
Gupta R, Singh S, Hedau S et al: Spindle cell carcinoma of head
and neck: an immunohistochemical and molecular approach
to its pathogenesis, J Clin Pathol 60:472-475, 2007.
Lewis JE, Olsen KD, Sebo TJ: Spindle cell carcinoma of the
larynx: review of 26 cases including DNA content and immu-
nohistochemistry, Hum Pathol 28:664-673, 1997.
Rizzardi C, Frezzini C, Maglione M et al: A look at the biology of
spindle cell squamous carcinoma of the oral cavity: report of
a case, J Oral Maxillofac Surg 61:264-268, 2003.
Shibuya Y, Umeda M, Yokoo S et al: Spindle cell squamous car-
cinoma of the maxilla: report of a case with immunohisto-
chemical analysis, J Oral Maxillofac Surg 58:1164-1169,
2000.
Slootweg PJ, Roholl PJ, Muller H et al: Spindle-cell carcinoma of
the oral cavity and larynx. Immunohistochemical aspects,
J Craniomaxillofac Surg 17:234-236, 1989.
Su HH, Chu ST, Hou YY et al: Spindle cell carcinoma of the oral
cavity and oropharynx: factors affecting outcome, J Chin Med
Assoc 69:478-483, 2006.
Adenosquamous Carcinoma
Abdelsayed RA, Sangueza OP, Newhouse RF et al: Adenosqua-
mous carcinoma: a case report with immunohistochemical
evaluation, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
85:173-177, 1998.
Alos L, Castillo M, Nadal A et al: Adenosquamous carcinoma of
the head and neck: criteria for diagnosis in a study of 12
cases, Histopathology 44:570-579, 2004.
Banks ER, Cooper PH: Adenosquamous carcinoma of the skin:
a report of 10 cases, J Cutan Pathol 18:227-234, 1991.
Gerughty RM, Hennigar GB, Brown FM: Adenosquamous carci-
noma of the nasal, oral and laryngeal cavities: a clinicopatho-
logic survey of ten cases, Cancer 22:1140-1155, 1968.
Keelawat S, Liu CZ, Roehm PC et al: Adenosquamous carcinoma
of the upper aerodigestive tract: a clinicopathologic study of
12 cases and review of the literature, Am J Otolaryngol 23:160-
168, 2002.
Martinez-Madrigal F, Baden E, Casiraghi O et al: Oral and pha-
ryngeal adenosquamous carcinoma: a report of four cases
with immunohistochemical studies, Eur Arch Otorhinolaryngol
248:255-258, 1991.
Scully C, Porter SR, Speight PM et al: Adenosquamous carci-
noma of the mouth: a rare variant of squamous cell carci-
noma, Int J Oral Maxillofac Surg 28:125-128, 1999.
Sheahan P, Fitzgibbon J, Lee G et al: Adenosquamous carcinoma
of the tongue in a 22-year-old female: report of a case with
immunohistochemistry, Eur Arch Otorhinolaryngol 260:509-
512, 2003.
Sheahan P, Toner M, Timon CV I: Clinicopathologic features of
head and neck adenosquamous carcinoma, ORL J Otorhino-
laryngol Relat Spec 67:10-15, 2005.
Yoshimura Y, Mishimma K, Ohara S et al: Clinical characteris-
tics of oral adenosquamous carcinoma: report of a case and
an analysis of the reported Japanese cases, Oral Oncol 39:309-
315, 2003.
Basaloid Squamous Carcinoma
Altavilla G, Mannara GM, Rinaldo A et al: Basaloid squamous
cell carcinoma of oral cavity and oropharynx, ORL J Otorhino-
laryngol Relat Spec 61:169-173, 1999.
Banks ER, Frierson HF Jr, Mills SE et al: Basaloid squamous cell
carcinoma of the head and neck: a clinicopathologic and
immunohistochemical study of 40 cases, Am J Surg Pathol
16:939-946, 1992.
Barnes L, Ferlito A, Altavilla G et al: Basaloid squamous cell car-
cinoma of the head and neck: clinicopathological features
and differential diagnosis, Ann Otol Rhinol Laryngol 105:75-
82, 1996.
Coletta RD, Cotrim P, Vargas PA et al: Basaloid squamous car-
cinoma of the oral cavity: report of 2 cases and study of
AgNOR, PCNA, p53, and MMP expression, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 91:563-569, 2001.
Coletta RD, Cotrim P, Almeida OP et al: Basaloid squamous
carcinoma of oral cavity: a histologic and immunohistochemi-
cal study, Oral Oncol 38:723-729, 2002.
De Sampaio Góes FC, Oliveira DT, Dorta RG et al: Prognoses of
oral basaloid squamous cell carcinoma and squamous cell
carcinoma: a comparison, Arch Otolaryngol Head Neck Surg
130:83-86, 2004.
Ide F, Shimoyama T, Horie N et al: Basaloid squamous cell car-
cinoma of the oral mucosa: a new case and review of 45 cases
in the literature, Oral Oncol 38:120-124, 2002.
Ide F, Shimoyama T, Suzuki T et al: Polypoid carcinoma of the
tongue, J Oral Pathol Med 25:90-92, 1996.
Oikawa k, Tabuchi K, Nomura M et al: Basaloid squamous cell
carcinoma of the maxillary sinus: a report of two cases, Auris
Nasus Larynx 34:119-123, 2007.
Paulino AF, Singh B, Shah JP et al: Basaloid squamous cell car-
cinoma of the head and neck, Laryngoscope 110:1479-1482,
2000.
Sampaio-Góes FCG, Oliveira DT, Dorta RG et al: Expression of
PCNA, p53, Bax, and Bcl-X in oral poorly differentiated and
basaloid squamous cell carcinoma: relationships with prog-
nosis, Head Neck 27:982-989, 2005.
Zbären P, Nuyens M, Stauffer E: Basaloid squamous cell carci-
noma of the head and neck, Curr Opin Otolaryngol Head Neck
Surg 12:116-121, 2004.
Carcinoma of the Maxillary Sinus
Bhattacharyya N: Factors affecting survival in maxillary sinus
cancer, J Oral Maxillofac Surg 61:1016-1021, 2003. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

450 ORAL AND MAXILLOFACIAL PATHOLOGY
Carrillo JF, Guemes A, Ramierz-Ortega MC et al: Prognostic
factors in maxillary sinus and nasal cavity carcinoma, Eur J
Surg Oncol 31:1206-1212, 2005.
Doig TN, McDonald SW, McGregor IA: Possible routes of spread
of carcinoma of the maxillary sinus to the oral cavity, Clin Anat
11:149-156, 1998.
Georgiou AF, Walker DM, Collins AP et al: Primary small cell
undifferentiated (neuroendocrine) carcinoma of the maxil-
lary sinus, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
98:572-578, 2004.
Giri SP, Reddy EK, Gemer LS et al: Management of advanced
squamous cell carcinomas of the maxillary sinus, Cancer
69:657-661, 1992.
Guntinas-Lichius O, Kreppel MP, Stuetzer H et al: Single modal-
ity and multimodality treatment of nasal and paranasal
sinuses cancer: a single institution experience of 229 patients,
Eur J Surg Oncol 33:222-228, 2007.
Hoppe BS, Stegman LD, Zelefsky MJ et al: Treatment of
nasal cavity and paranasal sinus cancer with modern
radiotherapy techniques in the postoperative setting—the
MKSCC experience, Int J Radiat Oncol Biol Phys 67:691-702,
2007.
Indudharan R, Das PK, Thida T: Verrucous carcinoma of maxil-
lary antrum, Singapore Med J 37:559-561, 1996.
Itami J, Uno T, Aruga M et al: Squamous cell carcinoma of the
maxillary sinus treated with radiation therapy and conserva-
tive surgery, Cancer 82:104-107, 1998.
Paulino AC, Marks JE, Bricker P et al: Results of treatment of
patients with maxillary sinus carcinoma, Cancer 83:457-465,
1998.
Smith SR, Som P, Fahmy A et al: A clinicopathological study
of sinonasal neuroendocrine carcinoma and sinonasal
undifferentiated carcinoma, Laryngoscope 110:1617-1622,
2000.
Tiwari R, Hardillo JA, Mehta D et al: Squamous cell carcinoma
of maxillary sinus, Head Neck 22:164-169, 2000.
Waldron JN, O’Sullivan B, Gullane P et al: Carcinoma of the
maxillary antrum: a retrospective analysis of 110 cases,
Radiother Oncol 57:167-173, 2000.
Sinonasal Undifferentiated Carcinoma
Ejaz A, Wenig BM: Sinonasal undifferentiated carcinoma: clini-
cal and pathologic features and a discussion on classiﬁcation,
cellular differentiation, and differential diagnosis, Adv Anat
Pathol 12:134-143, 2005.
Frierson HF Jr, Mills SE, Fechner RE et al: Sinonasal undifferen-
tiated carcinoma: an aggressive neoplasm derived from
schneiderian epithelium and distinct from olfactory neuro-
blastoma, Am J Surg Pathol 10:771-779, 1986.
Gorelick J, Ross D, Marentette L et al: Sinonasal undifferentiated
carcinoma: case series and review of literature, Neurosurgery
47:750-755, 2000.
Houston GD: Sinonasal undifferentiated carcinoma. Report of
two cases and review of the literature, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 85:185-188, 1998.
Houston GD, Gillies E: Sinonasal undifferentiated carcinoma: a
distinctive clinicopathologic entity, Adv Anat Pathol 6:317-
323, 1999.
Jeng YM, Sung MT, Fang CL et al: Sinonasal undifferentiated
carcinoma and nasopharyngeal-type carcinoma: two clini-
cally, biologically, and histopathologically distinct entities,
Am J Surg Pathol 26:371-376, 2002.
Jones AV, Robinson I, Speight PM: Sinonasal undifferentiated
carcinoma: report of a case and review of literature, Oral
Oncol 41:299-302, 2005.
Kim BS, Vongtama R, Juillard G: Sinonasal undifferentiated car-
cinoma: case series and literature review, Am J Otolaryngol
25:162-166, 2004.
Levine PA, Frierson HF, Stewart FM et al: Sinonasal undifferenti-
ated carcinoma: a distinctive and highly aggressive neoplasm,
Laryngoscope 97:905-908, 1987.
Righi PD, Francis F, Aron BS et al: Sinonasal undifferentiated
carcinoma: a 10-year experience, Am J Otolaryngol 17:167-
171, 1996.
Rischin D, Porceddu S, Peters L et al: Promising results with
chemoradiation in patients with sinonasal undifferentiated
carcinoma, Head Neck 26:435-441, 2004.
Sharara N, Muller S, Olson J et al: Sinonasal undifferentiated
carcinoma with orbital invasion: report of three cases, Ophthal
Plast Reconstr Surg 17:288-292, 2001.
Smith SR, Som P, Fahmy A et al: A clinicopathological study of
sinonasal neuroendocrine and sinonasal undifferentiated
carcinoma, Laryngoscope 110:1617-1622, 2000.
Nasopharyngeal Carcinoma
Agulnik M, Siu LL: State-of-the-art management of nasopharyn-
geal carcinoma: current and future directions, Br J Cancer
92:799-806, 2005.
August M, Dodson TB, Nastri A et al: Nasopharyngeal carcinoma:
clinical assessment and review of 176 cases, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 91:205-214, 2001.
Chen CL, Hsu MM: Second primary epithelial malignancy of
nasopharynx and nasal cavity after successful curative radia-
tion therapy of nasopharyngeal carcinoma, Hum Pathol
31:227-232, 2000.
Epstein JB, Jones CK: Presenting signs and symptoms of naso-
pharyngeal carcinoma, Oral Surg Oral Med Oral Pathol 75:32-
36, 1993.
Farrow DC, Vaughan TL, Berwick M et al: Diet and nasopharyn-
geal cancer in a low-risk population, Int J Cancer 78:675-679,
1998.
Ma BBY, Chan ATC: Recent perspectives in the role of chemo-
therapy in the management of advanced nasopharyngeal
carcinoma, Cancer 103:22-31, 2005.
O’Meara WP, Lee N: Advances in nasopharyngeal carcinoma,
Curr Opin Oncol 17:225-230, 2005.
Ou SHI, Zell JA, Ziogas A et al: Epidemiology of nasopharyngeal
carcinoma in the United States: improved survival of Chinese
patients within the keratinizing squamous cell carcinoma
histology, Ann Oncol 18:29-35, 2007.
Wei WI, Sham JST: Nasopharyngeal carcinoma, Lancet 365:2041-
2052, 2005.
Wenig BM: Nasopharyngeal carcinoma, Ann Diagn Pathol 3:374-
385, 1999.
Yu MC, Yuan JM: Epidemiology of nasopharyngeal carcinoma,
Cancer Biol 12:421-429, 2002.
Basal Cell Carcinoma
Bath-Hextall FJ, Perkins W, Bong J et al: Interventions for basal
cell carcinoma of the skin, Cochrane Database Syst Rev 1:
CD003412, 2007.
Ceilley RI, Del Rosso JQ: Current modalities and new advances
in the treatment of basal cell carcinoma, Int J Dermatol
45:489-498, 2006.
Christenson LF, Borrowman TA, Vachon CM et al: Incidence of
basal cell and squamous cell carcinomas in a population
younger than 40 years, JAMA 294:681-690, 2005.
Crowson AN: Basal cell carcinoma: biology, morphology and
clinical implications, Mod Pathol 19:S127-S147, 2006.
Daya-Grosjean L, Couvé-Privat S: Sonic hedgehog signaling in
basal cell carcinomas, Cancer Lett 225:181-192, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 10 EPITHELIAL PATHOLOGY 451
Del Rosario RN, Barr RJ, Jensen JL et al: Basal cell carcinoma
of the buccal mucosa, Am J Dermatopathol 23:203-205,
2001.
Gutierrez MM, Mora RG: Nevoid basal cell carcinoma syndrome:
a review and case report of a patient with unilateral basal cell
nevus syndrome, J Am Acad Dermatol 15:1023-1030, 1986.
Kato N, Endo Y, Tamura G et al: Ameloblastoma with basal cell
carcinoma-like feature emerging as a nasal polyp, Pathol Int
49:747-751, 1999.
Kuijpers DIM, Thissen MRTM, Neumann MHA: Basal cell carci-
noma. Treatment options and prognosis, a scientiﬁc approach
to a common malignancy, Am J Clin Dermatol 3:247-259,
2002.
Martin RC 2
nd
, Edwards MJ, Cawte TG et al: Basosquamous car-
cinoma: analysis of prognostic factors inﬂuencing recurrence,
Cancer 88:1365-1369, 2000.
Niederhagen B, Lindern J, Berge S et al: Staged operations for
basal cell carcinoma of the face, Br J Oral Maxillofac Surg
38:477-479, 2000.
Rishiraj B, Epstein JB: Basal cell carcinoma: what dentists need
to know, J Am Dent Assoc 130:375-380, 1999.
Rubin AI, Chen EH, Ratner D: Basal-cell carcinoma, N Engl J Med
353:2262-2269, 2005.
Telfer NR, Colver GB, Bowers PW: Guidelines for the manage-
ment of basal cell carcinoma, Br J Dermatol 141:415-423,
1999.
Merkel Cell Carcinoma
Agelli M, Clegg LX: Epidemiology of primary Merkel cell carci-
noma in the United States, J Am Acad Dermatol 49:832-841,
2003.
Bickle K, Glass LF, Messina JF et al: Merkel cell carcinoma: a
clinical, histopathologic, and immunohistochemical review,
Semin Cutan Med Surg 23:46-53, 2004.
Chan JK, Suster S, Wenig BM et al: Cytokeratin 20 immunore-
activity distinguishes Merkel cell (primary cutaneous neuro-
endocrine) carcinomas and salivary gland small cell
carcinomas from small cell carcinomas of various sites, Am J
Surg Pathol 21:226-234, 1997.
Dancey AL, Rayatt SS, Soon C et al: Merkel cell carcinoma: a
report of 34 cases and literature review, J Plast Reconstr Aesthet
Surg 59:1294-1299, 2006.
Garneski KM, Nghiem P: Merkel cell carcinoma adjuvant
therapy: current data support radiation but not chemother-
apy, J Am Acad Dermatol 57:166-169, 2007.
Gollard R, Weber R, Kosty MP et al: Merkel cell carcinoma.
Review of 22 cases with surgical, pathologic, and therapeutic
considerations, Cancer 8:1842-1851, 2000.
Hendrikx SMGA, de Wilde PCM, Kaanders JHAM et al: Merkel
cell carcinoma in the oral cavity: a case presentation and
review of the literature, Oral Oncol 41:202-206, 2005.
Jabbour J, Cumming R, Scolyer RA et al: Merkel cell carcinoma:
assessing the effect of wide local excision, lymph node dissec-
tion, and radiotherapy on recurrence and survival in early-
stage disease—results from a review of 82 consecutive cases
diagnosed between 1992 and 2004, Ann Surg Oncol 14:
1943-1952, 2007.
Lewis KG, Weinstock MA, Weaver AL et al: Adjuvant local irra-
diation for Merkel cell carcinoma, Arch Dermatol 142:693-
700, 2006.
Longo F, Califano L, Mangone GM et al: Neuroendocrine (Merkel
cell) carcinoma of the oral mucosa: report of a case with
immunohistochemical study and review of the literature,
J Oral Pathol Med 28:88-91, 1999.
Mendenhall WM, Mendenhall CM, Mendenhall NP: Merkel cell
carcinoma, Laryngoscope 114:906-910, 2004.
Miller SJ, Alam M, Andersen J et al: Merkel cell carcinoma, J Natl
Compr Canc Netw 4:704-712, 2006.
Pectasides D, Pectasides M, Economopoulos T: Merkel cell car-
cinoma of the skin, Ann Oncol 17:1489-1495, 2006.
Suárez C, Rodrigo JP, Ferlito et al: Merkel cell carcinoma of the
head and neck, Oral Oncol 40:773-779, 2004.
Yom SS, Rosenthal DI, El-Naggar AK et al: Merkel cell carcinoma
of the tongue and head and neck oral mucosal sites, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 101:761-768,
2006.
Melanoma
Abassi NR, Shaw HM, Rigel DS et al: Early diagnosis of cutaneous
melanoma. Revisiting the ABCD criteria, JAMA 292:2771-
2776, 2004.
Balch CM, Buzaid AC, Soong SJ et al: Final version of the Ameri-
can Joint Committee on Cancer staging system for cutaneous
melanoma, J Clin Oncol 19:3635-3648, 2001.
Barnhill RL, Mihm MC Jr: The histopathology of cutaneous
malignant melanoma, Semin Diagn Pathol 10:47-75, 1993.
Barrett AW, Bennett JH, Speight PM: A clinicopathological and
immunohistochemical analysis of primary oral mucosal mel-
anoma, Oral Oncol 31:100-105, 1995.
Batsakis JG, Suarez P: Mucosal melanomas: a review, Adv Anat
Pathol 7:167-180, 2000.
Chidzonga MM, Mahomva L, Marimo C et al: Primary malignant
melanoma of the oral mucosa, J Oral Maxillofac Surg 65:1117-
1120, 2007.
Curtin JA, Fridlyand J, Kageshita T et al: Distinct sets of genetic
alterations in melanoma, N Engl J Med 353:2135-2147,
2005.
Garbe C, Eigentler TK: Diagnosis and treatment of cutaneous
melanoma: state of the art 2006, Melanoma Res 17:117-127,
2007.
Garzino-Demo P, Fasolis M, Maggiore GM et al: Oral mucosal
melanoma: a series of case reports, J Craniomaxillofac Surg
32:251-257, 2004.
Gorsky M, Epstein JB: Melanoma arising from the mucosal sur-
faces of the head and neck, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 86:715-719, 1998.
Gray-Schopfer V, Wellbrock C, Marais R: Melanoma biology and
new targeted therapy, Nature 445:851-857, 2007.
Greene FL, Page DL, Fleming ID et al, editors: Melanoma of the
skin. In AJCC cancer staging manual, ed 6, pp 209-217, New
York, 2002, Springer-Verlag.
Hall HI, Miller DR, Rogers JD et al: Update on the incidence and
mortality from melanoma in the United States, J Am Acad
Dermatol 40:35-42, 1999.
Hicks MJ, Flaitz CM: Oral mucosal melanoma: epidemiology and
pathobiology, Oral Oncol 36:152-169, 2000.
Jemal A, Siegel R, Ward E et al: Cancer statistics, 2007, CA
Cancer J Clin 57:43-66, 2007.
Kahn M, Weathers DR, Hoffman JG: Transformation of a benign
oral pigmentation to primary oral mucosal melanoma, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 100:454-459,
2005.
Kilpatrick SE, White WL, Browne JD: Desmoplastic malignant
melanoma of the oral mucosa. An underrecognized diagnos-
tic pitfall, Cancer 78:383-389, 1996.
Manganaro AM, Hammond HL, Dalton MJ et al: Oral melanoma:
case reports and review of the literature, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 80:670-677, 1995.
Markovic SN, Erickson LA, Rao RD et al: Malignant melanoma
in the 21st century, part 1: epidemiology, risk factors, screen-
ing, prevention, and diagnosis, Mayo Clin Proc 82:364-380,
2007. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

452 ORAL AND MAXILLOFACIAL PATHOLOGY
Markovic SN, Erickson LA, Rao RD et al: Malignant melanoma
in the 21st century, part 2: staging, prognosis, and treatment,
Mayo Clin Proc 82:490-513, 2007.
Miller AJ, Mihm MC: Mechanisms of disease. Melanoma, N Engl
J Med 355:51-65, 2006.
Morton DL, Thompson JF, Cochran AJ et al: Sentinel-node biopsy
or nodal observation in melanoma, N Engl J Med 355:1307-
1317, 2006.
Nandapalan V, Roland NJ, Helliwell TR et al: Mucosal melanoma
of the head and neck, Clin Otolaryngol 23:107-116, 1998.
Patrick RJ, Fenske NA, Messina JL: Primary mucosal melanoma,
J Am Acad Dermatol 56:828-834, 2007.
Rapini RP, Golitz LE, Greer RO et al: Primary malignant mela-
noma of the oral cavity: a review of 177 cases, Cancer 55:1543-
1551, 1985.
Ringbörg U, Afzelius LE, Lagerlöf B et al: Cutaneous malignant
melanoma of the head and neck: analysis of treatment results
and prognostic factors in 581 patients: a report from the
Swedish Melanoma Study Group, Cancer 71:751-758,
1993.
Tanaka N, Mimura M, Ogi K et al: Primary malignant melanoma
of the oral cavity: assessment of outcome from the clinical
records of 35 patients, Int J Oral Maxillofac Surg 33:761-765,
2004.
Umeda M, Komatsubara H, Shibuya Y et al: Premalignant mela-
nocytic dysplasia and malignant melanoma of the oral
mucosa, Oral Oncol 38:714-722, 2002.
Wang BY, Lawson W, Robinson RA et al: Malignant melanomas
of the parotid: comparison of survival for patients with metas-
tases from known vs unknown primary tumor sites, Arch Oto-
laryngol Head Neck Surg 125:635-639, 1999.
Welch HG, Woloshin S, Schwartz LM: Skin biopsy rates and
incidence of melanoma: population based ecological study,
BMJ 331:481, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
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453
11
Salivary Gland Pathology
CHAPTER OUTLINE
Salivary Gland Aplasia
Mucocele
Ranula
Salivary Duct Cyst
Sialolithiasis
Sialadenitis
Cheilitis Glandularis
Sialorrhea
Xerostomia
Benign Lymphoepithelial Lesion
Sjögren Syndrome
Sialadenosis
Adenomatoid Hyperplasia of the Minor Salivary
Glands
Necrotizing Sialometaplasia
SALIVARY GLAND TUMORS
General Considerations
Pleomorphic Adenoma
the largest glands (both parotids and submandibular
glands), but others may be missing only one to three of
the four glands. In spite of the absence of the glands,
the face still has a normal appearance because the sites
are ﬁlled in by fat or connective tissue. Intraorally, the
oriﬁces of the missing glands are absent.
As would be anticipated, the most signiﬁcant
symptom associated with salivary gland aplasia is
severe xerostomia with its attendant problems (see
page 464). The tongue may appear leathery, and the
patient is at greater risk for developing dental caries
and erosion (Fig. 11-1). However, some degree of mois-
ture still may be present because of the continued
activity of the minor salivary glands. Absence of the
major glands can be conﬁrmed by technetium-99m
SALIVARY GLAND APLASIA
Salivary gland aplasia is a rare developmental
anomaly that can affect one or more of the major sali-
vary glands. The condition may occur alone, although
agenesis of the glands is often a component of one of
several syndromes, including mandibulofacial dysosto-
sis (Treacher Collins syndrome; see page 45), hemifa-
cial microsomia, and lacrimo-auriculo-dento-digital
(LADD) syndrome.
CLINICAL AND RADIOGRAPHIC
FEATURES
Salivary gland aplasia has been reported more fre-
quently in men than women by a 2:1 ratio. Some
individuals are affected by agenesis of all four of
Oncocytoma
Oncocytosis
Warthin Tumor
Monomorphic Adenoma
Canalicular Adenoma
Basal Cell Adenoma
Ductal Papillomas
Mucoepidermoid Carcinoma
Intraosseous Mucoepidermoid Carcinoma
Acinic Cell Adenocarcinoma
Malignant Mixed Tumors
Adenoid Cystic Carcinoma
Polymorphous Low-Grade Adenocarcinoma
Salivary Adenocarcinoma, Not Otherwise Speciﬁed `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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454 ORAL AND MAXILLOFACIAL PATHOLOGY
pertechnetate scintiscan, computed tomography (CT),
or magnetic resonance imaging (MRI).
LADD syndrome is an autosomal dominant disor-
der that is caused by mutations in the ﬁbroblast growth
factor 10 (FGF10) gene. It is characterized by aplasia
or hypoplasia of the lacrimal and salivary glands, cup-
shaped ears, and dental and digital anomalies. Dental
features may include hypodontia, microdontia, and
mild enamel hypoplasia.
TREATMENT AND PROGNOSIS
Patient management is directed toward compensating
for the saliva deﬁciency, and saliva substitutes are often
necessary. If any residual functional salivary gland
tissue is present, then sialagogue medications such as
pilocarpine or cevimeline may be used to increase
saliva production. Salivary ﬂow also may be stimulated
via the use of sugarless gum or sour candy. Regular
preventive dental care is important to avoid xero-
stomia-related caries and enamel breakdown.
MUCOCELE (MUCUS EXTRAVASATION
PHENOMENON; MUCUS
ESCAPE REACTION)
The mucocele is a common lesion of the oral mucosa
that results from rupture of a salivary gland duct and
spillage of mucin into the surrounding soft tissues. This
spillage is often the result of local trauma, although
there is no known history of trauma in many cases.
Unlike the salivary duct cyst (see page 457), the muco-
cele is not a true cyst because it lacks an epithelial
lining. Some authors, however, have included true sali-
vary duct cysts in their reported series of cases, some-
times under the classiﬁcation of retention mucocele.
Because these two entities exhibit distinctly different
clinical and histopathologic features, they are discussed
as separate topics in this chapter.
CLINICAL FEATURES
Mucoceles typically appear as dome-shaped mucosal
swellings that can range from 1 or 2 mm to several
centimeters in size (Figs. 11-2 to 11-4). They are most
common in children and young adults, perhaps because
younger people are more likely to experience trauma
that induces mucin spillage. However, mucoceles have
been reported in patients of all ages, including infants
and older adults. The spilled mucin below the mucosal
surface often imparts a bluish translucent hue to the
swelling, although deeper mucoceles may be normal
in color. The lesion characteristically is ﬂuctuant, but
some mucoceles feel ﬁrmer to palpation. The reported
Fig. 11-1 Salivary gland aplasia. Dry, leathery tongue and
diffuse enamel erosion in a child with aplasia of the major
salivary glands.
Fig. 11-2 Mucocele. Blue-pigmented nodule on the lower
lip.
Fig. 11-3 Mucocele. Nodule on the posterior buccal
mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 11 SALIVARY GLAND PATHOLOGY 455
duration of the lesion can vary from a few days to
several years; most patients report that the lesion has
been present for several weeks. Many patients relate a
history of a recurrent swelling that periodically may
rupture and release its ﬂuid contents.
The lower lip is by far the most common site for the
mucocele; a recent large study of 1824 cases found
that 81% occurred at this one site (Table 11-1). Lower
lip mucoceles usually are found lateral to the midline.
Less common sites include the ﬂoor of mouth (ranulas:
5.8%), anterior ventral tongue (from the glands of
Blandin-Nuhn: 5.7%), buccal mucosa (4.7%), palate
(1.4%), and retromolar pad (0.5%). Mucoceles rarely
develop on the upper lip. In the large series summa-
rized in Table 11-1, not a single example was identiﬁed
from the upper lip. This is in contrast to salivary gland
tumors, which are not unusual in the upper lip but are
distinctly uncommon in the lower lip.
As noted, the soft palate and retromolar area are
uncommon sites for mucoceles. However, one interest-
ing variant, the superﬁcial mucocele, does develop in
these areas and along the posterior buccal mucosa.
Superﬁcial mucoceles present as single or multiple
tense vesicles that measure 1 to 4 mm in diameter (Fig.
11-5). The lesions often burst, leaving shallow, painful
ulcers that heal within a few days. Repeated episodes
at the same location are not unusual. Some patients
relate the development of the lesions to mealtimes.
Superﬁcial mucoceles also have been reported to occur
in association with lichenoid disorders, such as lichen
planus, lichenoid drug eruptions, and chronic graft-
versus-host disease (GVHD). The vesicular appearance
is created by the superﬁcial nature of the mucin spill-
age, which causes a separation of the epithelium from
the connective tissue. The pathologist must be aware
of this lesion and should not mistake it microscopically
for a vesiculobullous disorder, especially mucous mem-
brane (cicatricial) pemphigoid.
HISTOPATHOLOGIC FEATURES
On microscopic examination, the mucocele shows an
area of spilled mucin surrounded by a granulation
tissue response (Figs. 11-6 and 11-7). The inﬂamma-
Fig. 11-4 Mucocele. Exophytic lesion on the anterior
ventral tongue.
Table 11-1 Location of Mucoceles
Location Number of Cases Percentage of All Cases
Lower lip 1477 81.0
Floor of mouth 106 5.8
Ventral tongue 106 5.8
Buccal mucosa 87 4.8
Palate 26 1.4
Retromolar 10 0.5
Unknown 12 0.7
Upper lip 0 0.0
Total 1824 100
Data from Chi A, Lambert P, Richardson M et al: Oral mucoceles: a clinicopathologic review of 1,824 cases including unusual variants, Abstract No. 19. Paper
presented at the annual meeting of the American Academy of Oral and Maxillofacial Pathology, Kansas City, Mo, 2007.
Fig. 11-5 Superﬁcial mucocele. Vesicle-like lesion on the
soft palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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456 ORAL AND MAXILLOFACIAL PATHOLOGY
tion usually includes numerous foamy histiocytes
(macrophages). In some cases a ruptured salivary duct
may be identiﬁed feeding into the area. The adjacent
minor salivary glands often contain a chronic inﬂam-
matory cell inﬁltrate and dilated ducts.
TREATMENT AND PROGNOSIS
Some mucoceles are short-lived lesions that rupture
and heal by themselves. Many lesions, however, are
chronic in nature, and local surgical excision is neces-
sary. To minimize the risk of recurrence, the surgeon
should remove any adjacent minor salivary glands that
may be feeding into the lesion when the area is excised.
The excised tissue should be submitted for microscopic
examination to conﬁrm the diagnosis and rule out the
possibility of a salivary gland tumor. The prognosis is
excellent, although occasional mucoceles will recur,
necessitating reexcision, especially if the feeding glands
are not removed.
RANULA
Ranula is a term used for mucoceles that occur in the
ﬂoor of the mouth. The name is derived from the Latin
word rana, which means “frog,” because the swelling
may resemble a frog’s translucent underbelly. The term
ranula also has been used to describe other similar
swellings in the ﬂoor of the mouth, including true sali-
vary duct cysts, dermoid cysts, and cystic hygromas.
However, the term is best used for mucus escape reac-
tions (mucoceles). The source of mucin spillage is
usually from the sublingual gland, but ranulas also may
arise from the submandibular duct or, possibly, from
minor salivary glands in the ﬂoor of the mouth. Larger
ranulas usually arise from the body of the sublingual
gland, although smaller lesions can develop along the
sublingual plica from the superﬁcial ducts of Rivini of
this gland.
CLINICAL FEATURES
The ranula usually appears as a blue, dome-shaped,
ﬂuctuant swelling in the ﬂoor of the mouth (Fig. 11-8),
but deeper lesions may be normal in color. Ranulas are
seen most frequently in children and young adults.
They tend to be larger than mucoceles in other oral
locations, often developing into large masses that ﬁll
the ﬂoor of the mouth and elevate the tongue. The
Fig. 11-6 Mucocele. Mucin-ﬁlled cystlike cavity beneath
the mucosal surface. Minor salivary glands are present below
and lateral to the spilled mucin.
Fig. 11-7 Mucocele. High-power view showing spilled
mucin that is associated with granulation tissue containing
foamy histiocytes (arrows).
Fig. 11-8 Ranula. Blue-pigmented swelling in the left ﬂoor
of the mouth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 11 SALIVARY GLAND PATHOLOGY 457
ranula usually is located lateral to the midline, a feature
that may help to distinguish it from a midline dermoid
cyst (see page 33). Like other mucoceles, ranulas may
rupture and release their mucin contents, only to
re-form.
An unusual clinical variant, the plunging or cervi-
cal ranula, occurs when the spilled mucin dissects
through the mylohyoid muscle and produces swelling
within the neck (Fig. 11-9). A concomitant swelling in
the ﬂoor of the mouth may or may not be present. If
no lesion is produced in the mouth, then the clinical
diagnosis of ranula may not be suspected. Imaging
studies can be helpful in supporting a diagnosis of
plunging ranula and in determining the origin of the
lesion. CT and MRI images of plunging ranulas that
arise from the sublingual gland often exhibit a slight
extension of the lesion into the sublingual space (“tail
sign”)—an imaging feature not observed in lesions that
develop from the submandibular gland.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of a ranula is similar to
that of a mucocele in other locations. The spilled mucin
elicits a granulation tissue response that typically con-
tains foamy histiocytes.
TREATMENT AND PROGNOSIS
Treatment of the ranula consists of removal of the
feeding sublingual gland and/or marsupialization.
Marsupialization (exteriorization) entails removal of
the roof of the intraoral lesion, which often can be suc-
cessful for small, superﬁcial ranulas associated with the
ducts of Rivini. However, marsupialization is often
unsuccessful for larger ranulas developing from the
body of the sublingual gland, and most authors empha-
size that removal of the offending gland is the most
important consideration in preventing a recurrence of
the lesion. If the gland is removed, then meticulous
dissection of the lining of the lesion may not be neces-
sary for the lesion to resolve, even for the plunging
ranula.
SALIVARY DUCT CYST (MUCUS
RETENTION CYST; MUCUS DUCT
CYST; SIALOCYST)
The salivary duct cyst is an epithelium-lined cavity
that arises from salivary gland tissue. Unlike the more
common mucocele (see page 454), it is a true develop-
mental cyst that is lined by epithelium that is separate
from the adjacent normal salivary ducts. The cause of
such cysts is uncertain.
Cystlike dilatation of salivary ducts also may develop
secondary to ductal obstruction (e.g., mucus plug),
which creates increased intraluminal pressure.
Although some authors refer to such lesions as mucus
retention cysts, such lesions probably represent sali-
vary ductal ectasia rather than a true cyst.
CLINICAL FEATURES
Salivary duct cysts usually occur in adults and can arise
within either the major or minor glands. Cysts of the
major glands are most common within the parotid
gland, presenting as slowly growing, asymptomatic
swellings. Intraoral cysts can occur at any minor gland
site, but most frequently they develop in the ﬂoor of
the mouth, buccal mucosa, and lips (Fig. 11-10). They
often look like mucoceles and are characterized by a
soft, ﬂuctuant swelling that may appear bluish, depend-
ing on the depth of the cyst below the surface. Some
cysts may feel relatively ﬁrm to palpation. Cysts in the
ﬂoor of the mouth often arise adjacent to the subman-
dibular duct and sometimes have an amber color.
On rare occasions, patients have been observed to
develop prominent ectasia of the excretory ducts of
many of the minor salivary glands throughout the
mouth. Such lesions have been termed “mucus reten-
tion cysts,” although they probably represent multi-
focal ductal dilatation. The individual lesions often
Fig. 11-9 Plunging ranula. Soft swelling in the neck. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

458 ORAL AND MAXILLOFACIAL PATHOLOGY
present as painful nodules that demonstrate dilated
ductal oriﬁces on the mucosal surface. Mucus or pus
may be expressed from these dilated ducts.
HISTOPATHOLOGIC FEATURES
The lining of the salivary duct cyst is variable and may
consist of cuboidal, columnar, or atrophic squamous
epithelium surrounding thin or mucoid secretions in
the lumen (Fig. 11-11). In contrast, ductal ectasia sec-
ondary to salivary obstruction is characterized by onco-
cytic metaplasia of the epithelial lining. This epithelium
often demonstrates papillary folds into the cystic lumen,
somewhat reminiscent of a small Warthin tumor (see
page 482) but without the prominent lymphoid stroma
(Fig. 11-12). If this proliferation is extensive enough,
then these lesions sometimes are diagnosed as papil-
lary cystadenoma, although it seems likely that most
are not true neoplasms. The individual lesions of
patients with multiple “mucus retention cysts” also
show prominent oncocytic metaplasia of the epithelial
lining.
TREATMENT AND PROGNOSIS
Isolated salivary duct cysts are treated by conservative
surgical excision. For cysts in the major glands, partial
or total removal of the gland may be necessary. The
lesion should not recur.
For rare patients who develop multifocal salivary
ductal ectasia (“mucus retention cysts”), local excision
may be performed for the more problematic swellings;
Fig. 11-10 Salivary duct cyst. Nodular swelling (arrow)
overlying Wharton’s duct.
A B
Fig. 11-11 Salivary duct cyst. A, Low-power photomicrograph showing a cyst below the
mucosal surface. B, High-power view of cystic cavity (top) lined by thin cuboidal epithelium.
Adjacent to the cyst is an excretory salivary gland duct lined by columnar epithelium (bottom).
Fig. 11-12 Oncocytic salivary ductal ectasia. This dilated
duct is lined by columnar eosinophilic oncocytes that exhibit
papillary folds into the ductal lumen. Such lesions may
develop secondary to ductal obstruction. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 459
however, surgical management does not appear feasi-
ble or advisable for all of the lesions, which may number
as many as 100. In one reported case, systemic eryth-
romycin and chlorhexidine mouth rinses were helpful
in relieving pain and reducing drainage of pus. Siala-
gogue medications also may be helpful in stimulating
salivary ﬂow, thereby preventing the accumulation of
inspissated mucus within the dilated excretory ducts.
SIALOLITHIASIS (SALIVARY CALCULI;
SALIVARY STONES)
Sialoliths are calciﬁed structures that develop within
the salivary ductal system. Researchers believe that
they arise from deposition of calcium salts around a
nidus of debris within the duct lumen. This debris may
include inspissated mucus, bacteria, ductal epithelial
cells, or foreign bodies. The cause of sialoliths is unclear,
but their formation can be promoted by chronic sial-
adenitis and partial obstruction. Their development is
not related to any systemic derangement in calcium
and phosphorus metabolism.
CLINICAL AND RADIOGRAPHIC
FEATURES
Sialoliths most often develop within the ductal system
of the submandibular gland; the formation of stones
within the parotid gland system is distinctly less fre-
quent. The long, tortuous, upward path of the subman-
dibular (Wharton’s) duct and the thicker, mucoid
secretions of this gland may be responsible for its
greater tendency to form salivary calculi. Sialoliths also
can form within the minor salivary glands, most often
within the glands of the upper lip or buccal mucosa.
Salivary stones can occur at almost any age, but they
are most common in young and middle-aged adults.
Major gland sialoliths most frequently cause epi-
sodic pain or swelling of the affected gland, especially
at mealtime. The severity of the symptoms varies,
depending on the degree of obstruction and the amount
of resultant backpressure produced within the gland.
If the stone is located toward the terminal portion of
the duct, then a hard mass may be palpated beneath
the mucosa (Fig. 11-13).
Sialoliths typically appear as radiopaque masses on
radiographic examination. However, not all stones are
visible on standard radiographs (perhaps because of
the degree of calciﬁcation of some lesions). They may
be discovered anywhere along the length of the duct
or within the gland itself (Fig. 11-14). Stones in the
terminal portion of the submandibular duct are best
demonstrated with an occlusal radiograph. On pan-
oramic or periapical radiographs, the calciﬁcation may
appear superimposed on the mandible and care must
be exercised not to confuse it with an intrabony lesion
(Fig. 11-15). Multiple parotid stones radiographically
can mimic calciﬁed parotid lymph nodes, such as
might occur in tuberculosis. Sialography, ultrasound,
and CT scanning may be helpful additional imaging
studies for sialoliths.
Minor gland sialoliths often are asymptomatic but
may produce local swelling or tenderness of the affected
gland (Fig. 11-16). A small radiopacity often can be
demonstrated with a soft tissue radiograph.
HISTOPATHOLOGIC FEATURES
On gross examination, sialoliths appear as hard masses
that are round, oval, or cylindrical. They are typically
yellow, although they may be a white or yellow-brown
color. Submandibular stones tend to be larger than
those of the parotid or minor glands. Sialoliths are
usually solitary, although occasionally two or more
stones may be discovered at surgery.
Microscopically, the calciﬁed mass exhibits con-
centric laminations that may surround a nidus of
Fig. 11-13 Sialolithiasis. Hard mass at the oriﬁce of
Wharton’s duct.
Fig. 11-14 Sialolithiasis. Radiopaque mass located at the
left angle of the mandible. (Courtesy of Dr. Roger Bryant.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

460 ORAL AND MAXILLOFACIAL PATHOLOGY
amorphous debris (Fig. 11-17). If the associated duct
also is removed, then it often demonstrates squamous,
oncocytic, or mucous cell metaplasia. Periductal
inﬂammation is also evident. The ductal obstruction
frequently is associated with an acute or chronic sial-
adenitis of the feeding gland.
TREATMENT AND PROGNOSIS
Small sialoliths of the major glands sometimes can be
treated conservatively by gentle massage of the gland
in an effort to milk the stone toward the duct oriﬁce.
Sialagogues (drugs that stimulate salivary ﬂow), moist
heat, and increased ﬂuid intake also may promote
A
B
Fig. 11-15 Sialolithiasis. A, Periapical ﬁlm showing
discrete radiopacity (arrow) superimposed on the body of the
mandible. Care must be taken not to confuse such lesions
with intrabony pathosis. B, Occlusal radiograph of same
patient demonstrating radiopaque stone in Wharton’s duct.
A
B
Fig. 11-16 Sialolithiasis. A, Minor salivary gland sialolith
presenting as a hard nodule in the upper lip. B, A soft tissue
radiograph of the same lesion revealed a laminated calciﬁed
mass.
Fig. 11-17 Sialolithiasis. Intraductal calciﬁed mass
showing concentric laminations. The duct exhibits squamous
metaplasia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 461
passage of the stone. Larger sialoliths usually need to
be removed surgically. If signiﬁcant inﬂammatory
damage has occurred within the feeding gland, then
the gland may need to be removed. Minor gland sialo-
liths are best treated by surgical removal, including the
associated gland.
Shock wave lithotripsy (extracorporeal or intracor-
poreal), salivary gland endoscopy, and radiologically
guided basket retrieval are newer techniques that have
been shown to be effective in the removal of sialoliths
from the major glands. These minimally invasive tech-
niques have low morbidity and may preclude the
necessity of gland removal.
SIALADENITIS
Inﬂammation of the salivary glands (sialadenitis) can
arise from various infectious and noninfectious causes.
The most common viral infection is mumps (see page
263), although a number of other viruses also can
involve the salivary glands, including Coxsackie A,
ECHO, choriomeningitis, parainﬂuenza, and cytomeg-
alovirus (CMV) (in neonates). Most bacterial infections
arise as a result of ductal obstruction or decreased sali-
vary ﬂow, allowing retrograde spread of bacteria
throughout the ductal system. Blockage of the duct can
be caused by sialolithiasis (see page 459), congenital
strictures, or compression by an adjacent tumor.
Decreased ﬂow can result from dehydration, debilita-
tion, or medications that inhibit secretions.
One of the more common causes of sialadenitis is
recent surgery (especially abdominal surgery), after
which an acute parotitis (surgical mumps) may arise
because the patient has been kept without food or ﬂuids
(NPO) and has received atropine during the surgical
procedure. Other medications that produce xerostomia
as a side effect also can predispose patients to such an
infection. Most cases of acute bacterial sialadenitis are
caused by Staphylococcus aureus, but they also may arise
from streptococci or other organisms. Noninfectious
causes of salivary inﬂammation include Sjögren syn-
drome (see page 466), sarcoidosis (see page 338), radi-
ation therapy (see page 295), and various allergens.
CLINICAL AND RADIOGRAPHIC
FEATURES
Acute bacterial sialadenitis is most common in the
parotid gland and is bilateral in 10% to 25% of cases.
The affected gland is swollen and painful, and the over-
lying skin may be warm and erythematous (Fig. 11-18).
An associated low-grade fever and trismus may be
present. A purulent discharge often is observed
from the duct oriﬁce when the gland is massaged
(Fig. 11-19).
Recurrent or persistent ductal obstruction (most
commonly caused by sialoliths) can lead to a chronic
sialadenitis. Periodic swelling and pain occur within
the affected gland, usually developing at mealtime
when salivary ﬂow is stimulated. In the submandibular
gland, persistent enlargement may develop (Küttner
tumor), which is difﬁcult to distinguish from a true
neoplasm. Sialography often demonstrates sialectasia
(ductal dilatation) proximal to the area of obstruction
(Fig. 11-20). In chronic parotitis, Stensen’s duct may
show a characteristic sialographic pattern known as
“sausaging,” which reﬂects a combination of dilatation
plus ductal strictures from scar formation. Chronic
sialadenitis also can occur in the minor glands, possibly
as a result of blockage of ductal ﬂow or local trauma.
Subacute necrotizing sialadenitis is a form of sali-
vary inﬂammation that occurs most commonly in teen-
agers and young adults. The lesion usually involves
the minor salivary glands of the hard or soft palate,
Fig. 11-18 Sialadenitis. Tender swelling of the
submandibular gland.
Fig. 11-19 Sialadenitis. A purulent exudate can be seen
arising from Stensen’s duct when the parotid gland is
massaged. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

462 ORAL AND MAXILLOFACIAL PATHOLOGY
presenting as a painful nodule that is covered by intact,
erythematous mucosa. Unlike necrotizing sialometa-
plasia (see page 471), the lesion does not ulcerate or
slough necrotic tissue. An infectious or allergic cause
has been hypothesized.
HISTOPATHOLOGIC FEATURES
In patients with acute sialadenitis, accumulation of
neutrophils is observed within the ductal system and
acini. Chronic sialadenitis is characterized by scattered
or patchy inﬁltration of the salivary parenchyma by
lymphocytes and plasma cells. Atrophy of the acini is
common, as is ductal dilatation. If associated ﬁbrosis is
present, then the term chronic sclerosing sialadeni-
tis is used (Fig. 11-21).
Subacute necrotizing sialadenitis is characterized by
a heavy mixed inﬂammatory inﬁltrate consisting of
neutrophils, lymphocytes, histiocytes, and eosinophils.
There is loss of most of the acinar cells, and many of
the remaining ones exhibit necrosis. The ducts tend to
be atrophic and do not show hyperplasia or squamous
metaplasia.
TREATMENT AND PROGNOSIS
The treatment of acute sialadenitis includes appropri-
ate antibiotic therapy and rehydration of the patient
to stimulate salivary ﬂow. Surgical drainage may be
needed if there is abscess formation. Although this
regimen is usually sufﬁcient, a 20% to 50% mortality
rate has been reported in debilitated patients because
of the spread of the infection and sepsis.
The management of chronic sialadenitis depends
on the severity of the condition and ranges from
conservative therapy to surgical intervention. Initial
management often includes antibiotics, analgesics,
sialagogues, and glandular massage. Early cases that
develop secondary to ductal blockage may respond to
removal of the sialolith or other obstruction. However,
if sialectasia is present, then the dilated ducts can lead
to stasis of secretions and predispose the gland to
further sialolith formation. Sialadenoscopy and ductal
irrigation are newer techniques that can be used to
dilate ductal strictures and to eliminate sialoliths and
mucus plugs. Second-line treatment options for chronic
parotitis have included ligation of Stensen’s duct, but
this method has a high failure rate. Tympanic neurec-
tomy, which results in decreased secretion by the
parotid gland via transection of the parasympathetic
secretory ﬁbers at the tympanic plexus, produces
improvement in 75% of patients with chronic parotitis.
If conservative methods cannot control chronic sialad-
enitis, then surgical removal of the affected gland may
be necessary.
Subacute necrotizing sialadenitis is a self-limiting
condition that usually resolves within 2 weeks of diag-
nosis without treatment.
CHEILITIS GLANDULARIS
Cheilitis glandularis is a rare inﬂammatory condition
of the minor salivary glands. The cause is uncertain,
although several etiologic factors have been suggested,
including actinic damage, tobacco, syphilis, poor
hygiene, and heredity.
CLINICAL FEATURES
Cheilitis glandularis characteristically occurs on the
lower lip, although there are also purported cases
involving the upper lip and palate. Affected individuals
experience swelling and eversion of the lower lip as a
result of hypertrophy and inﬂammation of the glands
Fig. 11-20 Chronic sialadenitis. Parotid sialogram
demonstrating ductal dilatation proximal to an area of
obstruction. (Courtesy of Dr. George Blozis.)
Fig. 11-21 Chronic sclerosing sialadenitis. Chronic
inﬂammatory inﬁltrate with associated acinar atrophy, ductal
dilatation, and ﬁbrosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 463
(Fig. 11-22). The openings of the minor salivary ducts
are inﬂamed and dilated, and pressure on the glands
may produce mucopurulent secretions from the ductal
openings. The condition most often has been reported
in middle-aged and older men, although cases also
have been described in women and children. However,
some of the childhood cases may represent other enti-
ties, such as exfoliative cheilitis (see page 304).
Historically, cheilitis glandularis has been classiﬁed
into three types, based on the severity of the disease:
1.Simple
2.Superﬁcial suppurative (Baelz’s disease)
3.Deep suppurative (cheilitis glandularis aposte-
matosa)
The latter two types represent progressive stages of the
disease with bacterial involvement; they are character-
ized by increasing inﬂammation, suppuration, ulcer-
ation, and swelling of the lip.
HISTOPATHOLOGIC FEATURES
The microscopic ﬁndings of cheilitis glandularis are
not speciﬁc and usually consist of chronic sialadenitis
and ductal dilatation. Concomitant dysplastic changes
may be observed in the overlying surface epithelium in
some cases.
TREATMENT AND PROGNOSIS
The treatment of choice for most cases of persistent
cheilitis glandularis associated with actinic damage is
vermilionectomy (lip shave), which usually produces a
satisfactory cosmetic result. A signiﬁcant percentage of
cases (18% to 35%) have been associated with the devel-
opment of squamous cell carcinoma of the overlying
epithelium of the lip. Because actinic damage has been
implicated in many cases of cheilitis glandularis, it is
likely that this same solar radiation is responsible for
the malignant degeneration.
SIALORRHEA
Sialorrhea, or excessive salivation, is an uncommon
condition that has various causes. Minor sialorrhea
may result from local irritations, such as aphthous
ulcers or ill-ﬁtting dentures. Patients with new den-
tures often experience excess saliva production until
they become accustomed to the prosthesis. Episodic
hypersecretion of saliva, or “water brash,” may occur
as a protective buffering system to neutralize stomach
acid in individuals with gastroesophageal reﬂux dis-
ease. Sialorrhea is a well-known clinical feature of
rabies and heavy-metal poisoning (see page 313). It
also may occur as a consequence of certain medica-
tions, such as antipsychotic agents, especially clozap-
ine, and cholinergic agonists used to treat dementia of
the Alzheimer’s type and myasthenia gravis.
Drooling can be a problem for patients who are
mentally retarded, who have undergone surgical resec-
tion of the mandible, or who have various neurologic
disorders such as cerebral palsy, Parkinson’s disease,
or amyotrophic lateral sclerosis (ALS). In these
instances, the drooling is probably not caused by over-
production of saliva but by poor neuromuscular
control.
In addition, there is a second group of patients who
report complaints of drooling; however, no obvious
clinical evidence of excessive saliva production is
observed, and they do not have any of the recognized
causes for sialorrhea. Personality analysis has suggested
that the complaint of sialorrhea in such otherwise
healthy patients does not have an organic basis but may
be associated with high levels of neuroticism and a
tendency to dissimulate.
CLINICAL FEATURES
The excess saliva production typically produces drool-
ing and choking, which may cause social embarrass-
ment. In children with mental retardation or cerebral
palsy, the uncontrolled salivary ﬂow may lead to mac-
erated sores around the mouth, chin, and neck that can
become secondarily infected. The constant soiling of
clothes and bed linens can be a signiﬁcant problem for
the parents and caretakers of these patients.
An interesting type of supersalivation of unknown
cause has been termed idiopathic paroxysmal sialor-
rhea. Individuals with this condition experience short
episodes of excessive salivation lasting from 2 to 5
Fig. 11-22 Cheilitis glandularis. Prominent lower lip with
inﬂamed openings of the minor salivary gland ducts. An early
squamous cell carcinoma has developed on the patient’s left
side just lateral to the midline (arrow). (Courtesy of Dr. George
Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

464 ORAL AND MAXILLOFACIAL PATHOLOGY
minutes. These episodes are associated with a pro-
drome of nausea or epigastric pain.
TREATMENT AND PROGNOSIS
Some causes of sialorrhea are transitory or mild,
and no treatment is needed. For individuals with
increased salivation associated with gastroesophageal
reﬂux disease, medical management of their reﬂux
problem may be beneﬁcial.
For persistent severe drooling, therapeutic interven-
tion may be indicated. Speech therapy can be used to
improve neuromuscular control, but patient coopera-
tion is necessary. Anticholinergic medications can
decrease saliva production but may produce unaccept-
able side effects. Transdermal scopolamine has been
tried with some success, but it should not be used in
children younger than age 10. Intraglandular injection
of botulinum toxin has been shown to be successful in
reducing salivary secretions, with a duration of action
that varies from 6 weeks to 6 months.
Several surgical techniques have been used success-
fully to control severe drooling in individuals with poor
neuromuscular control:
●Relocation of the submandibular ducts (some-
times along with excision of the sublingual
glands)
●Relocation of the parotid ducts
●Submandibular gland excision plus parotid duct
ligation
●Ligation of the parotid and submandibular ducts
●Bilateral tympanic neurectomy with sectioning of
the chorda tympani
In ductal relocation, the ducts are repositioned pos-
teriorly to the tonsillar fossa, thereby redirecting sali-
vary ﬂow and minimizing drooling. The use of bilateral
tympanic neurectomy and sectioning of the chorda
tympani destroys parasympathetic innervation to the
glands, reducing salivary secretions and possibly induc-
ing xerostomia. However, this procedure also produces
a loss of taste to the anterior two thirds of the tongue.
XEROSTOMIA
Xerostomia refers to a subjective sensation of a dry
mouth; it is frequently, but not always, associated with
salivary gland hypofunction. A number of factors may
play a role in the cause of xerostomia, and these are
listed in Box 11-1. Xerostomia is a common problem
that has been reported in 25% of older adults. In the
past, complaints of dry mouth in older patients often
were ascribed to the predictable result of aging.
However, it is now generally accepted that any reduc-
tions in salivary function associated with age are modest
and probably are not associated with any signiﬁcant
reduction in salivary function. Instead, xerostomia in
older adults is more likely to be the result of other
factors, especially medications. More than 500 drugs
have been reported to produce xerostomia as a side
effect, including 63% of the 200 most frequently pre-
scribed medicines in the United States. A list of the
most common and signiﬁcant drugs associated with
xerostomia is provided in Table 11-2. Not only are
speciﬁc drugs known to produce dry mouth, but the
prevalence of xerostomia also increases in relation to
the total number of drugs that a person takes, regard-
less of whether the individual medications are xero-
genic or not.
CLINICAL FEATURES
Examination of the patient typically demonstrates a
reduction in salivary secretions, and the residual saliva
appears either foamy or thick and “ropey.” The mucosa
appears dry, and the clinician may notice that the
examining gloves stick to the mucosal surfaces. The
dorsal tongue often is ﬁssured with atrophy of the ﬁli-
form papillae (see Fig. 11-1). The patient may com-
plain of difﬁculty with mastication and swallowing, and
Box 11-1
Causes of Xerostomia
DEVELOPMENTAL ORIGIN
Salivary gland aplasia
WATER/METABOLITE LOSS
Impaired ﬂuid intake
Hemorrhage
Vomiting/diarrhea
IATROGENIC ORIGIN
Medications
Radiation therapy to the head and neck
Chemotherapy
SYSTEMIC DISEASES
Sjögren syndrome
Diabetes mellitus
Diabetes insipidus
Sarcoidosis
Human immunodeﬁciency virus (HIV) infection
Hepatitis C infection
Graft-versus-host disease (GVHD)
Psychogenic disorders
LOCAL FACTORS
Decreased mastication
Smoking
Mouth breathing `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 465
they may even indicate that food adheres to the oral
membranes during eating. The clinical ﬁndings,
however, do not always correspond to the patient’s
symptoms. Some patients who complain of dry mouth
may appear to have adequate salivary ﬂow and oral
moistness. Conversely, some patients who clinically
appear to have a dry mouth have no complaints. The
degree of saliva production can be assessed by measur-
ing both resting and stimulated salivary ﬂow.
There is an increased prevalence of oral candidiasis
in patients with xerostomia because of the reduction in
the cleansing and antimicrobial activity normally pro-
vided by saliva. In addition, these patients are more
prone to dental decay, especially cervical and root
caries. This problem has been associated more often
with radiation therapy, and it is sometimes called
radiation-induced caries but more appropriately should
be called xerostomia-related caries (see page 296).
TREATMENT AND PROGNOSIS
The treatment of xerostomia is difﬁcult and often
unsatisfactory. Artiﬁcial salivas are available and may
help make the patient more comfortable, as may con-
tinuous sips of water throughout the day. In addition,
sugarless candy can be used in an effort to stimulate
salivary ﬂow. One of the better patient-accepted man-
agement approaches includes the use of oral hygiene
products that contain lactoperoxidase, lysozyme, and
lactoferrin (e.g., Biotene toothpaste and mouth rinse,
Oralbalance gel). If the dryness is secondary to the
patient’s medication, then discontinuation or dose
modiﬁcation in consultation with the patient’s physi-
cian may be considered; a substitute drug can also be
tried.
Systemic pilocarpine is a parasympathomimetic
agonist that can be used as a sialagogue. At doses of 5
to 10 mg, three to four times daily, it can be an effective
promoter of salivary secretion. Excess sweating is a
common side effect, but more serious problems, such
as increased heart rate and blood pressure, are uncom-
mon. The U.S. Food and Drug Administration (FDA)
has also approved cevimeline hydrochloride, an acetyl-
choline derivative, for use as a sialagogue. Both pilocar-
pine and cevimeline are contraindicated in patients
with narrow-angle glaucoma.
Because of the increased potential for dental caries
in patients with xerostomia, frequent dental visits are
recommended. Ofﬁce and daily home ﬂuoride applica-
tions can be used to help prevent decay, and chlorhexi-
dine mouth rinses minimize plaque buildup.
BENIGN LYMPHOEPITHELIAL LESION
(MYOEPITHELIAL SIALADENITIS)
In the late 1800s, Johann von Mikulicz-Radecki
described the case of a patient with an unusual bilat-
eral painless swelling of the lacrimal glands and all of
the salivary glands. Histopathologic examination of the
involved glands showed an intense lymphocytic inﬁl-
trate, with features that today are recognized micro-
scopically as the benign lymphoepithelial lesion.
This clinical presentation became known as Mikulicz
disease, and clinicians began using this term to
describe a variety of cases of bilateral parotid and lac-
rimal enlargement. However, many of these cases were
not examples of benign lymphoepithelial lesions micro-
scopically; instead, they represented salivary and lacri-
mal involvement by other disease processes, such as
tuberculosis, sarcoidosis, and lymphoma. These cases
of parotid and lacrimal enlargement secondary to other
diseases were later recognized as being different and
termed Mikulicz syndrome, with the term Mikulicz
disease reserved for cases associated with benign lym-
phoepithelial lesions. However, these two terms have
become so confusing and ambiguous that they should
no longer be used.
Many cases of so-called Mikulicz disease may be
examples of what is now more commonly known as
Sjögren syndrome (see page 466). Sjögren syndrome
is an autoimmune disease that may produce bilateral
salivary and lacrimal enlargement, with microscopic
Table 11-2 Medications That May
Produce Xerostomia
Class of Drug Example
Antihistamine agents Diphenhydramine
Chlorpheniramine
Decongestant agents Pseudoephedrine
Antidepressant agents Amitriptyline
Citalopram
Fluoxetine
Paroxetine
Sertraline
Bupropion
Antipsychotic agents Phenothiazine derivatives
Haloperidol
Sedatives and anxiolytic agentsDiazepam
Lorazepam
Alprazolam
Antihypertensive agents Reserpine
Methyldopa
Chlorothiazide
Furosemide
Metoprolol
Calcium channel blockers
Anticholinergic agents Atropine
Scopolamine `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

466 ORAL AND MAXILLOFACIAL PATHOLOGY
features of benign lymphoepithelial lesion. However,
not all benign lymphoepithelial lesions are necessarily
associated with the clinical disease complex of Sjögren
syndrome.
CLINICAL FEATURES
Most benign lymphoepithelial lesions develop as a
component of Sjögren syndrome. Those not associated
with Sjögren syndrome are usually unilateral, although
occasional bilateral examples are seen. On occasion,
benign lymphoepithelial lesions occur in association
with other salivary gland pathologic conditions, such as
sialoliths and benign or malignant epithelial tumors.
The benign lymphoepithelial lesion most often
develops in adults, with a mean age of 50. From 60%
to 80% of cases occur in women. Eighty-ﬁve percent of
cases occur in the parotid gland, with infrequent exam-
ples also reported in the submandibular gland and
minor salivary glands. The lesion usually appears as a
ﬁrm, diffuse swelling of the affected gland that some-
times is dramatic in size. It may be asymptomatic or
associated with mild pain.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the benign lymphoepithe-
lial lesion shows a heavy lymphocytic inﬁltrate associ-
ated with the destruction of the salivary acini (Fig.
11-23). Germinal centers may or may not be seen.
Although the acini are destroyed, the ductal epithelium
persists. The ductal cells and surrounding myoepithe-
lial cells become hyperplastic, forming highly charac-
teristic groups of cells, known as epimyoepithelial islands,
throughout the lymphoid proliferation. The presence
of epimyoepithelial islands once was considered indica-
tive of a benign process, but now it is recognized that
these islands also can be found in low-grade salivary
lymphomas of the mucosa-associated lymphoid
tissue (MALT lymphomas, marginal zone B-cell
lymphomas).
TREATMENT AND PROGNOSIS
Although the benign lymphoepithelial lesion fre-
quently necessitates surgical removal of the involved
gland, the prognosis in most cases is good. However,
individuals with benign lymphoepithelial lesions have
an increased risk for lymphoma, either within the
affected gland or in an extrasalivary site. Although the
exact risk is uncertain, one study showed the risk in
patients with Sjögren syndrome to be more than 40
times higher than expected in the general population.
(The management of patients with Sjögren syndrome
is discussed on page 470.)
With the development of modern molecular tech-
niques to assess for gene rearrangements and mono-
clonality within lymphoid inﬁltrates, it is now
recognized that some lesions originally believed to rep-
resent benign lymphoepithelial lesions are actually
early-stage MALT lymphomas. Many experts now rec-
ognize a spectrum of salivary lymphoid proliferations,
which range from benign lymphoepithelial lesions to
borderline lesions to frank lymphomas. Because of this,
some authors have dropped the term benign from this
spectrum and refer to these proliferations only as lym-
phoepithelial lesions. Fortunately, most MALT lympho-
mas are low-grade tumors that tend to remain localized
with good survival rates. However, occasional tumors
transform to higher-grade lymphomas with more
aggressive behavior.
In addition, a rare malignant counterpart of this
lesion, called a malignant lymphoepithelial lesion
or lymphoepithelial carcinoma, represents a poorly
differentiated salivary carcinoma with a prominent
lymphoid stroma. Most of these lesions have occurred
in Inuit and Asian populations and appear to have
arisen de novo as carcinomas; however, some cases
(especially in non-Inuits) have been reported to develop
from a prior benign lymphoepithelial lesion. The
Epstein-Barr virus (EBV) has been strongly associated
in the cause of malignant lymphoepithelial lesions,
especially those cases arising in Inuit and Asian popu-
lations. The 5-year survival rate has been reported to
range from 70% to 85%.
SJÖGREN SYNDROME
Sjögren syndrome is a chronic, systemic autoimmune
disorder that principally involves the salivary and lac-
rimal glands, resulting in xerostomia (dry mouth) and
xerophthalmia (dry eyes). The effects on the eye often
Fig. 11-23 Benign lymphoepithelial lesion. Lymphocytic
inﬁltrate of the parotid gland with an associated
epimyoepithelial island. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 467
are called keratoconjunctivitis sicca (sicca means
“dry”), and the clinical presentation of both xerostomia
and xerophthalmia is also sometimes called the sicca
syndrome. Two forms of the disease are recognized:
1.Primary Sjögren syndrome (sicca syndrome
alone; no other autoimmune disorder is
present)
2.Secondary Sjögren syndrome (the patient mani-
fests sicca syndrome in addition to another asso-
ciated autoimmune disease)
The cause of Sjögren syndrome is unknown.
Although it is not a hereditary disease per se, there is
evidence of a genetic inﬂuence. Examples of Sjögren
syndrome have been reported in twins or in two or
more members of the same family. Relatives of affected
patients have an increased frequency of other autoim-
mune diseases. In addition, certain histocompatibility
antigens (HLAs) are found with greater frequency in
patients with Sjögren syndrome. HLA-DRw52 is asso-
ciated with both forms of the disease; HLA-B8 and
HLA-DR3 are seen with increased frequency in the
primary form of the disease. Researchers have sug-
gested that viruses, such as Epstein-Barr virus (EBV) or
human T-cell lymphotropic virus, may play a pathoge-
netic role in Sjögren syndrome, but evidence for this is
still speculative.
CLINICAL AND RADIOGRAPHIC
FEATURES
Sjögren syndrome is not a rare condition. Although the
exact prevalence depends on the clinical criteria used,
current estimates place the population prevalence at
0.5%, with a 9:1 female-to-male ratio. It is seen pre-
dominantly in middle-aged adults, but rare examples
have been described in children. The revised classiﬁca-
tion criteria suggested by the American-European Con-
sensus Group are shown in Box 11-2.
When the condition is associated with another
connective tissue disease, it is called secondary Sjögren
syndrome. It can be associated with almost any other
autoimmune disease, but the most common associated
disorder is rheumatoid arthritis. About 15% of patients
with rheumatoid arthritis have Sjögren syndrome. In
addition, secondary Sjögren syndrome may develop in
30% of patients with systemic lupus erythematosus
(SLE).
The principal oral symptom is xerostomia, which is
caused by decreased salivary secretions; however, the
severity of this dryness can vary widely from patient to
patient. The saliva may appear frothy, with a lack of the
usual pooling saliva in the ﬂoor of the mouth. Affected
patients may complain of difﬁculty in swallowing,
altered taste, or difﬁculty in wearing dentures. The
tongue often becomes ﬁssured and exhibits atrophy of
the papillae (Fig. 11-24). The oral mucosa may be red
and tender, usually as a result of secondary candidiasis.
Related denture sore mouth and angular cheilitis are
common. The lack of salivary cleansing action predis-
poses the patient to dental decay, especially cervical
caries.
From one third to one half of patients have diffuse,
ﬁrm enlargement of the major salivary glands during
the course of their disease (Fig. 11-25). This swelling is
usually bilateral, may be nonpainful or slightly tender,
Fig. 11-24 Sjögren syndrome. Dry and ﬁssured tongue.
(Courtesy of Dr. David Schaffner.)
Fig. 11-25 Sjögren syndrome. Benign lymphoepithelial
lesion of the parotid gland. (Courtesy of Dr. David Schaffner.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

468 ORAL AND MAXILLOFACIAL PATHOLOGY
and may be intermittent or persistent in nature. The
greater the severity of the disease, the greater the likeli-
hood of this salivary enlargement. In addition, the
reduced salivary ﬂow places these individuals at
increased risk for retrograde bacterial sialadenitis.
Although it is not diagnostic, sialographic examina-
tion often reveals punctate sialectasia and lack of
normal arborization of the ductal system, typically
demonstrating a “fruit-laden, branchless tree” pattern
(Fig. 11-26). Scintigraphy with radioactive technetium-
99m pertechnetate characteristically shows decreased
uptake and delayed emptying of the isotope.
The term keratoconjunctivitis sicca describes not
only the reduced tear production by the lacrimal glands
but also the pathologic effect on the epithelial cells of
the ocular surface. As in xerostomia, the severity of
xerophthalmia can vary widely from one patient to the
next. The lacrimal inﬂammation causes a decrease of
the aqueous layer of the tear ﬁlm; however, mucin
production is normal and may result in a mucoid dis-
charge. Patients often complain of a scratchy, gritty
sensation or the perceived presence of a foreign body
in the eye. Defects of the ocular surface epithelium
develop and can be demonstrated with rose bengal
dye. Vision may become blurred, and sometimes there
is an aching pain. The ocular manifestations are least
severe in the morning on wakening and become more
pronounced as the day progresses.
Box 11-2
Revised International Classiﬁcation Criteria for Sjögren Syndrome
I.Ocular symptoms: A positive response to at least one
of the following questions:
A. Have you had daily, persistent, troublesome dry
eyes for more than 3 months?
B. Do you have a recurrent sensation of sand or gravel
in the eyes?
C. Do you use tear substitutes more than three times
a day?
II.Oral symptoms: A positive response to at least one of
the following questions:
A. Have you had a daily feeling of dry mouth for more
than 3 months?
B. Have you had recurrently or persistently swollen
salivary glands as an adult?
C. Do you frequently drink liquids to aid in swallowing
dry food?
III.Ocular signs: Objective evidence of ocular involvement
deﬁned as a positive result for at least one of the
following two tests:
A. Schirmer I test, performed without anesthesia
(≤5 mm in 5 minutes)
B. Rose bengal score or other ocular dye score (≥4
according to van Bijsterveld’s scoring system)
IV. Histopathology: In minor salivary glands (obtained
through normal-appearing mucosa) focal lymphocytic
sialadenitis, evaluated by an expert histopathologist,
with a focus score ≥1, deﬁned as a number of
lymphocytic foci (which are adjacent to normal-
appearing mucous acini and contain more than 50
lymphocytes) per 4 mm
2
of glandular tissue
V.Salivary gland involvement: Objective evidence of
salivary gland involvement deﬁned by a positive result
for at least one of the following diagnostic tests:
A. Unstimulated whole salivary ﬂow (≤1.5 ml in 15
minutes)
B. Parotid sialography showing the presence of diffuse
sialectasias (punctate, cavitary, or destructive
pattern), without evidence of obstruction in the
major ducts
C. Salivary scintigraphy showing delayed uptake,
reduced concentration, and/or delayed excretion of
tracer
VI. Autoantibodies: Presence in the serum of the
following autoantibodies:
A. Antibodies to Ro(SS-A) or La(SS-B) antigens, or both
RULES FOR CLASSIFICATION
Primary Sjögren Syndrome
In patients without any potentially associated disease,
primary Sjögren syndrome is deﬁned as follows:
I.Presence of any four of the six items is indicative of
primary Sjögren syndrome, as long as either item IV
(histopathology) or VI (serology) is positive
II.Presence of any three of the four objective criteria
items (items III, IV, V, and VI)
Secondary Sjögren Syndrome
In patients with a potentially associated disease (e.g.,
another well-deﬁned connective tissue disease), presence
of item I or item II plus any two from among items III, IV,
and V considered indicative of secondary Sjögren
syndrome
Exclusion Criteria
Past head and neck radiation treatment
Hepatitis C infection
Acquired immunodeﬁciency syndrome (AIDS)
Preexisting lymphoma
Sarcoidosis
Graft-versus-host disease (GVHD)
Use of anticholinergic drugs `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 469
A simple means to conﬁrm the decreased tear secre-
tion is the Schirmer test. A standardized strip of sterile
ﬁlter paper is placed over the margin of the lower
eyelid, between the medial and lateral third of the lid
of the unanesthetized eye, so that the tabbed end rests
just inside the lower lid. By measuring the length of
wetting of the ﬁlter paper, tear production can be
assessed. Values less than 5 mm (after a 5-minute
period) are considered diagnostic of keratoconjunctivi-
tis sicca.
Sjögren syndrome is a systemic disease, and the
inﬂammatory process also can affect various other
body tissues. The skin is often dry, as are the nasal and
vaginal mucosae. Fatigue is fairly common, and depres-
sion sometimes can occur. Other possible associated
problems include lymphadenopathy, primary biliary
cirrhosis, Raynaud’s phenomenon, interstitial nephri-
tis, interstitial lung ﬁbrosis, vasculitis, and peripheral
neuropathies.
LABORATORY VALUES
In patients with Sjögren syndrome, the erythrocyte
sedimentation rate is high and serum immunoglobulin
(Ig) levels, especially IgG, typically are elevated. A
variety of autoantibodies can be produced, and although
none of these is speciﬁcally diagnostic, their presence
can be another helpful clue to the diagnosis. A positive
rheumatoid factor (RF) is found in approximately 60%
of cases, regardless of whether the patient has rheuma-
toid arthritis. Antinuclear antibodies (ANAs) are also
present in 75% to 85% of patients. Two particular
nuclear autoantibodies—anti-SS-A (anti-Ro) and anti-
SS-B (anti-La)—may be found, especially in patients
with primary Sjögren syndrome. Anti-SS-A antibodies
have been detected in approximately 40% of patients,
whereas anti-SS-B antibodies have been discovered in
about 25% of these individuals. Occasionally, salivary
duct autoantibodies also can be demonstrated, usually
in secondary Sjögren syndrome. However, because
these are infrequent in primary cases, they are believed
to occur as a secondary phenomenon (rather than
playing a primary role in pathogenesis).
HISTOPATHOLOGIC FEATURES
The basic microscopic ﬁnding in Sjögren syndrome
is a lymphocytic inﬁltration of the salivary glands,
with destruction of the acinar units. If the major
glands are enlarged, then microscopic examination
usually shows progression to a lymphoepithelial lesion
(see page 466), with characteristic epimyoepithelial
islands in a background lymphoid stroma. Lympho-
cytic inﬁltration of the minor glands also occurs,
although epimyoepithelial islands are rarely seen in
this location.
Biopsy of the minor salivary glands of the lower lip
has become a useful test in the diagnosis of Sjögren
syndrome. A 1.5- to 2.0-cm incision is made on clini-
cally normal lower labial mucosa, parallel to the ver-
milion border and lateral to the midline, allowing the
harvest of ﬁve or more accessory glands. These glands
then are examined histopathologically for the presence
of focal chronic inﬂammatory aggregates (50 or more
lymphocytes and plasma cells). These aggregates should
be adjacent to normal-appearing acini and should be
found consistently in most of the glands in the speci-
men. The ﬁnding of more than one focus of 50 or more
cells within a 4-mm
2
area of glandular tissue is consid-
ered supportive of the diagnosis of Sjögren syndrome
(Fig. 11-27). The greater the number of foci (up to 10
or conﬂuent foci) is, the greater is the correlation with
this diagnosis. The focal nature of this chronic inﬂam-
mation among otherwise normal acini is a highly
Fig. 11-26 Sjögren syndrome. Parotid sialogram
demonstrating atrophy and punctate sialectasia (“fruit-laden,
branchless tree”). (Courtesy of Dr. George Blozis.)
Fig. 11-27 Sjögren syndrome. Labial gland biopsy showing
multiple lymphocytic foci. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

470 ORAL AND MAXILLOFACIAL PATHOLOGY
suggestive pattern; in contrast, the ﬁnding of scattered
inﬂammation with ductal dilatation and ﬁbrosis
(chronic sclerosing sialadenitis) does not support the
diagnosis of Sjögren syndrome.
Although labial salivary gland biopsy has become a
widely used test in the diagnosis of Sjögren syndrome,
it is not 100% reliable. Some patients diagnosed with
Sjögren syndrome will show no signiﬁcant labial gland
inﬂammation; conversely, examination of labial glands
removed incidentally from non-Sjögren patients some-
times will show focal lymphocytic inﬁltrates. Sjögren
syndrome patients who smoke have been shown to
have a signiﬁcantly lower frequency of abnormal lym-
phocytic foci scores in their labial gland specimens. It
also is important that a pathologist experienced in the
analysis of these specimens examines the labial gland
biopsies. One study showed that slightly more than half
of labial gland specimens required a revised diagnosis
after being reviewed by a second pathologist.
Other authors have advocated incisional biopsy
of the parotid gland through a posterior auricular
approach instead of a labial salivary gland biopsy. One
study has shown this technique to be more sensitive in
demonstrating inﬂammatory changes that support the
diagnosis of Sjögren syndrome; however, other authors
think that this technique confers no increased beneﬁt
over labial gland biopsy. Parotid biopsy may enable the
clinician to evaluate an enlarged gland for the develop-
ment of lymphoma and rule out the possibility of sial-
adenosis or sarcoidosis.
TREATMENT AND PROGNOSIS
The treatment of the patient with Sjögren syndrome is
mostly supportive. The dry eyes are best managed by
periodic use of artiﬁcial tears. In addition, attempts can
be made to conserve the tear ﬁlm through the use of
sealed glasses to prevent evaporation. Sealing the lac-
rimal punctum at the inner margin of the eyelids also
can be helpful by blocking the normal drainage of any
lacrimal secretions into the nose.
Artiﬁcial salivas are available for the treatment of
xerostomia; sugarless candy or gum can help to keep
the mouth moist. Symptoms often can be relieved by
the use of oral hygiene products that contain lactoper-
oxidase, lysozyme, and lactoferrin (e.g., Biotene tooth-
paste and mouth rinse, Oralbalance gel). Sialagogue
medications, such as pilocarpine and cevimeline, can
be useful to stimulate salivary ﬂow if enough functional
salivary tissue still remains. Medications known to
diminish secretions should be avoided, if at all possible.
Because of the increased risk of dental caries, daily
ﬂuoride applications may be indicated in dentulous
patients. Antifungal therapy often is needed to treat
secondary candidiasis.
Patients with Sjögren syndrome have an increased
risk for lymphoma, up to 40 times higher than the
normal population. These tumors may arise initially
within the salivary glands or within lymph nodes. With
the advent of modern molecular pathology techniques
to detect B-cell monoclonality (e.g., in situ hybridiza-
tion, polymerase chain reaction [PCR]), many salivary
gland inﬁltrates formerly thought to represent benign
lymphoepithelial lesions are now being diagnosed as
lymphomas. These tumors are predominantly low-
grade non-Hodgkin’s B-cell lymphomas of the mucosa-
associated lymphoid tissue (i.e., MALT lymphomas),
although occasionally, high-grade MALT lymphomas
can develop that demonstrate more aggressive behav-
ior. The detection of immunoglobulin gene rearrange-
ments in labial salivary gland biopsies may prove to be
a useful marker for predicting the development of
lymphoma.
SIALADENOSIS (SIALOSIS)
Sialadenosis is an unusual noninﬂammatory disorder
characterized by salivary gland enlargement, particu-
larly involving the parotid glands. The condition fre-
quently is associated with an underlying systemic
problem, which may be endocrine, nutritional, or neu-
rogenic in origin (Box 11-3). The best known of these
conditions include diabetes mellitus, general malnutri-
tion, alcoholism, and bulimia.
These conditions are believed to result in dysregula-
tion of the autonomic innervation of the salivary acini,
causing an aberrant intracellular secretory cycle. This
Box 11-3
Conditions Associated
with Sialadenosis
ENDOCRINE DISORDERS
● Diabetes mellitus
● Diabetes insipidus
● Acromegaly
● Hypothyroidism
● Pregnancy
NUTRITIONAL CONDITIONS
● General malnutrition
● Alcoholism
● Anorexia nervosa
● Bulimia
NEUROGENIC MEDICATIONS
● Antihypertensive drugs
● Psychotropic drugs
●Sympathomimetic drugs used for treating asthma `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 471
leads to excessive accumulation of secretory granules,
with marked enlargement of the acinar cells.
CLINICAL AND RADIOGRAPHIC
FEATURES
Sialadenosis usually appears as a slowly evolving swell-
ing of the parotid glands, which may or may not be
painful (Fig. 11-28). The condition is usually bilateral,
but it also can be unilateral. In some patients, the sub-
mandibular glands may be affected, but involvement
of minor salivary glands is distinctly rare. Decreased
salivary secretion may occur. Sialography demon-
strates a “leaﬂess tree” pattern, which is thought to be
caused by compression of the ﬁner ducts by hypertro-
phic acinar cells.
HISTOPATHOLOGIC FEATURES
Microscopic examination reveals hypertrophy of the
acinar cells, sometimes two to three times greater than
normal size. The nuclei are displaced to the cell base,
and the cytoplasm is engorged with zymogen granules.
In cases associated with long-standing diabetes or alco-
holism, there may be acinar atrophy and fatty inﬁltra-
tion. Signiﬁcant inﬂammation is not observed.
TREATMENT AND PROGNOSIS
The clinical management of sialadenosis is often unsat-
isfactory because it is closely related to the control of the
underlying cause. Mild examples may cause few pro-
blems. If the swelling becomes a cosmetic concern, then
partial parotidectomy can be performed. Pilocarpine
recently has been reported to be beneﬁcial in reducing
salivary gland enlargement in bulimic patients.
ADENOMATOID HYPERPLASIA OF
THE MINOR SALIVARY GLANDS
CLINICAL FEATURES
Adenomatoid hyperplasia is a rare lesion of the
minor salivary glands characterized by localized swell-
ing that mimics a neoplasm. This pseudotumor most
often occurs on the hard or soft palate, although it also
has been reported in other oral minor salivary gland
sites. The pathogenesis of adenomatoid hyperplasia is
uncertain, but it has been speculated that local trauma
may play a role. It is most common in the fourth to sixth
decades of life. Most examples present as sessile, pain-
less masses that may be soft or ﬁrm to palpation. They
usually are normal in color, although a few lesions are
red or bluish.
HISTOPATHOLOGIC FEATURES
Microscopic examination demonstrates lobular aggre-
gates of relatively normal-appearing mucous acini that
are greater in number than normally would be found
in the area. These glands also sometimes appear to be
increased in size. In some instances, the glands are situ-
ated close to the mucosal surface. Chronic inﬂamma-
tion occasionally is seen, but it usually is mild and
localized.
TREATMENT AND PROGNOSIS
Because the clinical presentation of adenomatoid
hyperplasia mimics a tumor, biopsy is necessary to
establish the diagnosis. Once the diagnosis has been
established, no further treatment is indicated and the
lesion should not recur.
NECROTIZING SIALOMETAPLASIA
Necrotizing sialometaplasia is an uncommon, locally
destructive inﬂammatory condition of the salivary
glands. Although the cause is uncertain, most authors
believe it is the result of ischemia of the salivary tissue
that leads to local infarction. The importance of this
lesion rests in the fact that it mimics a malignant
process, both clinically and microscopically.
Fig. 11-28 Sialadenosis. Enlargement of the parotid and
submandibular glands secondary to alcoholism. (Courtesy of
Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

472 ORAL AND MAXILLOFACIAL PATHOLOGY
A number of potential predisposing factors have
been suggested, including the following:
● Traumatic injuries
● Dental injections
● Ill-ﬁtting dentures
●Upper respiratory infections
● Adjacent tumors
● Previous surgery
Researchers have suggested that these factors may play
a role in compromising the blood supply to the involved
glands, resulting in ischemic necrosis. However, many
cases occur without any known predisposing factors.
CLINICAL FEATURES
Necrotizing sialometaplasia most frequently develops
in the palatal salivary glands; more than 75% of all
cases occur on the posterior palate. The hard palate is
affected more often than the soft palate. About two
thirds of palatal cases are unilateral, with the rest being
bilateral or midline in location. Necrotizing sialometa-
plasia also has been reported in other minor salivary
gland sites and, occasionally, in the parotid gland. The
submandibular and sublingual glands are rarely
affected. Although it can occur at almost any age, nec-
rotizing sialometaplasia is most common in adults;
the mean age of onset is 46 years. Males are affected
nearly twice as often as females.
The condition appears initially as a nonulcerated
swelling, often associated with pain or paresthesia
(Fig. 11-29). Within 2 to 3 weeks, necrotic tissue
sloughs out, leaving a craterlike ulcer that can range
from less than 1 cm to more than 5 cm in diameter
(Fig. 11-30). The patient may report that “a part of my
palate fell out.” At this point, the pain often subsides.
In rare instances, there can be destruction of the under-
lying palatal bone.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of necrotizing sialometa-
plasia is characterized by acinar necrosis in early
lesions, followed by associated squamous metaplasia of
the salivary ducts (Fig. 11-31). Although the mucous
acinar cells are necrotic, the overall lobular architec-
ture of the involved glands is still preserved—a helpful
histopathologic clue. There may be liberation of mucin,
with an associated inﬂammatory response. The squa-
mous metaplasia of the salivary ducts can be striking
and produce a pattern that is easily misdiagnosed as
squamous cell carcinoma or mucoepidermoid carci-
noma. The frequent association of pseudoepithelioma-
tous hyperplasia of the overlying epithelium may
further compound this mistaken impression. In most
cases, however, the squamous proliferation has a bland
cytologic appearance.
Fig. 11-29 Necrotizing sialometaplasia. Early lesion
demonstrating swelling of the posterior lateral hard palate.
(From Allen CM, Camisa C: Diseases of the mouth and lips. In Sams WM,
Lynch P, editors: Principles of dermatology, New York, 1990, Churchill
Livingstone.)
Fig. 11-30 Necrotizing sialometaplasia. Later-stage lesion
showing craterlike defect of the posterior palate.
Fig. 11-31 Necrotizing sialometaplasia. Necrotic mucous
acini (left) and adjacent ductal squamous metaplasia (right). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 473
TREATMENT AND PROGNOSIS
Because of the worrisome clinical presentation of nec-
rotizing sialometaplasia, biopsy usually is indicated to
rule out the possibility of malignant disease. Once the
diagnosis has been established, no speciﬁc treatment is
indicated or necessary. The lesion typically resolves on
its own accord, with an average healing time of 5 to 6
weeks.
Salivary Gland Tumors
GENERAL CONSIDERATIONS
Tumors of the salivary glands constitute an important
area in the ﬁeld of oral and maxillofacial pathology.
Although such tumors are uncommon, they are by no
means rare. The annual incidence of salivary gland
tumors around the world ranges from about 1.0 to 6.5
cases per 100,000 people. Although soft tissue neo-
plasms (e.g., hemangioma), lymphoma, and metastatic
tumors can occur within the salivary glands, the discus-
sion in this chapter is limited to primary epithelial
neoplasms.
An often-bewildering array of different salivary
tumors has been identiﬁed and categorized. In addi-
tion, the classiﬁcation scheme is a dynamic one that
changes as clinicians learn more about these lesions.
Box 11-4 includes most of the currently recognized
tumors. Some of the tumors on this list are not speciﬁ-
cally discussed because their rarity places them outside
the scope of this text.
A number of investigators have published their ﬁnd-
ings on salivary gland neoplasia, but a comparison of
these studies is often difﬁcult. Some studies have been
limited to only the major glands or have not included
all the minor salivary gland sites. In addition, the ever-
evolving classiﬁcation system makes an evaluation of
some older studies difﬁcult, especially when research-
ers attempt to compare them with more recent
analyses. (For example, the polymorphous low-grade
adenocarcinoma was ﬁrst identiﬁed in 1983, but clini-
cians now recognize that it is one of the more common
malignancies in the minor glands.) Notwithstanding
these difﬁculties, it is still helpful to compare these
studies because they provide a good overview of sali-
vary neoplasia in general. An evaluation of various
studies shows fairly consistent trends (with minor vari-
ations) with regard to salivary gland tumors.
Tables 11-3 and 11-4 summarize four large series
of primary epithelial salivary gland tumors, analyzed
by sites of occurrence and frequency of malignancy,
respectively. Some variations between studies may rep-
resent differences in diagnostic criteria, geographic dif-
ferences, or referral bias in the cases seen. (Some
centers may tend to see more malignant tumors on
referral from other sources.)
The most common site for salivary gland tumors is
the parotid gland, accounting for 64% to 80% of all
cases. Fortunately, a relatively low percentage of paro-
tid tumors are malignant, ranging from 15% to 32%.
Overall, it can be stated that two thirds to three quar-
ters of all salivary tumors occur in the parotid gland,
and two thirds to three quarters of these parotid tumors
are benign.
Table 11-5 summarizes ﬁve large, well-known series
of parotid neoplasms. The pleomorphic adenoma is
Box 11-4
Classiﬁcation of Salivary Gland Tumors
BENIGN
●Pleomorphic adenoma (mixed tumor)
● Myoepithelioma
●Basal cell adenoma
● Canalicular adenoma
●Warthin tumor (papillary cystadenoma
lymphomatosum)
● Oncocytoma
● Sebaceous adenoma
● Sebaceous lymphadenoma
● Ductal papillomas
● Sialadenoma papilliferum
● Intraductal papilloma
●Inverted ductal papilloma
● Papillary cystadenoma
● Sialoblastoma
MALIGNANT
●Malignant mixed tumors
●Carcinoma ex pleomorphic adenoma
● Carcinosarcoma
●Metastasizing mixed tumor
● Mucoepidermoid carcinoma
●Acinic cell adenocarcinoma
●Adenoid cystic carcinoma
●Polymorphous low-grade adenocarcinoma
●Basal cell adenocarcinoma
● Epithelial-myoepithelial carcinoma
●Salivary duct carcinoma
● Myoepithelial carcinoma
● Cystadenocarcinoma
● Sebaceous adenocarcinoma
● Sebaceous lymphadenocarcinoma
●Clear cell adenocarcinoma
● Oncocytic carcinoma
●Squamous cell carcinoma
●Malignant lymphoepithelial lesion (lymphoepithelial
carcinoma)
●Small cell carcinoma
●Adenocarcinoma, not otherwise speciﬁed (NOS) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

474 ORAL AND MAXILLOFACIAL PATHOLOGY
Table 11-3 Sites of Occurrence of Primary Epithelial Salivary Gland Tumors
SITE OF OCCURRENCE
Author (Year) Number of Cases Parotid Submandibular Sublingual Minor
Eveson and Cawson (1985) 2,410 73% 11% 0.3% 14%
Seifert et al. (1986) 2,579 80% 10% 1.0% 9%
Spiro (1986) 2,807 70% 8% (Included with
minor gland
tumors)
22%
Ellis et al. (1991) 13,749 64% 10% 0.3% 23%
Table 11-4 Frequency of Malignancy for Salivary Tumors at Different Sites
PERCENTAGE OF CASES THAT ARE MALIGNANT
Author (Year) Number of Cases Parotid Submandibular Sublingual Minor
Eveson and Cawson (1985) 2,410 15% 37% 86% 46%
Seifert et al. (1986) 2,579 20% 45% 90% 45%
Spiro (1986) 2,807 25% 43% (Included with
minor gland
tumors)
82%
Ellis et al. (1991) 13,749 32% 41% 70% 49%
Table 11-5 Parotid Tumors
Ellis et al.
(United
States, 1991)
Eveson & Cawson
(Great Britain,
1985)
Thackray &
Lucas (Great
Britain, 1974)
Eneroth
(Sweden,
1971)
Foote & Frazell
(United States,
1953)
Total number of cases 8222 1756 651 2158 764
BENIGN TUMORS
Pleomorphic adenoma 53.0% 63.3% 72.0% 76.8% 58.5%
Warthin tumor 7.7% 14.0% 9.0% 4.7% 6.5%
Oncocytoma 1.9% 0.9% 0.6% 1.0% 0.1%
Basal cell adenoma 1.4% — — — —
Other benign tumors 3.7% 7.1%* 1.8% — 0.7%
TOTAL 67.7% 85.3% 83.4% 82.5% 65.8%
MALIGNANT TUMORS
Mucoepidermoid carcinoma 9.6% 1.5% 2.3% 4.1% 11.8%
Acinic cell adenocarcinoma 8.6% 2.5% 1.2% 3.1% 2.7%
Adenoid cystic carcinoma 2.0% 2.0% 3.3% 2.3% 2.1%
Malignant mixed tumor 2.5% 3.2% 4.1% 1.5% 6.0%
Squamous cell carcinoma 2.1% 1.1% 1.0% 0.3% 3.4%
Other malignant tumors 7.5% 4.4% 4.7% 6.3% 8.1%
TOTAL 32.3% 14.7% 16.6% 17.5% 34.2%
*Includes all “other monomorphic adenomas.” `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 475
overwhelmingly the most common tumor (53% to 77%
of all cases in the parotid gland). Warthin tumors are
also fairly common; they account for 6% to 14% of cases.
A variety of malignant tumors occur, with the mucoepi-
dermoid carcinoma appearing to be the most frequent
overall. However, two studies from Great Britain show
a signiﬁcantly lower prevalence of this tumor, possibly
indicative of a geographic difference, especially com-
pared with reports of cases from the United States.
From 8% to 11% of all salivary tumors occur in the
submandibular gland, but the frequency of malignancy
in this gland is almost double that of the parotid gland,
ranging from 37% to 45%. However, as shown in Table
11-6, the pleomorphic adenoma is still the most
common tumor and makes up 44% to 68% of all neo-
plasms. Unlike its occurrence in the parotid gland, the
Warthin tumor is unusual in the submandibular gland,
making up no more than 1% to 2% of all tumors. Adenoid
cystic carcinoma is the most common malignancy,
ranging from 12% to 27% of all cases.
Tumors of the sublingual gland are rare, comprising
no more than 1% of all salivary neoplasms. However,
70% to 90% of sublingual tumors are malignant.
Tumors of the various smaller minor salivary glands
make up 9% to 23% of all tumors, which makes this
group the second most common site for salivary neo-
plasia. Table 11-7 summarizes the ﬁndings of ﬁve large
surveys of minor gland tumors. Unfortunately, a rela-
tively high proportion (almost 50%) of these have been
malignant in most studies. Excluding rare sublingual
tumors, it can be stated that the smaller the gland is,
the greater is the likelihood of malignancy for a salivary
gland tumor.
As observed in the major glands, the pleomorphic
adenoma is the most common minor gland tumor and
accounts for about 40% of all cases. Mucoepidermoid
carcinoma and adenoid cystic carcinoma generally
have been considered the two most common malig-
nancies, although polymorphous low-grade adenocar-
cinoma also is becoming recognized as one of the more
common minor gland tumors.
The palate is the most frequent site for minor sali-
vary gland tumors, with 42% to 54% of all cases found
there (Table 11-8). Most of these occur on the posterior
lateral hard or soft palate, which have the greatest con-
centration of glands. Table 11-9 shows the relative
prevalence of various tumors on the palate. The lips are
the second most common location for minor gland
tumors (21% to 25% of cases), followed by the buccal
mucosa (11% to 15% of cases). Labial tumors are signiﬁ-
cantly more common in the upper lip, which accounts
for 77% to 89% of all lip tumors (Table 11-10). Although
mucoceles are commonly found on the lower lip, this
is a surprisingly rare site for salivary gland tumors.
Signiﬁcant differences in the percentage of malig-
nancies and the relative frequency of various tumors
Table 11-6 Submandibular Tumors
Ellis et al.
(United
States, 1991)
Eveson & Cawson
(Great Britain,
1985)
Thackray &
Lucas (Great
Britain, 1974)
Eneroth
(Sweden,
1971)
Foote &
Frazell (United
States, 1953)
Total number of cases 1235 257 60 170 107
BENIGN TUMORS
Pleomorphic adenoma 53.3% 59.5% 68.0% 60.0% 43.9%
Warthin tumor 1.3% 0.8% 1.7% 2.4% 0.0%
Oncocytoma 1.5% 0.4% 0.0% 0.6% 0.0%
Basal cell adenoma 1.0% — — — —
Other benign tumors 1.7% 1.9%* 0.0% — 0.0%
TOTAL 58.8% 62.6% 69.7% 62.9% 43.9%
MALIGNANT TUMORS
Mucoepidermoid carcinoma 9.1% 1.6% 0.0% 3.5% 7.5%
Acinic cell adenocarcinoma 2.7% 0.4% 0.0% 0.6% 0.0%
Adenoid cystic carcinoma 11.7% 16.8% 17.0% 15.3% 15.9%
Malignant mixed tumor 3.5% 7.8% 1.7% 1.8% 10.3%
Squamous cell carcinoma 3.4% 1.9% 3.3% 7.1% 12.1%
Other malignant tumors 10.8% 8.9% 8.3% 8.8% 10.3%
TOTAL 41.2% 37.4% 30.3% 37.1% 56.1%
*Includes all “other monomorphic adenomas.” `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

476 ORAL AND MAXILLOFACIAL PATHOLOGY
Table 11-7 Minor Salivary Gland Tumors
Pires et al.
(2006)
Yih et al.
(2005)
Ellis et al.
(1991)
Waldron et al.
(1988)
Eveson &
Cawson (1985)
Total number of cases 546 213 3355 426 336
BENIGN TUMORS
Pleomorphic adenoma 33.2% 43.7% 38.1% 40.8% 42.6%
“Monomorphic” adenoma
(canalicular and basal cell
adenoma)
9.2% 11.7% 4.5% 10.8% 11.0%
Other benign tumors 13.5% 0.5% 8.8% 5.9% —
TOTAL 55.9% 55.9% 51.3% 57.5% 53.6%
MALIGNANT TUMORS
Mucoepidermoid carcinoma 22.9% 21.1% 21.5% 15.3% 8.9%
Acinic cell adenocarcinoma 3.8% 0.5% 3.5% 3.5% 1.8%
Adenoid cystic carcinoma 6.4% 10.3% 7.7% 9.4% 13.1%
Malignant mixed tumor 0.4% 0.9% 1.7% 1.4% 7.1%
Polymorphous low-grade
adenocarcinoma
5.1% 8.4% 2.2% 11.0% —
Other malignant tumors 5.5% 2.8% 12.1% 1.9% 15.2%
TOTAL 44.1% 44.1% 48.7% 42.5% 46.4%
Table 11-8 Location of Minor Salivary Gland Tumors
Author (Year)
Number of
Cases PalateLipsBuccalRetromolar
Floor of
Mouth TongueOther
Eveson and Cawson (1985) 336 54% 21% 11% 1% — 4% 8%
Waldron et al. (1988) 426 42% 22% 15% 5% 5% 1% 9%
Ellis et al. (1991) 3355 44% 21% 12% 2% 3% 5% 12%
Yih et al. (2005) 213 48% 25% 14% 4% 1% — 8%
Table 11-9 Palatal Salivary Gland Tumors
Pires et al.
(2006)
Yih et al.
(2005)
Ellis et al.
(1991)
Waldron et al.
(1988)
Eveson &
Cawson (1985)
Total number of cases 181 102 1478 181 183
BENIGN TUMORS
Pleomorphic adenoma 39.8% 49.0% 48.2% 51.9% 47.0%
Other benign tumors 13.2% 6.9% 5.0% 6.0% 6.0%
TOTAL 53.0% 55.9% 53.2% 58.0% 53.0%
MALIGNANT TUMORS
Mucoepidermoid carcinoma 23.8% 19.6% 20.7% 9.9% 9.3%
Acinic cell adenocarcinoma 2.2% 1.0% 1.4% 1.7% 1.1%
Adenoid cystic carcinoma 7.7% 12.7% 8.3% 10.5% 15.3%
Malignant mixed tumor 0.0% 0.0% 2.4% 2.2% 8.2%
Polymorphous low-grade
adenocarcinoma
6.1% 7.8% 3.0% 16.0% —
Other malignant tumors 7.2% 2.9% 11.0% 1.7% 13.1%
TOTAL 47.0% 44.1% 46.8% 42.0% 47.0% `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 477
can be noted for different minor salivary gland sites. As
shown in Table 11-11, 38% to 50% of tumors of the
palate and buccal mucosa sites are malignant, similar
to the overall prevalence of malignancy in all minor
salivary gland sites combined. In the upper lip, however,
only 5% to 25% of tumors are malignant because of the
high prevalence of the canalicular adenoma, which has
a special afﬁnity for this location. In contrast, although
lower lip tumors are uncommon, 50% to 90% are malig-
nant (mostly mucoepidermoid carcinomas). Up to 91%
of retromolar tumors are malignant, also because of a
predominance of mucoepidermoid carcinomas. Unfor-
tunately, most tumors in the ﬂoor of the mouth and
tongue are also malignant.
PLEOMORPHIC ADENOMA (BENIGN
MIXED TUMOR)
The pleomorphic adenoma, or benign mixed tumor,
is easily the most common salivary neoplasm. It
accounts for 53% to 77% of parotid tumors, 44% to 68%
of submandibular tumors, and 33% to 43% of minor
gland tumors.
Pleomorphic adenomas are derived from a mixture
of ductal and myoepithelial elements. A remarkable
microscopic diversity can exist from one tumor to the
next, as well as in different areas of the same tumor.
The terms pleomorphic adenoma and mixed tumor both
represent attempts to describe this tumor’s unusual
histopathologic features, but neither term is entirely
accurate. Although the basic tumor pattern is highly
variable, rarely are the individual cells actually pleo-
morphic. (However, focal minor atypia is acceptable.)
Likewise, although the tumor often has a prominent
mesenchyme-appearing “stromal” component, it is not
truly a mixed neoplasm that is derived from more than
one germ layer.
CLINICAL AND RADIOGRAPHIC
FEATURES
Regardless of the site of origin, the pleomorphic
adenoma typically appears as a painless, slowly growing,
ﬁrm mass (Figs. 11-32 to 11-34). The patient may be
aware of the lesion for many months or years before
seeking a diagnosis. The tumor can occur at any age
but is most common in young and middle-aged adults
between the ages of 30 and 60. Pleomorphic adenoma
is also the most common primary salivary gland tumor
to develop during childhood. There is a slight female
predilection.
Table 11-10 Location of Labial Salivary Gland Tumors
Author (Year) Number of Cases Upper Lip Lower Lip
Eveson and Cawson (1985) 71 89% 11%
Waldron et al. (1988) 93 85% 15%
Neville et al. (1988) 103 84% 16%
Ellis et al. (1991) 536 77% 23%
Yih et al. (2005) 53 81% 19%
Table 11-11 Intraoral Minor Salivary Gland Tumors: Percentage Malignant by Site
Author (Year) PalateUpper LipLower LipBuccalRetromolarFloor of MouthTongue
Eveson and Cawson (1985)47% 25% 50% 50% 60% — 92%
Waldron et al. (1988) 42% 14% 86% 46% 91% 80% 75%
Ellis et al. (1991) 47% 22% 60% 50% 90% 88% 86%
Yih et al. (2005) 44% 5% 90% 38% 75% 100% —
Fig. 11-32 Pleomorphic adenoma. Small, ﬁrm nodule
located below the left ear in the parotid gland. (Courtesy of Dr.
Mike Hansen.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

478 ORAL AND MAXILLOFACIAL PATHOLOGY
Most pleomorphic adenomas of the parotid gland
occur in the superﬁcial lobe and present as a swelling
overlying the mandibular ramus in front of the ear.
Facial nerve palsy and pain are rare. Initially, the tumor
is movable but becomes less mobile as it grows larger.
If neglected, then the lesion can grow to grotesque
proportions. About 10% of parotid mixed tumors
develop within the deep lobe of the gland beneath the
facial nerve (Fig. 11-35). Sometimes these lesions grow
in a medial direction between the ascending ramus
and stylomandibular ligament, resulting in a dumbbell-
shaped tumor that appears as a mass of the lateral
pharyngeal wall or soft palate. On rare occasions, bilat-
eral pleomorphic adenomas of the parotid glands have
been reported, developing in either a synchronous or
metachronous fashion.
The palate is the most common site for minor gland
mixed tumors, accounting for approximately 50% of
intraoral examples. This is followed by the upper lip
(27%) and buccal mucosa (17%). Palatal tumors almost
always are found on the posterior lateral aspect of the
palate, presenting as smooth-surfaced, dome-shaped
masses (Figs. 11-36 and 11-37). If the tumor is trauma-
tized, then secondary ulceration may occur. Because of
the tightly bound nature of the hard palate mucosa,
tumors in this location are not movable, although those
in the lip or buccal mucosa frequently are mobile.
HISTOPATHOLOGIC FEATURES
The pleomorphic adenoma is typically a well-
circumscribed, encapsulated tumor (Fig. 11-38).
However, the capsule may be incomplete or show
inﬁltration by tumor cells. This lack of complete encap-
sulation is more common for minor gland tumors,
Fig. 11-33 Pleomorphic adenoma. Slowly growing tumor
of the parotid gland.
Fig. 11-34 Pleomorphic adenoma. Tumor of the
submandibular gland. (Courtesy of Dr. Román Carlos.)
Fig. 11-35 Pleomorphic adenoma. T1-weighted, fat-
suppressed, contrast-enhanced coronal magnetic resonance
image (MRI) of a tumor of the deep lobe of the parotid gland.
(Courtesy of Dr. Joel Curé.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 479
especially along the superﬁcial aspect of palatal tumors
beneath the epithelial surface.
The tumor is composed of a mixture of glan-
dular epithelium and myoepithelial cells within a mes-
enchyme-like background. The ratio of the epithelial
elements and the mesenchyme-like component is
highly variable among different tumors. Some tumors
may consist almost entirely of background “stroma.”
Others are highly cellular with little background
alteration.
The epithelium often forms ducts and cystic struc-
tures or may occur as islands or sheets of cells. Keratin-
izing squamous cells and mucus-producing cells also
can be seen. Myoepithelial cells often make up a large
percentage of the tumor cells and have a variable mor-
phology, sometimes appearing angular or spindled.
Some myoepithelial cells are rounded and demon-
strate an eccentric nucleus and eosinophilic hyalinized
cytoplasm, thus resembling plasma cells (Fig. 11-39).
These characteristic plasmacytoid myoepithelial cells
are more prominent in tumors arising in the minor
glands.
The highly characteristic “stromal” changes are
believed to be produced by the myoepithelial cells.
Extensive accumulation of mucoid material may occur
between the tumor cells, resulting in a myxomatous
background (Fig. 11-40). Vacuolar degeneration of
cells in these areas can produce a chondroid appear-
ance (Fig. 11-41). In many tumors, the stroma exhibits
areas of an eosinophilic, hyalinized change (Fig.
11-42). At times, fat or osteoid also is seen.
Occasionally, salivary tumors are seen that are com-
posed almost entirely of myoepithelial cells with no
ductal elements. Such tumors often are called myoepi-
theliomas, although they probably represent one end
of the spectrum of mixed tumors.
Fig. 11-36 Pleomorphic adenoma. Firm mass of the hard
palate lateral to the midline.
Fig. 11-37 Pleomorphic adenoma. Tumor of the
pterygomandibular area.
Fig. 11-38 Pleomorphic adenoma. Low-power view
showing a well-circumscribed, encapsulated tumor mass.
Even at this power, the variable microscopic pattern of the
tumor is evident.
Fig. 11-39 Pleomorphic adenoma. Plasmacytoid
myoepithelial cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

480 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
Pleomorphic adenomas are best treated by surgical
excision. For lesions in the superﬁcial lobe of the
parotid gland, superﬁcial parotidectomy with identiﬁ-
cation and preservation of the facial nerve is recom-
mended. Local enucleation should be avoided because
the entire tumor may not be removed or the capsule
may be violated, resulting in seeding of the tumor bed.
For tumors of the deep lobe of the parotid, total paroti-
dectomy is usually necessary, also with preservation of
the facial nerve, if possible. Submandibular tumors are
best treated by total removal of the gland with the
tumor. Tumors of the hard palate usually are excised
down to periosteum, including the overlying mucosa.
In other oral sites the lesion often enucleates easily
through the incision site.
With adequate surgery the prognosis is excellent,
with a cure rate of more than 95%. The risk of recur-
rence appears to be lower for tumors of the minor
glands. Conservative enucleation of parotid tumors
often results in recurrence, with management of these
cases made difﬁcult as a result of multifocal seeding of
the primary tumor bed. In such cases, multiple recur-
rences are not unusual. Tumors with a predominantly
myxoid appearance are more susceptible to recur than
those with other microscopic patterns.
Malignant degeneration is a potential complication,
resulting in a carcinoma ex pleomorphic adenoma (see
page 492). The risk of malignant transformation is
probably small, but it may occur in as many as 5% of
all cases.
ONCOCYTOMA (OXYPHILIC
ADENOMA)
The oncocytoma is a benign salivary gland tumor
composed of large epithelial cells known as oncocytes.
The preﬁx onco- is derived from the Greek word onk-
oustai, which means to swell. The swollen granular cyto-
plasm of oncocytes is due to excessive accumulation of
mitochondria. Focal oncocytic metaplasia of salivary
ductal and acinar cells is a common ﬁnding that is
related to patient age; oncocytes are uncommon in
persons younger than 50, but they can be found in
almost all individuals by age 70. In addition to salivary
glands, oncocytes have been identiﬁed in a number of
other organs, especially the thyroid, parathyroid, and
kidney. The oncocytoma is a rare neoplasm, represent-
ing approximately 1% of all salivary tumors.
CLINICAL FEATURES
The oncocytoma is predominantly a tumor of older
adults, with a peak prevalence in the eighth decade of
life. A slight female predilection has been observed but
Fig. 11-40 Pleomorphic adenoma. Ductal structures (left)
with associated myxomatous background (right).
Fig. 11-41 Pleomorphic adenoma. Chondroid material
(right) with adjacent ductal epithelium and myoepithelial
cells.
Fig. 11-42 Pleomorphic adenoma. Many of the ducts and
myoepithelial cells are surrounded by a hyalinized,
eosinophilic background alteration. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 481
may not be signiﬁcant. Oncocytomas occur primarily
in the major salivary glands, especially the parotid
gland, which accounts for about 85% to 90% of all cases.
Oncocytomas of the minor salivary glands are exceed-
ingly rare.
The tumor appears as a ﬁrm, slowly growing, pain-
less mass that rarely exceeds 4 cm in diameter. Parotid
oncocytomas usually are found in the superﬁcial lobe
and are clinically indistinguishable from other benign
tumors. On occasion, bilateral tumors can occur,
although these may represent examples of multinodu-
lar oncocytic hyperplasia (oncocytosis).
HISTOPATHOLOGIC FEATURES
The oncocytoma is usually a well-circumscribed tumor
that is composed of sheets of large polyhedral cells
(oncocytes), with abundant granular, eosinophilic cyto-
plasm (Fig. 11-43). Sometimes these cells form an
alveolar or glandular pattern. The cells have centrally
located nuclei that can vary from small and hyperchro-
matic to large and vesicular. Little stroma is present,
usually in the form of thin ﬁbrovascular septa. An asso-
ciated lymphocytic inﬁltrate may be noted.
The granularity of the cells corresponds to an over-
abundance of mitochondria, which can be demon-
strated by electron microscopy. These granules also
can be identiﬁed on light microscopic examination
with a phosphotungstic acid hematoxylin (PTAH) stain.
The cells also contain glycogen, as evidenced by their
positive staining with the periodic acid-Schiff (PAS)
technique but by negative PAS staining after digestion
with diastase.
Oncocytomas may contain variable numbers of cells
with a clear cytoplasm. In rare instances, these clear
cells may compose most of the lesion and create difﬁ-
culty in distinguishing the tumor from low-grade sali-
vary clear cell adenocarcinoma or metastatic renal cell
carcinoma.
TREATMENT AND PROGNOSIS
Oncocytomas are best treated by surgical excision. In
the parotid gland, this usually entails partial parotidec-
tomy (lobectomy) to avoid violation of the tumor
capsule. The facial nerve should be preserved when-
ever possible. For tumors in the submandibular gland,
treatment consists of total removal of the gland. Onco-
cytomas of the oral minor salivary glands should be
removed with a small margin of normal surrounding
tissue.
The prognosis after removal is good, with a low rate
of recurrence. However, oncocytomas of the sinonasal
glands can be locally aggressive and have been consid-
ered to be low-grade malignancies. Rare examples of
histopathologically malignant oncocytomas (oncocytic
carcinoma) also have been reported. These carcino-
mas have a relatively poor prognosis.
ONCOCYTOSIS (NODULAR
ONCOCYTIC HYPERPLASIA)
Oncocytic metaplasia is the transformation of ductal
and acinar cells to oncocytes. Such cells are uncom-
mon before the age of 50; however, as people get older,
occasional oncocytes are common ﬁndings in the sali-
vary glands. Focal oncocytic metaplasia also may be a
feature of other salivary gland tumors. Oncocytosis
refers to both the proliferation and the accumulation
of oncocytes within salivary gland tissue. It may mimic
a tumor, both clinically and microscopically, but it also
is considered to be a metaplastic process rather than a
neoplastic one.
CLINICAL FEATURES
Oncocytosis is found primarily in the parotid gland;
however, in rare instances, it may involve the subman-
dibular or minor salivary glands. It can be an incidental
ﬁnding in otherwise normal salivary gland tissue, but
it may be extensive enough to produce clinical swell-
ing. Usually the proliferation is multifocal and nodular,
but sometimes the entire gland can be replaced by
oncocytes (diffuse hyperplastic oncocytosis). As
with other oncocytic proliferations, oncocytosis occurs
most frequently in older adults.
HISTOPATHOLOGIC FEATURES
Microscopic examination usually reveals focal nodular
collections of oncocytes within the salivary gland tissue.
These enlarged cells are polyhedral and demonstrate
Fig. 11-43 Oncocytoma. Sheet of large, eosinophilic
oncocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

482 ORAL AND MAXILLOFACIAL PATHOLOGY
abundant granular, eosinophilic cytoplasm as a result
of the proliferation of mitochondria. On occasion, these
cells may have a clear cytoplasm from the accumula-
tion of glycogen (Fig. 11-44). The multifocal nature of
the proliferation may be confused with that of a meta-
static tumor, especially when the oncocytes are clear
in appearance.
TREATMENT AND PROGNOSIS
Oncocytosis is a benign condition and often is discov-
ered only as an incidental ﬁnding. No further treat-
ment is necessary, and the prognosis is excellent.
WARTHIN TUMOR (PAPILLARY
CYSTADENOMA LYMPHOMATOSUM)
Warthin tumor is a benign neoplasm that occurs
almost exclusively in the parotid gland. Although it is
much less common than the pleomorphic adenoma, it
represents the second most common benign parotid
tumor, accounting for 5% to 14% of all parotid neo-
plasms. The name adenolymphoma also has been
used for this tumor, but this term should be avoided
because it overemphasizes the lymphoid component
and may give the mistaken impression that the lesion
is a type of lymphoma. Analyses of the epithelial and
lymphoid components of the Warthin tumor have
shown both to be polyclonal; this suggests that this
lesion may not represent a true neoplasm but would be
better classiﬁed as a tumorlike process.
The pathogenesis of these tumors is uncertain. The
traditional hypothesis suggests that they arise from
heterotopic salivary gland tissue found within parotid
lymph nodes. However, researchers have also sug-
gested that these tumors may develop from a prolifera-
tion of salivary gland ductal epithelium that is associated
with secondary formation of lymphoid tissue. This
latter theory is supported by studies that have found
cytogenetic abnormalities in the epithelial component.
A number of studies have demonstrated a strong asso-
ciation between the development of this tumor and
smoking. Smokers have an eightfold greater risk for
Warthin tumor than do nonsmokers.
CLINICAL FEATURES
The Warthin tumor usually appears as a slowly growing,
painless, nodular mass of the parotid gland (Fig.
11-45). It may be ﬁrm or ﬂuctuant to palpation. The
tumor most frequently occurs in the tail of the parotid
near the angle of the mandible, and it may be noted for
many months before the patient seeks a diagnosis. One
unique feature is the tendency of Warthin tumor to
occur bilaterally, which has been noted in 5% to 17%
of reported cases. Most of these bilateral tumors do not
occur simultaneously but are metachronous (occurring
at different times).
In rare instances, the Warthin tumor has been
reported within the submandibular gland or minor
salivary glands. However, because the lymphoid com-
ponent is often less pronounced in these extraparotid
sites, the pathologist should exercise caution to avoid
Fig. 11-44 Oncocytosis. Multifocal collections of clear
oncocytes (arrows) in the parotid gland.
Fig. 11-45 Warthin tumor. Mass in the tail of the parotid
gland. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 483
overdiagnosis of a lesion better classiﬁed as a papillary
cystadenoma or a salivary duct cyst with oncocytic
ductal metaplasia.
Warthin tumor most often occurs in older adults,
with a peak prevalence in the sixth and seventh decades
of life. The observed frequency of this tumor is much
lower in blacks than in whites. Most studies show a
decided male predilection, with some early studies
demonstrating a male-to-female ratio up to 10:1.
However, more recent investigations show a more bal-
anced sex ratio. Because Warthin tumors have been
associated with cigarette smoking, this changing sex
ratio may be a reﬂection of the increased prevalence
of smoking in women over the past few decades. This
association with smoking also may help explain the
frequent bilaterality of the tumor, because any tumori-
genic effects of smoking might be manifested in both
parotids.
HISTOPATHOLOGIC FEATURES
The Warthin tumor has one of the most distinctive
histopathologic patterns of any tumor in the body.
Although the term papillary cystadenoma lympho-
matosum is cumbersome, it accurately describes the
salient microscopic features.
The tumor is composed of a mixture of ductal
epithelium and a lymphoid stroma (Figs. 11-46 and
11-47). The epithelium is oncocytic in nature, forming
uniform rows of cells surrounding cystic spaces. The
cells have abundant, ﬁnely granular eosinophilic cyto-
plasm and are arranged in two layers. The inner luminal
layer consists of tall columnar cells with centrally
placed, palisaded, and slightly hyperchromatic nuclei.
Beneath this is a second layer of cuboidal or polygonal
cells with more vesicular nuclei. The lining epithelium
demonstrates multiple papillary infoldings that pro-
trude into the cystic spaces. Focal areas of squamous
metaplasia or mucous cell prosoplasia may be seen.
The epithelium is supported by a lymphoid stroma that
frequently shows germinal center formation.
TREATMENT AND PROGNOSIS
Surgical removal is the treatment of choice for patients
with Warthin tumor. The procedure usually is easily
accomplished because of the superﬁcial location of the
tumor. Some surgeons prefer local resection with
minimal surrounding tissue; others opt for superﬁcial
parotidectomy to avoid violating the tumor capsule and
because a tentative diagnosis may not be known pre-
operatively. A 6% to 12% recurrence rate has been
reported. Many authors, however, believe that the
tumor is frequently multicentric in nature; therefore, it
is difﬁcult to determine whether these are true recur-
rences or secondary tumor sites. Malignant Warthin
tumors (carcinoma ex papillary cystadenoma lym-
phomatosum) have been reported but are exceedingly
rare.
MONOMORPHIC ADENOMA
The term monomorphic adenoma originally was
used to describe a group of benign salivary gland
tumors demonstrating a more uniform histopathologic
pattern than the common pleomorphic adenoma. In
some classiﬁcation schemes, a variety of tumors were
included under the broad heading of monomorphic
adenoma, including Warthin tumor, oncocytoma, basal
cell adenoma, and canalicular adenoma. Other authors
have used this term more speciﬁcally as a synonym just
for the basal cell adenoma or canalicular adenoma.
Because of its ambiguous nature, the term monomorphic
adenoma probably should be avoided, and each of the
Fig. 11-46 Warthin tumor. Low-power view showing a
papillary cystic tumor with a lymphoid stroma.
Fig. 11-47 Warthin tumor. High-power view of epithelial
lining showing double row of oncocytes with adjacent
lymphoid stroma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

484 ORAL AND MAXILLOFACIAL PATHOLOGY
tumors mentioned should be referred to by its more
speciﬁc name.
CANALICULAR ADENOMA
The canalicular adenoma is an uncommon tumor
that occurs almost exclusively in the minor salivary
glands. Because of its uniform microscopic pattern, the
canalicular adenoma also has been called a mono-
morphic adenoma. However, because this term also has
been applied to other tumors, its use probably should
be discontinued. Likewise, the term basal cell
adenoma sometimes has been used synonymously for
this tumor but should be avoided because it refers to a
separate tumor with different clinical features (see next
topic).
CLINICAL FEATURES
The canalicular adenoma shows a striking predilection
for the upper lip, with nearly 75% occurring in this
location. It represents the ﬁrst or second most common
tumor (along with pleomorphic adenoma) of the upper
lip. The buccal mucosa is the second most common
site. Occurrence in other minor salivary glands is
uncommon, and canalicular adenomas of the parotid
gland are rare.
The tumor nearly always occurs in older adults, with
a peak prevalence in the seventh decade of life. There
is a deﬁnite female predominance, ranging from 1.2 to
1.8 females for each male.
The canalicular adenoma appears as a slowly
growing, painless mass that usually ranges from several
millimeters to 2 cm (Fig. 11-48). It may be ﬁrm or
somewhat ﬂuctuant to palpation. The overlying mucosa
may be normal in color or bluish and can be mistaken
for a mucocele. However, mucoceles of the upper lip
are rare. In some instances, the lesion has been noted
to be multifocal, with multiple separate tumors discov-
ered in the upper lip or buccal mucosa.
HISTOPATHOLOGIC FEATURES
The microscopic pattern of canalicular adenoma is
monomorphic in nature. This pattern is characterized
by single-layered cords of columnar or cuboidal epithe-
lial cells with deeply basophilic nuclei (Fig. 11-49). In
some areas, adjacent parallel rows of cells may be seen,
resulting in a bilayered appearance of the tumor cords.
These cells enclose ductal structures, sometimes in the
form of long canals. Larger cystic spaces often are
created, and the epithelium may demonstrate papillary
projections into the cystic lumina. The tumor cells are
supported by a loose connective tissue stroma with
prominent vascularity. Unlike the appearance in pleo-
morphic adenomas, stromal alterations, such as chon-
droid metaplasia, do not occur. A thin, ﬁbrous capsule
often surrounds the tumor, although satellite islands
are observed in the surrounding salivary gland tissue
in approximately 22% to 24% of cases, which explains
the tendency for multifocal tumors.
TREATMENT AND PROGNOSIS
The canalicular adenoma is best treated by local surgi-
cal excision. Recurrence is uncommon and actually
may represent cases that are multifocal in nature.
BASAL CELL ADENOMA
The basal cell adenoma is a benign salivary tumor
that derives its name from the basaloid appearance of
the tumor cells. It is an uncommon neoplasm that rep-
resents only 1% to 2% of all salivary tumors. Because of
its uniform histopathologic appearance, it often has
been classiﬁed as one of the monomorphic adenomas.
However, as mentioned previously, this term probably
Fig. 11-48 Canalicular adenoma. Mass in the upper lip.
(Courtesy of Dr. John Fantasia.)
Fig. 11-49 Canalicular adenoma. Uniform columnar cells
forming canal-like ductal structures. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 485
should be avoided because of its imprecise and fre-
quently confusing deﬁnition. In addition, ultrastruc-
tural and immunohistochemical studies have shown
that basal cell adenomas are not necessarily composed
of only one cell type but sometimes of a combination
of salivary ductal epithelium and myoepithelial cells.
The basal cell adenoma shows some histopathologic
similarity to the canalicular adenoma; in the past, these
two terms have been used synonymously. However,
histopathologic and clinical differences warrant that
they be considered as distinct entities.
CLINICAL FEATURES
Unlike the canalicular adenoma, the basal cell adenoma
is primarily a tumor of the parotid gland, with around
75% of all cases occurring there. However, the minor
glands represent the second most common site, speciﬁ-
cally the glands of the upper lip and buccal mucosa.
The tumor can occur at any age but is most common
in middle-aged and older adults, with a peak preva-
lence in the seventh decade of life. The tumor appears
to be more common in women, with some studies
showing as high as a 2:1 female-to-male ratio.
Clinically, the basal cell adenoma appears as a
slowly growing, freely movable mass similar to a pleo-
morphic adenoma. Most tumors are less than 3 cm in
diameter. Parotid tumors usually are located within the
superﬁcial lobe of the gland.
One subtype, the membranous basal cell adenoma,
deserves separate mention. This form of the tumor
appears to be hereditary, often occurring in combina-
tion with skin appendage tumors, such as dermal cyl-
indromas and trichoepitheliomas. Multiple bilateral
tumors may develop within the parotids. Because these
tumors often bear a histopathologic resemblance to the
skin tumors, they also have been called dermal ana-
logue tumors.
HISTOPATHOLOGIC FEATURES
The basal cell adenoma is usually encapsulated or well
circumscribed. The most common subtype is the solid
variant, which consists of multiple islands and cords of
epithelial cells that are supported by a small amount of
ﬁbrous stroma. The peripheral cells of these islands are
palisaded and cuboidal to columnar in shape, similar
to the microscopic appearance of basal cell carcinoma.
These peripheral cells are frequently hyperchromatic;
the central cells of the islands tend to have paler stain-
ing nuclei. The central cells occasionally form eddies
or keratin pearls.
The trabecular subtype demonstrates narrow cord-
like epithelial strands (Fig. 11-50). The tubular subtype
is characterized by the formation of small, round, duct-
like structures. Frequently, a mixture of histopathologic
subtypes is seen.
The membranous basal cell adenoma exhibits mul-
tiple large lobular islands of tumor that are molded
together in a jigsaw puzzle fashion. These islands are
surrounded by a thick layer of hyaline material, which
represents reduplicated basement membrane. Similar
hyaline droplets also are often found among the epi-
thelial cells. The microscopic appearance is similar to
that of a dermal cylindroma, one of the skin tumors
with which it is often associated.
TREATMENT AND PROGNOSIS
The treatment of basal cell adenoma is similar to that
of pleomorphic adenoma and consists of complete sur-
gical removal. Recurrence is rare for most histopatho-
logic subtypes. However, the membranous subtype has
a 25% to 37% recurrence rate, possibly related to its
multifocal nature.
The malignant counterpart of the basal cell adenoma
is the basal cell adenocarcinoma. Most basal cell
adenocarcinomas arise de novo, but some examples
develop from malignant degeneration of a preexisting
basal cell adenoma. Fortunately, these tumors have a
relatively good prognosis; although local recurrence is
common, the tumor rarely metastasizes or results in
death.
DUCTAL PAPILLOMAS (SIALADENOMA
PAPILLIFERUM; INTRADUCTAL
PAPILLOMA; INVERTED
DUCTAL PAPILLOMA)
A number of salivary gland tumors can be character-
ized microscopically by a papillomatous pattern, the
most common being Warthin tumor (papillary cystad-
Fig. 11-50 Basal cell adenoma. Parotid tumor showing
cords of basaloid cells arranged in a trabecular pattern. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

486 ORAL AND MAXILLOFACIAL PATHOLOGY
enoma lymphomatosum). The sialadenoma papil-
liferum, intraductal papilloma, and inverted ductal
papilloma are three rare salivary tumors that also
show unique papillomatous features.
It also should be mentioned that, on occasion, the
common squamous papilloma (see page 362) of the
oral mucosa will arise at the site where a minor salivary
gland duct merges with the surface epithelium. Because
of this location, such squamous papillomas also contain
scattered mucous cells within the exophytic papillary
growth, and these lesions have sometimes been called
ductal papillomas. However, it should be emphasized
that these lesions are viral (human papillomavirus
[HPV]) surface papillomas and not primary salivary
gland tumors.
CLINICAL FEATURES
The sialadenoma papilliferum most commonly arises
from the minor salivary glands, especially on the
palate, although it also has been reported in the parotid
gland. It usually is seen in older adults and has a
1.5:1.0 male-to-female ratio. The tumor appears as an
exophytic, papillary surface growth that is clinically
similar to the common squamous papilloma (Fig.
11-51).
The intraductal papilloma is an ill-deﬁned lesion
that often has been confused with other salivary gland
lesions, such as the papillary cystadenoma. It usually
occurs in adults and is most common in the minor
salivary glands, where it appears as a submucosal
swelling.
The inverted ductal papilloma is a rare tumor that
has been described only in the minor salivary glands
of adults. The lower lip and mandibular vestibule are
the most common locations. The lesion usually ap-
pears as an asymptomatic nodule, which sometimes
may show a pit or indentation in the overlying surface
mucosa (Fig. 11-52).
HISTOPATHOLOGIC FEATURES
At low-power magniﬁcation, the sialadenoma papilli-
ferum is somewhat similar to the squamous papilloma,
exhibiting multiple exophytic papillary projections that
are covered by stratiﬁed squamous epithelium. This
epithelium is contiguous with a proliferation of papil-
lomatous ductal epithelium found below the surface
and extending downward into the deeper connective
tissues (Fig. 11-53). Multiple ductal lumina are formed,
which characteristically are lined by a double-rowed
layer of cells consisting of a luminal layer of tall colum-
nar cells and a basilar layer of smaller cuboidal cells.
These ductal cells often have an oncocytic appearance.
An inﬂammatory inﬁltrate of plasma cells, lympho-
cytes, and neutrophils is characteristically present.
Because of their microscopic similarity, this tumor has
been considered to be an analogue of the cutaneous
syringocystadenoma papilliferum.
The intraductal papilloma exhibits a dilated, unicys-
tic structure that is located below the mucosal surface.
It is lined by a single or double row of cuboidal or
columnar epithelium, which has multiple arborizing
papillary projections into the cystic lumen. In contrast,
the inverted ductal papilloma is composed primarily of
a proliferation of squamoid epithelium with multiple
thick, bulbous papillary projections that ﬁll the ductal
lumen (Fig. 11-54). This epithelium may be contiguous
with the overlying mucosal epithelium, communicat-
ing with the surface through a small porelike opening.
Although the tumor is primarily squamous in nature,
the luminal lining cells of the papillary projections are
often cuboidal or columnar in shape, with scattered
mucus-producing cells.
Fig. 11-51 Sialadenoma papilliferum. Exophytic papillary
mass on the palate. (Courtesy of Dr. Peter Lyu.)
Fig. 11-52 Inverted ductal papilloma. Exophytic mass
with central papillary projections on the lower labial mucosa.
(Courtesy of Dr. Amy Bogardus.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 487
TREATMENT AND PROGNOSIS
All three forms of ductal papilloma are best treated by
conservative surgical excision. Recurrence is rare.
MUCOEPIDERMOID CARCINOMA
The mucoepidermoid carcinoma is one of the most
common salivary gland malignancies. Because of its
highly variable biologic potential, it was originally
called mucoepidermoid tumor. The term recognized
one subset that acted in a malignant fashion and a
second group that appeared to behave in a benign
fashion with favorable prognosis. However, research-
ers later recognized that even low-grade tumors occa-
sionally could exhibit malignant behavior; therefore,
the term mucoepidermoid carcinoma is the preferred
designation.
CLINICAL FEATURES
Most studies show that the mucoepidermoid carci-
noma is the most common malignant salivary gland
neoplasm. In the United States, it makes up 10% of all
major gland tumors and 15% to 23% of minor gland
tumors. However, British studies have shown a much
lower relative frequency, with mucoepidermoid carci-
noma accounting for only 1% to 2% of major gland
neoplasms and 9% of minor gland tumors. Perhaps a
true geographic difference exists in the prevalence of
this lesion.
The tumor occurs fairly evenly over a wide age
range, extending from the second to seventh decades
of life. Rarely is it seen in the ﬁrst decade of life.
However, mucoepidermoid carcinoma is the most
common malignant salivary gland tumor in children.
Some tumors have been associated with a previous
history of radiation therapy to the head and neck
region.
The mucoepidermoid carcinoma is most common
in the parotid gland and usually appears as an asymp-
tomatic swelling. Most patients are aware of the lesion
for 1 year or less, although some report a mass of many
years’ duration. Pain or facial nerve palsy may develop,
usually in association with high-grade tumors. The
minor glands constitute the second most common site,
especially the palate (Fig. 11-55). Minor gland tumors
also typically appear as asymptomatic swellings, which
are sometimes ﬂuctuant and have a blue or red color
that can be mistaken clinically for a mucocele. Although
the lower lip, ﬂoor of mouth, tongue, and retromolar
pad areas are uncommon locations for salivary gland
neoplasia, the mucoepidermoid carcinoma is the most
common salivary tumor in each of these sites (Fig.
11-56). Intraosseous tumors also may develop in the
jaws (see page 490).
A
B
Fig. 11-53 Sialadenoma papilliferum. A, Low-power view
showing a papillary surface tumor with associated ductal
structures in the superﬁcial lamina propria. B, High-power
view of cystic areas lined by papillary, oncocytic epithelium.
Fig. 11-54 Inverted ductal papilla. Papillary intraductal
proliferation located beneath the mucosal surface. Higher-
power view shows both squamous cells and mucous cells
(inset). (Courtesy of Dr. Dean K. White.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

488 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
As its name implies, the mucoepidermoid carcinoma is
composed of a mixture of mucus-producing cells and
squamous (epidermoid) cells (Figs. 11-57 to 11-59).
The mucous cells vary in shape but contain abundant
foamy cytoplasm that stains positively with mucin
stains. The epidermoid cells are characterized by
squamoid features, often demonstrating a polygonal
shape, intercellular bridges, and, rarely, keratinization.
In addition, a third type of cell—the intermediate cell—
is typically present and is believed to be a progenitor
of both the mucous and the epidermoid cells. Interme-
diate cells vary in appearance from small, basaloid
(“maternal”) cells to slightly larger ovoid cells with
scant, pale eosinophilic cytoplasm. Some tumors also
show variable numbers of clear cells, which sometimes
can predominate the microscopic picture (Fig. 11-60).
An associated lymphoid inﬁltrate is not unusual and
Fig. 11-55 Mucoepidermoid carcinoma. Blue-pigmented
mass of the posterior lateral hard palate. (Courtesy of Dr. James F.
Drummond.)
Fig. 11-56 Mucoepidermoid carcinoma. Mass of the
tongue.
Fig. 11-57 Mucoepidermoid carcinoma. Low-power view
of a moderately well-differentiated tumor showing ductal and
cystic spaces surrounded by mucous and squamous cells.
Fig. 11-58 Mucoepidermoid carcinoma. This low-grade
tumor shows numerous large mucous cells surrounding a
cystic space.
Fig. 11-59 Mucoepidermoid carcinoma. High-power
view showing a sheet of squamous cells with focal
mucus-producing cells (left). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 489
may be so prominent in some cases that the lesion can
be mistaken for a metastatic tumor within a lymph
node.
Traditionally, mucoepidermoid carcinomas have
been categorized into one of three histopathologic
grades based on the following:
1. Amount of cyst formation
2. Degree of cytologic atypia
3. Relative numbers of mucous, epidermoid, and
intermediate cells
Low-grade tumors show prominent cyst formation,
minimal cellular atypia, and a relatively high propor-
tion of mucous cells. High-grade tumors consist of
solid islands of squamous and intermediate cells, which
can demonstrate considerable pleomorphism and
mitotic activity (Fig. 11-61). Mucus-producing cells
may be infrequent, and the tumor sometimes can be
difﬁcult to distinguish from squamous cell carcinoma.
Intermediate-grade tumors show features that fall
between those of the low-grade and high-grade neo-
plasms. Cyst formation occurs but is less prominent
than that observed in low-grade tumors. All three major
cell types are present, but the intermediate cells usually
predominate. Cellular atypia may or may not be
observed.
However, some authors have found that the relative
proportion of the three different cell types does not
necessarily correlate with prognosis. To overcome this,
two expert groups have proposed evaluation schemes
based on signiﬁcant microscopic parameters, to which
relative point values have been assigned to determine
the grade of the tumor (Table 11-12).
Fig. 11-60 Mucoepidermoid carcinoma. Clear cell
mucoepidermoid carcinoma.
Fig. 11-61 Mucoepidermoid carcinoma. High-power view
showing a sheet of pleomorphic squamous epithelial cells
intermixed with mucous and intermediate cells.
Table 11-12 Mucoepidermoid Carcinoma: Com-
parison of Two Grading Systems
Parameter Point Value
AUCLAIR ET AL. (1992)
Intracystic component < 20% 2
Neural invasion present 2
Necrosis present 3
Four or more mitoses per 10 high-power
ﬁelds
3
Anaplasia present 4
Grade Total Point Score
Low 0-4
Intermediate 5-6
High 7-14
BRANDWEIN ET AL. (2001)
Intracystic component <25% 2
Tumor front invades in small nests and
islands
2
Pronounced nuclear atypia 2
Lymphatic or vascular invasion 3
Bony invasion 3
Greater than four mitoses per 10 high-
power ﬁelds
3
Perineural spread 3
Necrosis 3
Grade Total Point Score
I 0
II 2-3
III 4 or more
From Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of
intraoral salivary glands: evaluation and application of grading criteria in
143 cases, Cancer 69:2021-2030, 1992; Brandwein MS, Ivanov K,
Wallace DI et al: Mucoepidermoid carcinoma: a clinicopathologic study
of 80 patients with special reference to histological grading, Am J Surg
Pathol 25:835-845, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

490 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The treatment of mucoepidermoid carcinoma is predi-
cated by the location, histopathologic grade, and clini-
cal stage of the tumor. Early-stage tumors of the parotid
often can be treated by subtotal parotidectomy with
preservation of the facial nerve. Advanced tumors may
necessitate total removal of the parotid gland, with sac-
riﬁce of the facial nerve. Submandibular gland tumors
are treated by total removal of the gland. Mucoepider-
moid carcinomas of the minor glands usually are
treated by assured surgical excision. For low-grade
neoplasms, only a modest margin of surrounding
normal tissue may need to be removed, but high-grade
or large tumors warrant wider resection, similar to that
required for squamous cell carcinomas. If there is
underlying bone destruction, then the involved bone
must be excised.
Radical neck dissection is indicated for patients with
clinical evidence of metastatic disease and also may be
considered for patients with larger or high-grade
tumors. Postoperative radiation therapy also may be
used for more aggressive tumors.
The prognosis depends on the grade and stage of the
tumor. Patients with low-grade tumors generally have
a good prognosis. For most primary sites, local recur-
rences or regional metastases are uncommon, and
around 90% to 98% of patients are cured. The prognosis
for those with intermediate-grade tumors is slightly
worse than that for low-grade tumors. The outlook for
patients with high-grade tumors is guarded, with only
30% to 54% of patients surviving.
For unknown reasons, submandibular gland tumors
are associated with a poorer outlook than those in the
parotid gland. Mucoepidermoid carcinomas of the oral
minor salivary glands generally have a good prognosis,
probably because they are mostly low- to intermediate-
grade tumors. However, tumors of the tongue and ﬂoor
of the mouth are less predictable and may exhibit more
aggressive behavior.
INTRAOSSEOUS MUCOEPIDERMOID
CARCINOMA (CENTRAL
MUCOEPIDERMOID CARCINOMA)
On rare occasions, salivary gland tumors arise centrally
within the jaws. The most common and best- recognized
intrabony salivary tumor is the intraosseous muco-
epidermoid carcinoma. However, other salivary
tumors have been reported to develop within the jaws,
including adenoid cystic carcinoma, benign and malig-
nant mixed tumors, adenocarcinoma, acinic cell ade-
nocarcinoma, epithelial-myoepithelial carcinoma, and
monomorphic adenoma.
Several hypotheses have been proposed to explain
the pathogenesis of intraosseous salivary tumors. One
theory suggests that they may arise from ectopic sali-
vary gland tissue that was developmentally entrapped
within the jaws. However, the discovery of ectopic sali-
vary tissue is uncommon in biopsy specimens from the
jaws; therefore, this seems an unlikely source for most
intrabony salivary tumors. Some maxillary tumors may
arise from glands of the sinus lining, but this is often
difﬁcult to prove or disprove. The most likely source
for most intraosseous tumors is odontogenic epithe-
lium. Mucus-producing cells are common in odonto-
genic cyst linings, especially dentigerous cysts (see
page 679). In addition, many intraosseous muco-
epidermoid carcinomas develop in association with
impacted teeth or odontogenic cysts.
CLINICAL AND RADIOGRAPHIC
FEATURES
Intraosseous mucoepidermoid carcinomas are most
common in middle-aged adults and demonstrate a
slight female predilection. They are three times more
common in the mandible than in the maxilla and are
most often seen in the molar-ramus area. The most
frequent presenting symptom is cortical swelling,
although some lesions may be discovered as incidental
ﬁndings on radiographs. Pain, trismus, and paresthesia
are reported less frequently.
Radiographs usually reveal either a unilocular or
multilocular radiolucency with well-deﬁned borders
(Fig. 11-62). However, some examples are character-
ized by a more irregular and ill-deﬁned area of
bone destruction. Some cases are associated with an
unerupted tooth and, therefore, clinically may suggest
an odontogenic cyst or tumor.
Fig. 11-62 Intraosseous mucoepidermoid carcinoma.
Multilocular lesion of the posterior mandible. (Courtesy of
Dr. Joseph F. Finelli.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 491
HISTOPATHOLOGIC FEATURES
The microscopic appearance of intraosseous mucoepi-
dermoid carcinoma is similar to that of its soft tissue
counterpart. Most tumors are low-grade lesions,
although high-grade mucoepidermoid carcinomas also
have been reported within the jaws.
TREATMENT AND PROGNOSIS
The primary treatment modality for patients with
intraosseous mucoepidermoid carcinoma is surgery;
adjunctive radiation therapy also sometimes is used.
Radical surgical resection offers a better chance for
cure than do more conservative procedures, such as
enucleation or curettage. The local recurrence rate
with conservative treatment is 40%, in contrast to 13%
for more radical treatment. Metastasis has been
reported in about 12% of cases. The overall prognosis
is fairly good; around 10% of patients die, usually as a
result of local recurrence of the tumor.
ACINIC CELL ADENOCARCINOMA
The acinic cell adenocarcinoma is a salivary gland
malignancy with cells that show serous acinar differen-
tiation. Because many of these tumors act in a nonag-
gressive fashion and are associated with a good
prognosis, this neoplasm formerly was called acinic
cell tumor, a nonspeciﬁc designation that did not indi-
cate whether the lesion was benign or malignant.
However, because some of these tumors do metasta-
size or recur and cause death, it is generally agreed
today that acinic cell adenocarcinoma should be con-
sidered a low-grade malignancy.
CLINICAL FEATURES
Around 85% of all acinic cell adenocarcinomas occur
in the parotid gland, a logical ﬁnding because this is
the largest gland and one that is composed entirely of
serous elements (Fig. 11-63). Most surveys have shown
that this neoplasm makes up 1% to 3% of all parotid
tumors, although one study showed it represented 8.6%
of all parotid tumors (see Table 11-4). It is much less
common in the submandibular gland, which is the site
for only 2.7% to 4% of these tumors. About 9% of all
acinic cell adenocarcinomas develop in the oral minor
salivary glands, with the buccal mucosa, lips, and palate
being the most common sites (Fig. 11-64). Overall,
around 2% to 6.5% of all minor salivary gland tumors
are acinic cell adenocarcinomas.
The tumor occurs over a broad age range, with a
relatively even peak prevalence stretching from the
second to the seventh decades of life; the mean age is
in the middle 40s. Approximately 60% of cases occur
in women. The tumor usually appears as a slowly
growing mass, and the lesion often is present for many
months or years before a diagnosis is made. The tumor
may be otherwise asymptomatic, although associated
pain or tenderness sometimes is reported. Facial nerve
paralysis is an infrequent but ominous sign for parotid
tumors.
HISTOPATHOLOGIC FEATURES
Acinic cell adenocarcinomas are highly variable in
their microscopic appearance. The tumor often is
well circumscribed and sometimes may even appear
Fig. 11-63 Acinic cell adenocarcinoma. Large, ﬁrm mass
of the right parotid gland. (Courtesy of Dr. Guillermo Chacon.)
Fig. 11-64 Acinic cell adenocarcinoma. Bluish swelling of
the anterior buccal mucosa, which could be mistaken for a
mucocele. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

492 ORAL AND MAXILLOFACIAL PATHOLOGY
encapsulated; however, some tumors exhibit an inﬁl-
trative growth pattern. The most characteristic cell is
one with features of the serous acinar cell, with abun-
dant granular basophilic cytoplasm and a round, darkly
stained eccentric nucleus. These cells are fairly uniform
in appearance, and mitotic activity is uncommon.
Other cells may resemble intercalated duct cells, and
some tumors also have cells with a clear, vacuolated
cytoplasm.
Several growth patterns may be seen. The solid
variety consists of numerous well-differentiated acinar
cells arranged in a pattern that resembles normal
parotid gland tissue (Figs. 11-65 and 11-66). In the
microcystic variety, multiple small cystic spaces are
created that may contain some mucinous or eosino-
philic material. In the papillary-cystic variety, larger
cystic areas are formed that are lined by epithelium
having papillary projections into the cystic spaces
(Fig. 11-67). The follicular variety has an appearance
similar to that of thyroid tissue. A lymphoid inﬁltrate,
sometimes with germinal center formation, is not
unusual.
TREATMENT AND PROGNOSIS
Acinic cell adenocarcinomas conﬁned to the superﬁ-
cial lobe of the parotid gland are best treated by lobec-
tomy; for those in the deep lobe, total parotidectomy is
usually necessary. The facial nerve may need to be
sacriﬁced if it is involved by tumor. Submandibular
tumors are managed by total removal of the gland, and
minor gland tumors are treated with assured surgical
excision. Lymph node dissection is not indicated unless
there is clinical evidence of metastatic disease. Adjunc-
tive radiation therapy may be considered for uncon-
trolled local disease.
The acinic cell adenocarcinoma is associated with
one of the better prognoses of any of the malignant
salivary gland tumors. Approximately one third of
patients have recurrences locally, and metastases
develop in 10% to 15% of patients. From 6% to 26% of
patients die of their disease. The prognosis for minor
gland tumors is better than that for tumors arising in
the major glands.
MALIGNANT MIXED TUMORS
(CARCINOMA EX PLEOMORPHIC
ADENOMA; CARCINOMA EX MIXED
TUMOR; CARCINOSARCOMA;
METASTASIZING MIXED TUMOR)
Malignant mixed tumors represent malignant coun-
terparts to the benign mixed tumor or pleomorphic
adenoma. These uncommon neoplasms constitute 2%
to 6% of all salivary tumors and can be divided into
three categories:
Fig. 11-65 Acinic cell adenocarcinoma. Parotid tumor
demonstrating sheet of granular, basophilic serous acinar
cells.
Fig. 11-66 Acinic cell adenocarcinoma. High-power view
of serous cells with basophilic, granular cytoplasm.
Fig. 11-67 Acinic cell adenocarcinoma. Papillary-cystic
variant showing proliferation of tumor cells into a large cystic
space. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 493
1. Carcinoma ex pleomorphic adenoma (carcinoma
ex mixed tumor)
2. Carcinosarcoma
3. Metastasizing mixed tumor
The most common of these is the carcinoma ex
pleomorphic adenoma, which is characterized by
malignant transformation of the epithelial component
of a previously benign pleomorphic adenoma. The car-
cino sarcoma is a rare “mixed” tumor in which both
carcinomatous and sarcomatous elements are present.
The metastasizing mixed tumor has histopathologic
features that are identical to the common pleomorphic
adenoma (mixed tumor). In spite of its benign appear-
ance, however, the lesion metastasizes. The metastatic
tumor also has a benign microscopic appearance,
usually similar to that of the primary lesion.
CLINICAL FEATURES
CARCINOMA EX PLEOMORPHIC ADENOMA
There is fairly convincing evidence that the carcinoma
ex pleomorphic adenoma represents a malignant trans-
formation within what was previously a benign neo-
plasm. First of all, the mean age of patients with this
tumor is about 15 years older than that for the benign
pleomorphic adenoma. It is most common in middle-
aged and older adults, with a peak prevalence in the
sixth to eighth decades of life. In addition, patients may
report that a mass has been present for many years,
sometimes undergoing a recent rapid growth with
associated pain or ulceration. However, some tumors
may have a short duration. The histopathologic fea-
tures, which are discussed later, also support malignant
transformation of a benign pleomorphic adenoma. It
has been noted that the risk for malignant change in a
pleomorphic adenoma increases with the duration of
the tumor.
More than 80% of cases of carcinoma ex pleomor-
phic adenoma are seen within the major glands, pri-
marily the parotid gland (Fig. 11-68). Nearly two thirds
of minor salivary gland cases occur on the palate (Fig.
11-69). Although pain or recent rapid growth is not
unusual, many cases present as a painless mass that is
indistinguishable from a benign tumor. Parotid tumors
may produce facial nerve palsy.
CARCINOSARCOMA
The carcinosarcoma is an extremely rare tumor. Most
cases have been reported in the parotid gland, but the
lesion also has been seen in the submandibular gland
and minor salivary glands. The clinical signs and symp-
toms are similar to those of the carcinoma ex pleomor-
phic adenoma. Some patients have a previous history
of a benign pleomorphic adenoma, although other
cases appear to arise de novo.
METASTASIZING MIXED TUMOR
The metastasizing mixed tumor is also quite rare. As
with other malignant mixed tumors, most cases origi-
nate in the parotid gland, but the primary tumor also
may occur in the submandibular gland or minor sali-
vary glands. Metastases have been found most fre-
quently in the bones or lung, but they also can occur
in other sites, such as regional lymph nodes, skin, or
the liver. Most patients have a history of a benign mixed
Fig. 11-68 Carcinoma ex pleomorphic adenoma. Mass of
the parotid gland.
Fig. 11-69 Carcinoma ex pleomorphic adenoma.
Granular exophytic and ulcerated mass ﬁlling the vault of the
palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

494 ORAL AND MAXILLOFACIAL PATHOLOGY
tumor, which may have been excised many years
earlier. Many times the primary tumor exhibits multi-
ple recurrences before metastasis occurs.
HISTOPATHOLOGIC FEATURES
CARCINOMA EX PLEOMORPHIC ADENOMA
The carcinoma ex pleomorphic adenoma shows a vari-
able microscopic appearance. Areas of typical benign
pleomorphic adenoma usually can be found and may
constitute most or only a small portion of the lesion.
Within the tumor are areas of malignant degeneration
of the epithelial component, characterized by cellular
pleomorphism and abnormal mitotic activity (Fig.
11-70). This change is most often in the form of a
poorly differentiated adenocarcinoma, but other pat-
terns also can develop, including polymorphous low-
grade adenocarcinoma, salivary duct carcinoma,
mucoepidermoid carcinoma, and adenoid cystic carci-
noma. The malignant component often has an aggres-
sive growth pattern, with capsular invasion and
inﬁltration into surrounding tissues. However, in rare
instances it is discovered as a small focus within the
center of an encapsulated mixed tumor. Because such
tumors have a markedly better prognosis than invasive
tumors, they have been designated as noninvasive
carcinoma ex mixed tumor or carcinoma in situ ex
mixed tumor.
CARCINOSARCOMA
The carcinosarcoma is a biphasic tumor, demonstrat-
ing both carcinomatous and sarcomatous areas. The
epithelial component usually consists of a poorly dif-
ferentiated adenocarcinoma or an undifferentiated
carcinoma. The sarcomatous portion often predomi-
nates the tumor and is usually in the form of chon drosar-
coma but also may show characteristics of osteosar-
coma, ﬁbrosarcoma, liposarcoma, rhabdomyosarcoma,
or malignant ﬁbrous histiocytoma. Some lesions have
evidence of an origin from a benign mixed tumor.
METASTASIZING MIXED TUMOR
The metastasizing mixed tumor has microscopic fea-
tures of a benign pleomorphic adenoma, within both
the primary and the metastatic sites. Malignant histo-
pathologic changes are not observed.
TREATMENT AND PROGNOSIS
CARCINOMA EX PLEOMORPHIC ADENOMA
Invasive carcinoma ex pleomorphic adenoma usually
is best treated by wide excision, possibly in conjunction
with local lymph node dissection and adjunctive radia-
tion therapy. The prognosis is guarded; the overall
5-year survival rate ranges from 25% to 65%, but this
rate drops to 10% to 35% at 15 years. The prognosis is
related to the histopathologic subtype of the malignant
component. One study showed that well-differentiated
carcinomas, such as polymorphous low-grade adeno-
carcinoma, have nearly a 90% 5-year survival rate. In
contrast, the outlook is much worse for patients with
tumors that are poorly differentiated or that have
invaded more than 8 mm beyond the residual capsule
or benign residual tumor. However, for cases of in situ
(noninvasive) carcinoma ex mixed tumor, the progno-
sis is similar to that for benign mixed tumor.
CARCINOSARCOMA
Carcinosarcomas are treated by radical surgical exci-
sion, which may be combined with radiation therapy
BA
Fig. 11-70 Carcinoma ex pleomorphic adenoma. A, Medium-power view of the benign
portion of the tumor showing sheets of plasmacytoid myoepithelial cells within a myxoid
background. B, Malignant portion of the tumor showing epithelial cells with pleomorphic
nuclei. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 495
and chemotherapy. The prognosis is poor, with around
75% of patients either dying from their disease or
developing recurrent local tumor or metastases.
METASTASIZING MIXED TUMOR
The treatment for a metastasizing mixed tumor con-
sists of surgical excision of both the primary tumor and
the metastatic sites. A mortality rate of 22% has been
reported.
ADENOID CYSTIC CARCINOMA
The adenoid cystic carcinoma is one of the more
common and best-recognized salivary malignancies.
Because of its distinctive histopathologic features, it
was originally called a cylindroma, and this term still
is used sometimes as a synonym for this neoplasm.
However, use of the term cylindroma should be avoided
because it does not convey the malignant nature of the
tumor, and also because this same term is used for a
skin adnexal tumor that has a markedly different clini-
cal presentation and prognosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
The adenoid cystic carcinoma can occur in any salivary
gland site, but approximately 50% to 60% develop
within the minor salivary glands. The palate is the most
common site for minor gland tumors (Fig. 11-71). The
remaining tumors are found mostly in the parotid and
submandibular glands, with a fairly even distribution
between these two sites. On an individual basis,
however, a striking difference can be seen among the
various glands. In the parotid gland, the adenoid cystic
carcinoma is relatively rare, constituting only 2% to 3%
of all tumors. In the submandibular gland, this tumor
accounts for 12% to 17% of all tumors and is the most
common malignancy. It is also relatively common
among palatal salivary neoplasms; it represents 8% to
15% of all such tumors. The lesion is most common in
middle-aged adults and is rare in people younger than
age 20. There is a fairly equal sex distribution, although
some studies have shown a slight female predilection.
The adenoid cystic carcinoma usually appears as a
slowly growing mass. Pain is a common and important
ﬁnding, occasionally occurring early in the course of
the disease before there is a noticeable swelling.
Patients often complain of a constant, low-grade, dull
ache, which gradually increases in intensity. Facial
nerve paralysis may develop with parotid tumors.
Palatal tumors can be smooth surfaced or ulcerated.
Tumors arising in the palate or maxillary sinus often
show radiographic evidence of bone destruction
(Fig. 11-72).
HISTOPATHOLOGIC FEATURES
The adenoid cystic carcinoma is composed of a mixture
of myoepithelial cells and ductal cells that can have a
varied arrangement (Fig. 11-73). Three major patterns
Fig. 11-71 Adenoid cystic carcinoma. Painful mass of the
hard palate and maxillary alveolar ridge. (Courtesy of Dr. George
Blozis.)
Fig. 11-72 Adenoid cystic carcinoma. Computed
tomography (CT) scan of this massive palatal tumor shows
extensive destruction of the hard palate with extension of the
tumor into the nasal cavity and both maxillary sinuses.
(Courtesy of Dr. Kevin Riker.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

496 ORAL AND MAXILLOFACIAL PATHOLOGY
are recognized: (1) cribriform, (2) tubular, and (3) solid.
Usually a combination of these is seen, and the tumor
is classiﬁed based on the predominant pattern.
The cribriform pattern is the most classic and best-
recognized appearance, characterized by islands of
basaloid epithelial cells that contain multiple cylindri-
cal, cystlike spaces resembling Swiss cheese. These
spaces often contain a mildly basophilic mucoid mate-
rial, a hyalinized eosinophilic product, or a combined
mucoid-hyalinized appearance. Sometimes the hyalin-
ized material also surrounds these cribriform islands
(Fig. 11-74), or small strands of tumor are found
embedded within this hyalinized “stroma.” The tumor
cells are small and cuboidal, exhibiting deeply baso-
philic nuclei and little cytoplasm. These cells are fairly
uniform in appearance, and mitotic activity is rarely
seen. The pathologist should be mindful that other
salivary tumors, especially polymorphous low-grade
adenocarcinoma, also may exhibit areas with a cribri-
form pattern.
In the tubular pattern, the tumor cells are similar
but occur as multiple small ducts or tubules within a
hyalinized stroma. The tubular lumina can be lined by
one to several layers of cells, and sometimes both a
layer of ductal cells and myoepithelial cells can be
discerned.
The solid variant consists of larger islands or sheets
of tumor cells that demonstrate little tendency toward
duct or cyst formation. Unlike the cribriform and
tubular patterns, cellular pleomorphism and mitotic
activity, as well as focal necrosis in the center of the
tumor islands, may be observed.
A highly characteristic feature of adenoid cystic car-
cinoma is its tendency to show perineural invasion (Fig.
11-75), which probably corresponds to the common
clinical ﬁnding of pain in these patients. Sometimes the
cells appear to have a swirling arrangement around
nerve bundles. However, perineural invasion is not
pathognomonic for adenoid cystic carcinoma; it also
may be seen in other salivary malignancies, especially
polymorphous low-grade adenocarcinomas.
Positive immunostaining reactions for CD43 and
c-kit (CD117) in adenoid cystic carcinoma have been
reported to be useful diagnostic features that can help
to distinguish this tumor from polymorphous low-grade
adenocarcinoma, basal cell adenoma, and canalicular
adenoma. In addition, the patterns of expression of a
variety of other immunohistochemical markers have
been suggested to be diagnostically relevant, including
stains for vimentin, collagen IV, laminin, integrins,
Ki-67, smooth muscle actin, and various cytokeratins.
TREATMENT AND PROGNOSIS
Adenoid cystic carcinoma is a relentless tumor that is
prone to local recurrence and eventual distant meta s-
tasis. Surgical excision is usually the treatment of
Fig. 11-73 Adenoid cystic carcinoma. Islands of
hyperchromatic cells forming cribriform and tubular
structures. Inset shows a high-power view of a small
cribriform island.
Fig. 11-74 Adenoid cystic carcinoma. The tumor cells are
surrounded by hyalinized material.
Fig. 11-75 Adenoid cystic carcinoma. Perineural invasion. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 497
choice, and adjunct radiation therapy may slightly
improve patient survival in some cases. Because meta-
stasis to regional lymph nodes is uncommon, neck dis-
section typically is not indicated. Because of the poor
overall prognosis, regardless of treatment, clinicians
should be cautioned against needlessly aggressive and
mutilating surgical procedures for large tumors or
cases already showing metastases.
Because the tumor is prone to late recurrence and
metastasis, the 5-year survival rate has little signiﬁ-
cance and does not equate to a cure. The 5-year sur-
vival rate may be as high as 70%, but this rate continues
to decrease over time. The 10-year survival is approxi-
mately 50%, and by 20 years, only 25% of patients are
still alive. Tumors with a solid histopathologic pattern
are associated with a worse outlook than those with a
cribriform or tubular arrangement. With respect to
site, the prognosis is poorest for tumors arising in the
maxillary sinus and submandibular gland. Most studies
have shown that microscopic identiﬁcation of perineu-
ral invasion has little effect on the prognosis. Tumor
DNA ploidy analysis may help to predict the prognosis
of adenoid cystic carcinoma; patients with diploid
tumors have been shown to have a signiﬁcantly better
outcome than patients with aneuploid tumors.
Death usually results from local recurrence or
distant metastases. Tumors of the palate or maxillary
sinus eventually may invade upward to the base of
the brain. Metastases occur in approximately 35% of
patients, most frequently involving the lungs and
bones.
POLYMORPHOUS LOW-GRADE
ADENOCARCINOMA (LOBULAR
CARCINOMA; TERMINAL
DUCT CARCINOMA)
The polymorphous low-grade adenocarcinoma is a
more recently recognized type of salivary malignancy
that was ﬁrst described in 1983. Before its identiﬁca-
tion as a distinct entity, examples of this tumor were
categorized as pleomorphic adenoma, an unspeciﬁed
form of adenocarcinoma, or sometimes as adenoid
cystic carcinoma. Once recognized as a speciﬁc entity,
however, it was realized that this tumor possesses dis-
tinct clinicopathologic features and is one of the more
common minor salivary gland malignancies.
CLINICAL FEATURES
The polymorphous low-grade adenocarcinoma is
almost exclusively a tumor of the minor salivary glands.
However, rare examples also have been reported in the
major glands, either arising de novo or as the malignant
component of a carcinoma ex pleomorphic adenoma.
Sixty-ﬁve percent occur on the hard or soft palate (Fig.
11-76), with the upper lip and buccal mucosa being
the next most common locations. It is most common in
older adults, having a peak prevalence in the sixth to
eighth decades of life. Two thirds of all cases occur in
females.
The tumor most often appears as a painless mass
that may have been present for a long time with slow
growth. Occasionally, it is associated with bleeding or
discomfort. Tumor can erode or inﬁltrate the underly-
ing bone.
HISTOPATHOLOGIC FEATURES
The tumor cells of polymorphous low-grade adenocar-
cinomas have a deceptively uniform appearance. They
are round to polygonal in shape, with indistinct cell
borders and pale to eosinophilic cytoplasm. The nuclei
may be round, ovoid, or spindled; these nuclei usually
are pale staining, although they can be more basophilic
in some areas. The cells can exhibit different growth
patterns, hence, the polymorphous term. The cells may
grow in a solid pattern or form cords, ducts, or larger
cystic spaces. In some tumors, a cribriform pattern can
be produced that mimics adenoid cystic carcinoma
(Fig. 11-77). Mitotic ﬁgures are uncommon.
At low power, the tumor sometimes appears well
circumscribed. However, the peripheral cells are
usually inﬁltrative, invading the adjacent tissue in a
single-ﬁle fashion (Fig. 11-78). Extension into underly-
ing bone or skeletal muscle may be observed. The
stroma is often mucoid in nature, or it may demon-
strate hyalinization. Perineural invasion is common—
another feature that may cause the tumor to be
mistaken for adenoid cystic carcinoma (Fig. 11-79).
However, a distinction between these two tumors is
important because of their vastly different prognoses.
Fig. 11-76 Polymorphous low-grade adenocarcinoma.
Ulcerated mass of the posterior lateral hard palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

498 ORAL AND MAXILLOFACIAL PATHOLOGY
Immunohistochemical staining can be helpful in
distinguishing polymorphous low-grade adenocarci-
noma from other salivary gland tumors that it may
mimic. When compared with adenoid cystic carci-
noma, polymorphous low-grade adenocarcinoma
exhibits signiﬁcantly weaker expression of CD43 and
c-kit (CD117). Likewise, lack of staining for glial ﬁbril-
lary acidic protein (GFAP) can help to differentiate this
tumor from pleomorphic adenoma, which is almost
always strongly positive for GFAP.
TREATMENT AND PROGNOSIS
The polymorphous low-grade adenocarcinoma is best
treated by wide surgical excision, sometimes including
resection of the underlying bone. Metastasis to regional
lymph nodes is relatively uncommon, occurring in
just under 10% of patients. Therefore, neck dissection
seems unwarranted unless there is clinical evidence of
cervical metastases. Distant metastasis is rare.
The overall prognosis is relatively good. Recurrent
disease has been reported in 9% to 17% of all patients,
but this usually can be controlled with reexcision.
Death from tumor is rare but may occur secondary to
direct extension into vital structures. Microscopic iden-
tiﬁcation of perineural invasion does not appear to
affect the prognosis.
SALIVARY ADENOCARCINOMA, NOT
OTHERWISE SPECIFIED
In spite of the wide variety of salivary gland malignan-
cies that have been speciﬁcally identiﬁed and catego-
rized, some tumors still defy the existing classiﬁcation
schemes. These tumors usually are designated as
salivary adenocarcinomas, not otherwise speciﬁed
(NOS).
CLINICAL AND HISTOPATHOLOGIC
FEATURES
Because these adenocarcinomas represent such a
diverse group of neoplasms, it is difﬁcult to generalize
about their clinical and microscopic features. Like most
salivary tumors, they appear to be most common in the
parotid gland, followed by the minor glands and the
submandibular gland (Figs. 11-80 and 11-81). They
may present as asymptomatic masses or cause pain or
facial nerve paralysis. The microscopic appearance is
highly variable but demonstrates features of a glandu-
lar malignancy with evidence of cellular pleomor-
phism, an inﬁltrative growth pattern, or both. These
tumors exhibit a wide spectrum of differentiation,
ranging from well-differentiated, low-grade neoplasms
to poorly differentiated, high-grade malignancies.
Fig. 11-77 Polymorphous low-grade adenocarcinoma.
This medium-power view shows a cribriform arrangement of
uniform tumor cells with pale-staining nuclei.
Fig. 11-78 Polymorphous low-grade adenocarcinoma.
Pale-staining cells that inﬁltrate as single-ﬁle cords.
Fig. 11-79 Polymorphous low-grade adenocarcinoma.
Perineural invasion. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 499
As these tumors are studied more, it should be pos-
sible to classify some of them into separate, speciﬁc
categories and allow more deﬁnitive analyses of their
clinical and microscopic features.
TREATMENT AND PROGNOSIS
Because of their diversity, it is difﬁcult to predict the
prognosis for salivary adenocarcinoma (NOS), but
patients with early-stage, well-differentiated tumors
appear to have a better outcome. The survival rate is
better for tumors of the oral cavity than for those in the
major salivary glands. The reported 10-year survival
rate for parotid tumors ranges from 26% to 55%; in
contrast, one study reported a 10-year survival rate of
76% for intraoral tumors.
BIBLIOGRAPHY
Salivary Gland Aplasia
Antoniades DZ, Markopoulos AK, Deligianni E et al: Bilateral
aplasia of parotid glands correlated with accessory parotid
tissue, J Laryngol Otol 120:327-329, 2006.
Mandel L: An unusual pattern of dental damage with salivary
gland aplasia, J Am Dent Assoc 137:984-989, 2006.
Matsuda C, Matsui Y, Ohno K et al: Salivary gland aplasia with
cleft lip and palate. A case report and review of the literature,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:594-599,
1999.
Milunsky JM, Zhao G, Maher TA et al: LADD syndrome is caused
by FGF10 mutations, Clin Genet 69:349-354, 2006.
Ramirez D, Lammer EJ: Lacrimoauriculodentodigital syndrome
with cleft lip/palate and renal manifestations, Cleft Palate Cra-
niofac J 41:501-506, 2004.
Mucocele
Baurmash HD: Mucoceles and ranulas, J Oral Maxillofac Surg
61:369-378, 2003.
Campana F, Sibaud V, Chauvel A et al: Recurrent superﬁcial
mucoceles associated with lichenoid disorders, J Oral Maxil-
lofac Surg 64:1830-1833, 2006.
Cataldo E, Mosadomi A: Mucoceles of the oral mucous mem-
brane, Arch Otolaryngol 91:360-365, 1970.
Chi A, Lambert P, Richardson M et al: Oral mucoceles: a clinico-
pathologic review of 1,824 cases including unusual variants,
Abstract No. 19. Paper presented at the annual meeting of
the American Academy of Oral and Maxillofacial Pathology,
Kansas City, Mo, 2007.
Eveson JW: Superﬁcial mucoceles: pitfall in clinical and micro-
scopic diagnosis, Oral Surg Oral Med Oral Pathol 66:318-322,
1988.
Jensen JL: Superﬁcial mucoceles of the oral mucosa, Am J Der-
matopathol 12:88-92, 1990.
Jinbu Y, Kusama M, Itoh H et al: Mucocele of the glands of
Blandin-Nuhn: clinical and histopathologic analysis of 26
cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:467-
470, 2003.
Jinbu Y, Tsukinoki K, Kusama M et al: Recurrent multiple super-
ﬁcial mucocele on the palate: histopathology and laser vapor-
ization, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
95:193-197, 2003.
Standish SM, Shafer WG: The mucous retention phenomenon,
J Oral Surg 17:15-22, 1959.
Sugerman PB, Savage NW, Young WG: Mucocele of the anterior
lingual salivary glands (glands of Blandin and Nuhn): report
of 5 cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
90:478-482, 2000.
Ranula
Anastassov GE, Haiavy J, Solodnik P et al: Submandibular gland
mucocele: diagnosis and management, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 89:159-163, 2000.
Baurmash HD: A case against sublingual gland removal as
primary treatment of ranulas, J Oral Maxillofac Surg 65:117-
121, 2007.
Fig. 11-80 Salivary adenocarcinoma. “Clear cell”
adenocarcinoma of the submandibular gland.
Fig. 11-81 Salivary adenocarcinoma. Mass of the posterior
lateral hard palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

500 ORAL AND MAXILLOFACIAL PATHOLOGY
Baurmash HD: Mucoceles and ranulas, J Oral Maxillofac Surg
61:369-378, 2003.
Davison MJ, Morton RP, McIvor NP: Plunging ranula: clinical
observations, Head Neck 20:63-68, 1998.
Galloway RH, Gross PD, Thompson SH et al: Pathogenesis and
treatment of ranula: report of three cases, J Oral Maxillofac
Surg 47:299-302, 1989.
Mahadevan M, Vasan N: Management of pediatric plunging
ranula, Int J Pediatr Otorhinolaryngol 70:1049-1054, 2006.
Kurabayashi T, Ida M, Yasumoto M et al: MRI of ranulas, Neuro-
radiology 42:917-922, 2000.
Yoshimura Y, Obara S, Kondoh T et al: A comparison of three
methods used for treatment of ranula, J Oral Maxillofac Surg
53:280-282, 1995.
Zhao Y-F, Jia Y, Chen X-M et al: Clinical review of 580 ranulas,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98:281-287,
2004.
Salivary Duct Cyst
Eversole LR: Oral sialocysts, Arch Otolaryngol 113:51-56, 1987.
Takeda Y, Yamamoto H: Salivary duct cyst: its frequency in a
certain Japanese population group (Tohoku districts), with
special reference to adenomatous proliferation of the epithe-
lial lining, J Oral Sci 43:9-13, 2001.
Tal H, Altini M, Lemmer J: Multiple mucous retention cysts of
the oral mucosa, Oral Surg Oral Med Oral Pathol 58:692-695,
1984.
Sialolithiasis
Arzoz E, Santiago A, Esnal F et al: Endoscopic intracorporeal
lithotripsy for sialolithiasis, J Oral Maxillofac Surg 54:847-850,
1996.
Baurmash HD: Submandibular salivary stones: current manage-
ment modalities, J Oral Maxillofac Surg 62:369-378, 2004.
Capaccio P, Ottaviani F, Manzo R et al: Extracorporeal lithotripsy
for salivary calculi: a long-term clinical experience, Laryngo-
scope 114:1069-1073, 2004.
Jensen JL, Howell FV, Rick GM et al: Minor salivary gland calculi:
a clinicopathologic study of forty-seven new cases, Oral Surg
Oral Med Oral Pathol 47:44-50, 1979.
McGurk M, Escudier MP, Brown JE: Modern management of
salivary calculi, Br J Surg 92:107-112, 2005.
Nahlieli O, Baruchin AM: Sialoendoscopy: three years’ experi-
ence as a diagnostic and treatment modality, J Oral Maxillofac
Surg 55:912-918, 1997.
Nahlieli O, Eliav E, Hasson O et al: Pediatric sialolithiasis, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 90:709-712,
2000.
Ottaviani F, Capaccio P, Rivolta R et al: Salivary gland stones: US
evaluation in shock wave lithotripsy, Radiology 204:437-441,
1997.
Williams MF: Sialolithiasis, Otolaryngol Clin North Am 32:819-
834, 1999.
Zenk J, Bozzato A, Winter M et al: Extracorporeal shock wave
lithotripsy of submandibular stones: evaluation after 10 years,
Ann Otol Rhinol Laryngol 113:378-383, 2004.
Ziegler CM, Steveling H, Seubert M et al: Endoscopy: a mini-
mally invasive procedure for diagnosis and treatment of dis-
eases of the salivary glands—six years of practical experience,
Br J Oral Maxillofac Surg 42:1-7, 2004.
Sialadenitis
Fattahi TT, Lyu PE, Van Sickels JE: Management of acute sup-
purative parotitis, J Oral Maxillofac Surg 60:446-448, 2002.
Fowler CB, Brannon RB: Subacute necrotizing sialadenitis:
report of 7 cases and a review of the literature, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 89:600-609, 2000.
Mandel L, Surattanont F: Bilateral parotid swelling: a review,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93:221-237,
2002.
McQuone SJ: Acute viral and bacterial infections of the salivary
glands, Otolaryngol Clin North Am 32:793-811, 1999.
Motamed M, Laugharne D, Bradley PJ: Management of chronic
parotitis: a review, J Laryngol Otol 117:521-526, 2003.
Nahlieli O, Bar T, Shacham R et al: Management of chronic
recurrent parotitis: current therapy, J Oral Maxillofac Surg
62:1150-1155, 2004.
Seifert G: Aetiological and histological classiﬁcation of sialadeni-
tis, Pathologica 89:7-17, 1997.
Suresh L, Aguirre A: Subacute necrotizing sialadenitis: a clinico-
pathological study, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 104:385-390, 2007.
Vasama J-P: Tympanic neurectomy and chronic parotitis, Acta
Otolaryngol 120:995-998, 2000.
Werning JT, Waterhouse JP, Mooney JW: Subacute necrotizing
sialadenitis, Oral Surg Oral Med Oral Pathol 70:756-759,
1990.
Williams HK, Connor R, Edmondson H: Chronic sclerosing sial-
adenitis of the submandibular and parotid glands: a report of
a case and review of the literature, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 89:720-723, 2000.
Cheilitis Glandularis
Carrington PR, Horn TD: Cheilitis glandularis: a clinical marker
for both malignancy and/or severe inﬂammatory disease of
the oral cavity, J Am Acad Dermatol 54:336-337, 2006.
Cohen DM, Green JG, Dickmann SL: Concurrent anomalies:
cheilitis glandularis and double lip: report of a case, Oral Surg
Oral Med Oral Pathol 66:397-399, 1988.
Doku HC, Shklar G, McCarthy PL: Cheilitis glandularis, Oral
Surg Oral Med Oral Pathol 20:563-571, 1965.
Oliver ID, Pickett AB: Cheilitis glandularis, Oral Surg Oral Med
Oral Pathol 49:526-529, 1980.
Stoopler ET, Carrasco L, Stanton DC et al: Cheilitis glandularis:
an unusual histopathologic presentation, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 95:312-317, 2003.
Swerlick RA, Cooper PH: Cheilitis glandularis: a re-evaluation,
J Am Acad Dermatol 10:466-472, 1984.
Sialorrhea
Banerjee KJ, Glasson C, O’Flaherty SJ: Parotid and submandibu-
lar botulinum toxin A injections for sialorrhoea in children
with cerebral palsy, Dev Med Child Neurol 48:883-887, 2006.
Contarino MF, Pompili M, Tittoto P et al: Botulinum toxin B
ultrasound-guided injections for sialorrhea in amyotrophic
lateral sclerosis and Parkinson’s disease, Parkinsonism Relat
Disord 13:299-303, 2007.
Ethunandan M, Macpherson DW: Persistent drooling: treatment
by bilateral submandibular duct transposition and simultane-
ous sublingual gland excision, Ann R Coll Surg Engl 80:279-
282, 1998.
Freudenreich O: Drug-induced sialorrhea, Drugs Today 41:411-
418, 2005.
Lamey P-J, Clifford TJ, El-Karim IA et al: Personality analysis of
patients complaining of sialorrhoea, J Oral Pathol Med 35:307-
310, 2006.
Lieblich S: Episodic supersalivation (idiopathic paroxysmal sial-
orrhea): description of a new clinical syndrome, Oral Surg
Oral Med Oral Pathol 68:159-161, 1989.
Mandel L, Tamari K: Sialorrhea and gastroesophageal reﬂux,
J Am Dent Assoc 126:1537-1541, 1995.
Meningaud J-P, Pitak-Arnnop P, Chikhani L et al: Drooling of
saliva: a review of the etiology and management options, Oral `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 11 SALIVARY GLAND PATHOLOGY 501
Surg Oral Med Oral Pathol Oral Radiol Endod 101:48-57,
2006.
O’Dwyer TP, Conlon BJ: The surgical management of drooling—a
15 year follow-up, Clin Otolaryngol 22:284-287, 1997.
Shirley WP, Hill JS, Woolley AL et al: Success and complications
of four-duct ligation for sialorrhea, Int J Pediatr Otorhinolaryn-
gol 67:1-6, 2003.
Talmi YP, Finkelstein Y, Zohar Y: Reduction of salivary ﬂow with
transdermal scopolamine: a four-year experience, Otolaryngol
Head Neck Surg 103:615-618, 1990.
Xerostomia
Cassolato SF, Turnbull RS: Xerostomia: clinical aspects and treat-
ment, Gerodontology 20:64-77, 2003.
Epstein JB, Emerton S, Le ND et al: A double-blind crossover trial
of Oral Balance gel and Biotene toothpaste versus placebo in
patients with xerostomia following radiation therapy, Oral
Oncol 35:132-137, 1999.
Fox PC: Salivary enhancement therapies, Caries Res 38:241-246,
2004.
Jensen SB, Pedersen AM, Reibel J et al: Xerostomia and hypo-
function of the salivary glands in cancer therapy, Support Care
Cancer 11:207-225, 2003.
Johnson JT, Ferretti GA, Nethery WJ et al: Oral pilocarpine for
post-irradiation xerostomia in patients with head and neck
cancer, N Engl J Med 329:390-395, 1993.
Kirstilä V, Lenander-Lumikari M, Söderling E et al: Effects of oral
hygiene products containing lactoperoxidase, lysozyme, and
lactoferrin on the composition of whole saliva and on subjec-
tive oral symptoms in patients with xerostomia, Acta Odontol
Scand 54:391-397, 1996.
Närhi, TO, Meurman JH, Ainamo A: Xerostomia and hyposaliva-
tion. Causes, consequences and treatment in the elderly,
Drugs Aging 15:103-116, 1999.
Nieuw Amerongen AV, Veerman ECI: Current therapies for
xerostomia and salivary gland hypofunction associated with
cancer therapies, Support Care Cancer 11:226-231, 2003.
Porter SR, Scully C, Hegarty AM: An update of the etiology and
management of xerostomia, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 97:28-46, 2004.
Scully C: Drug effects on salivary glands: dry mouth, Oral Dis
9:165-176, 2003.
Sreebny LM, Schwartz SS: A reference guide to drugs and dry
mouth—2nd edition, Gerodontology 14:33-47, 1997.
Warde P, Kroll B, O’Sullivan B et al: A phase II study of Biotene
in the treatment of postradiation xerostomia in patients
with head and neck cancer, Support Care Cancer 8:203-208,
2000.
Benign Lymphoepithelial Lesion
Bridges AJ, England DM: Benign lymphoepithelial lesion: rela-
tionship to Sjögren’s syndrome and evolving malignant lym-
phoma, Semin Arthritis Rheum 19:201-208, 1989.
Chaudhry AP, Cutler LS, Yamane GM et al: Light and ultrastruc-
tural features of lymphoepithelial lesions of the salivary
glands in Mikulicz’s disease, J Pathol 146:239-250, 1986.
DiGiuseppe JA, Corio RL, Westra WH: Lymphoid inﬁltrates of
the salivary glands: pathology, biology, and clinical signiﬁ-
cance, Curr Opin Oncol 8:232-237, 1996.
Herbst H, Niedobitek G: Sporadic EBV-associated lymphoepi-
thelial salivary gland carcinoma with EBV-positive low-
grade myoepithelial component, Virchows Arch 448:648-654,
2006.
Penfold CN: Mikulicz syndrome, J Oral Maxillofac Surg 43:900-
905, 1985.
Quintana PG, Kapadia SB, Bahler DW et al: Salivary gland lym-
phoid inﬁltrates associated with lymphoepithelial lesions: a
clinicopathologic, immunophenotypic, and genotypic study,
Hum Pathol 28:850-861, 1997.
Sato K, Kawana M, Sato Y et al: Malignant lymphoma in the head
and neck associated with benign lymphoepithelial lesion of
the parotid gland, Auris Nasus Larynx 29:209-214, 2002.
Saw D, Lau WH, Ho JHC et al: Malignant lymphoepithelial
lesion of the salivary gland, Hum Pathol 17:914-923,
1986.
Wu DL, Shemen L, Brady T et al: Malignant lymphoepithelial
lesion of the parotid gland: a case report and review of the
literature, Ear Nose Throat J 80:803-806, 2001.
Sjögren Syndrome
Al-Hashimi I: Xerostomia secondary to Sjögren’s syndrome in
the elderly, Drugs Aging 22:887-899, 2005.
Biasi D, Caramaschi P, Ambrosetti A et al: Mucosa-associated
lymphoid tissue lymphoma of the salivary glands occurring
in patients affected by Sjögren’s syndrome: report of 6 cases,
Acta Haematol 105:83-88, 2001.
Daniels TE: Labial salivary gland biopsy in Sjögren’s syndrome:
assessment as a diagnostic criterion in 362 suspected cases,
Arthritis Rheum 27:147-156, 1984.
Daniels TE, Fox PC: Salivary and oral components of Sjögren’s
syndrome, Rheum Dis Clin North Am 18:571-589, 1992.
Delaleu N, Jonsson R, Koller MM: Sjögren’s syndrome, Eur J Oral
Sci 113:101-113, 2005.
Fox RI: Sjögren’s syndrome, Lancet 366:321-331, 2005.
Fox RI, Törnwall J, Maruyama T et al: Evolving concepts of diag-
nosis, pathogenesis, and therapy of Sjögren’s syndrome, Curr
Opin Rheumatol 10:446-456, 1998.
Friedlaender MH: Ocular manifestations of Sjögren’s syndrome:
keratoconjunctivitis sicca, Rheum Dis Clin North Am 18:591-
608, 1992.
García-Carrasco M, Ramos-Casals M, Rosas J et al: Primary
Sjögren syndrome: clinical and immunologic disease patterns
in a cohort of 400 patients, Medicine 81:270-280, 2002.
Jonsson R, Moen K, Vestrheim D et al: Current issues in Sjögren’s
syndrome, Oral Dis 8:130-140, 2002.
Jordan R, Diss TC, Lench NJ et al: Immunoglobulin gene rear-
rangements in lymphoplasmacytic inﬁltrates of labial salivary
glands in Sjögren’s syndrome. A possible predictor of lym-
phoma development, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 79:723-729, 1995.
Jordan RCK, Speight PM: Lymphoma in Sjögren’s syndrome.
From histopathology to molecular pathology, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 81:308-320, 1996.
Manthorpe R, Benoni C, Jacobsson L et al: Lower frequency of
focal lip sialadenitis (focus score) in smoking patients. Can
tobacco diminish the salivary gland involvement as judged by
histological examination and anti-SSA/Ro and anti-SSB/La
antibodies in Sjögren’s syndrome, Ann Rheum Dis 59:54-60,
2000.
Marx RE, Hartman KS, Rethman KV: A prospective study com-
paring incisional labial to incisional parotid biopsies in the
detection and conﬁrmation of sarcoidosis, Sjögren’s disease,
sialosis and lymphoma, J Rheumatol 15:621-629, 1988.
Pedersen AM, Reibel J, Nauntofte B: Primary Sjögren’s syndrome
(pSS): subjective symptoms and salivary ﬁndings, J Oral Pathol
Med 28:303-311, 1999.
Vitali C, Bombardieri S, Jonsson R et al: Classiﬁcation criteria for
Sjögren’s syndrome: a revised version of the European crite-
ria proposed by the American-European Consensus Group,
Ann Rheum Dis 61:554-558, 2002.
Vivino FB, Gala I, Hermann GA: Change in ﬁnal diagnosis on
second evaluation of labial minor salivary gland biopsies,
J Rheumatol 29:938-944, 2002. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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502 ORAL AND MAXILLOFACIAL PATHOLOGY
Sialadenosis
Chilla R: Sialadenosis of the salivary glands of the head: studies
on the physiology and pathophysiology of parotid secretion,
Adv Otorhinolaryngol 26:1-38, 1981.
Coleman H, Altini M, Nayler S et al: Sialadenosis: a presenting
sign in bulimia, Head Neck 20:758-762, 1998.
Mehler PS, Wallace JA: Sialadenosis in bulimia: a new treatment,
Arch Otolaryngol Head Neck Surg 119:787-788, 1993.
Mignogna MD, Fedele S, Lo Russo L: Anorexia/bulimia-related
sialadenosis of palatal minor salivary glands, J Oral Pathol Med
33:441-442, 2004.
Pape SA, MacLeod RI, McLean NR et al: Sialadenosis of the sali-
vary glands, Br J Plast Surg 48:419-422, 1995.
Satoh M, Yoshihara T: Clinical and ultracytochemical investiga-
tion of sialadenosis, Acta Otolaryngol Suppl 553:122-127,
2004.
Adenomatoid Hyperplasia
Arafat A, Brannon RB, Ellis GL: Adenomatoid hyperplasia of
mucous salivary glands, Oral Surg Oral Med Oral Pathol 52:51-
55, 1981.
Barrett AW, Speight PM: Adenomatoid hyperplasia of oral minor
salivary glands, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 79:482-487, 1995.
Buchner A, Merrell PW, Carpenter WM et al: Adenomatoid
hyperplasia of minor salivary glands, Oral Surg Oral Med Oral
Pathol 71:583-587, 1991.
Giansanti JS, Baker GO, Waldron CA: Intraoral, mucinous,
minor salivary gland lesions presenting clinically as tumors,
Oral Surg Oral Med Oral Pathol 32:918-922, 1971.
Shimoyama T, Wakabayashi M, Kato T et al: Adenomatoid
hyperplasia of the palate mimicking clinically as a salivary
gland tumor, J Oral Sci 43:135-138, 2001.
Necrotizing Sialometaplasia
Abrams AM, Melrose RJ, Howell FV: Necrotizing sialometapla-
sia: a disease simulating malignancy, Cancer 32:130-135,
1973.
Brannon RB, Fowler CB, Hartman KS: Necrotizing sialometapla-
sia: a clinicopathologic study of sixty-nine cases and review of
the literature, Oral Surg Oral Med Oral Pathol 72:317-325,
1991.
Imbery TA, Edwards PA: Necrotizing sialometaplasia: literature
review and case reports, J Am Dent Assoc 127:1087-1092,
1996.
Schöning H, Emshoff R, Kreczy A: Necrotizing sialometaplasia
in two patients with bulimia and chronic vomiting, Int J Oral
Maxillofac Surg 27:463-465, 1998.
Sneige N, Batsakis JG: Necrotizing sialometaplasia, Ann Otol
Rhinol Laryngol 101:282-284, 1992.
Salivary Gland Tumors: General Considerations
Dardick I: Color atlas/text of salivary gland tumor pathology, New
York, 1996, Igaku-Shoin.
Ellies M, Schaffranietz F, Arglebe C et al: Tumor of the salivary
glands in childhood and adolescence, J Oral Maxillofac Surg
64:1049-1058, 2006.
Ellis GL, Auclair PL: Tumors of the salivary glands, Washington DC,
1996, Armed Forces Institute of Pathology.
Ellis GL, Auclair PL, Gnepp DR: Surgical pathology of the salivary
glands, Philadelphia, 1991, WB Saunders.
Eneroth C-M: Salivary gland tumors in the parotid gland, sub-
mandibular gland, and the palate region, Cancer 27:1415-
1418, 1971.
Eveson JW, Cawson RA: Salivary gland tumours: a review of
2410 cases with particular reference to histological types,
site, age, and sex distribution, J Pathol 146:51-58, 1985.
Eveson JW, Cawson RA: Tumours of the minor (oropharyngeal)
salivary glands: a demographic study of 336 cases, J Oral
Pathol 14:500-509, 1985.
Foote FW, Frazell EL: Tumors of the major salivary glands, Cancer
6:1065-1113, 1953.
Neville BW, Damm DD, Weir JC et al: Labial salivary gland
tumors: an analysis of 103 cases, Cancer 61:2113-2116,
1988.
Pires FR, Pringle GA, de Almeida OP et al: Intra-oral minor sali-
vary gland tumors: a clinicopathological study of 546 cases,
Oral Oncol 43:463-470, 2007.
Seifert G, Brocheriou C, Cardesa A et al: WHO international
histological classiﬁcation of tumours: tentative histological
classiﬁcation of salivary gland tumours, Pathol Res Pract
186:555-581, 1990.
Seifert G, Miehlke A, Haubrich J et al: Diseases of the salivary
glands. Pathology—diagnosis—treatment—facial nerve surgery, New
York, 1986, George Thieme Verlag.
Spiro RH: Salivary neoplasms: overview of a 35-year experience
with 2,807 patients, Head Neck Surg 8:177-184, 1986.
Thackray AC, Lucas RB: Tumors of the major salivary glands: atlas
of tumor pathology, series 2, fascicle 10, Washington, DC,
1974, Armed Forces Institute of Pathology.
Waldron CA, EI-Mofty SK, Gnepp DR: Tumors of the intraoral
minor salivary glands: a demographic and histologic study of
426 cases, Oral Surg Oral Med Oral Pathol 66:323-333,
1988.
Whatley WS, Thompson JW, Rao B: Salivary gland tumors in
survivors of childhood cancer, Otolaryngol Head Neck Surg
134:385-388, 2006.
Yih W-Y, Kratochvil FJ, Stewart JCB: Intraoral minor salivary
gland neoplasms: review of 213 cases, J Oral Maxillofac Surg
63:805-810, 2005.
Pleomorphic Adenoma
Chau MNY, Radden BG: A clinical-pathological study of 53
intraoral pleomorphic adenomas, Int J Oral Maxillofac Surg
18:158-162, 1989.
Dardick I: Myoepithelioma: deﬁnitions and diagnostic criteria,
Ultrastruct Pathol 19:335-345, 1995.
Friedrich RE, Li L, Knop J et al: Pleomorphic adenoma of the
salivary glands: analysis of 94 patients, Anticancer Res 25:
1703-1705, 2005.
Kanazawa H, Furuya T, Watanabe T et al: Plasmacytoid myoepi-
thelioma of the palate, J Oral Maxillofac Surg 57:857-860,
1999.
Myssiorek D, Ruah CB, Hybels RL: Recurrent pleomorphic
adenomas of the parotid gland, Head Neck 12:332-336,
1990.
Noguchi S, Aihara T, Yoshino K et al: Demonstration of mono-
clonal origin of human parotid gland pleomorphic adenoma,
Cancer 77:431-435, 1996.
Silva SJ, Costa GT, Brant Filho AC et al: Metachronous
bilateral pleomorphic adenoma of the parotid gland, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 101:333-338,
2006.
Sciubba JJ, Brannon R: Myoepithelioma of salivary glands: report
of 23 cases, Cancer 47:562-572, 1982.
Stennert E, Guntinas-Lichius O, Klussman JP et al: Histopathol-
ogy of pleomorphic adenoma in the parotid gland: a prospec-
tive unselected series of 100 cases, Laryngoscope 111:
2195-2200, 2001.
Stennert E, Wittekindt C, Klussman JP et al: Recurrent pleomor-
phic adenoma of the parotid gland: a prospective histopatho-
logical and immunohistochemical study, Laryngoscope 114:
158-163, 2004. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
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Chapter 11 SALIVARY GLAND PATHOLOGY 503
Oncocytoma and Oncocytosis
Brandwein MS, Huvos AG: Oncocytic tumors of major salivary
glands: a study of 68 cases with follow-up of 44 patients, Am
J Surg Pathol 15:514-528, 1991.
Capone RB, Ha PK, Westra WH et al: Oncocytic neoplasms of
the parotid gland: a 16-year institutional review, Otolaryngol
Head Neck Surg 126:657-662, 2002.
Damm DD, White DK, Geissler RH Jr et al: Benign solid onco-
cytoma of intraoral minor salivary glands, Oral Surg Oral Med
Oral Pathol 67:84-86, 1989.
Ellis GL: “Clear cell” oncocytoma of salivary gland, Human Pathol
19:862-867, 1988.
Goode RK, Corio RL: Oncocytic adenocarcinoma of salivary
glands, Oral Surg Oral Med Oral Pathol 65:61-66, 1988.
Loreti A, Sturla M, Gentileschi S et al: Diffuse hyperplastic onco-
cytosis of the parotid gland, Br J Plast Surg 55:151-152,
2002.
Ozolek JA, Bastacky SI, Myers EN et al: Immunophenotypic com-
parison of salivary gland oncocytoma and metastatic renal
cell carcinoma, Laryngoscope 115:1097-1100, 2005.
Palmer TJ, Gleeson MJ, Eveson JW et al: Oncocytic adenomas
and oncocytic hyperplasia of salivary glands: a clinicopatho-
logical study of 26 cases, Histopathology 16:487-493, 1990.
Stomeo F, Meloni F, Bozzo C et al: Bilateral oncocytoma of the
parotid gland, Acta Otolaryngol 126:324-326, 2006.
Thompson LD, Wenig BM, Ellis GL: Oncocytomas of the sub-
mandibular gland. A series of 22 cases and a review of the
literature, Cancer 78:2281-2287, 1996.
Warthin Tumor
Aguirre JM, Echebarría MA, Martínez-Conde R et al: Warthin
tumor. A new hypothesis concerning its development, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 85:60-63, 1998.
Batsakis JG: Carcinoma ex papillary cystadenoma lymphomato-
sum. Malignant Warthin’s tumor, Ann Otol Rhinol Laryngol
96:234-235, 1987.
Dietert SE: Papillary cystadenoma lymphomatosum (Warthin’s
tumor) in patients in a general hospital over a 24-year period,
Am J Clin Pathol 63:866-875, 1975.
Fantasia JE, Miller AS: Papillary cystadenoma lymphomatosum
arising in minor salivary glands, Oral Surg Oral Med Oral
Pathol 52:411-416, 1981.
Honda K, Kashima K, Daa T et al: Clonal analysis of the epithelial
component of Warthin’s tumor, Hum Pathol 31:1377-1380,
2000.
Klussmann JP, Wittekindt C, Preuss SF et al: High risk for bilat-
eral Warthin tumor in heavy smokers—review of 185 cases,
Acta Otolaryngol 126:1213-1217, 2006.
Kotwall CA: Smoking as an etiologic factor in the development
of Warthin’s tumor of the parotid gland, Am J Surg 164:646-
647, 1992.
Martins C, Fonseca I, Roque L et al: Cytogenetic characterisation
of Warthin’s tumour, Oral Oncol 33:344-347, 1997.
Monk JS Jr, Church JS: Warthin’s tumor: a high incidence and
no sex predominance in central Pennsylvania, Arch Otolaryn-
gol Head Neck Surg 118:477-478, 1992.
Takezawa K, Jackson C, Gnepp DR et al: Molecular characteriza-
tion of Warthin tumor, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 85:569-575, 1998.
Teymoortash A, Werner JA: Tissue that has lost its track:
Warthin’s tumour, Virchows Arch 446:585-588, 2005.
van der Wal JE, Davids JJ, van der Waal I: Extraparotid Warthin’s
tumours—report of 10 cases, Br J Oral Maxillofac Surg 31:43-
44, 1993.
Zappia JJ, Sullivan MJ, McClatchey KD: Unilateral multicentric
Warthin’s tumors, J Otolaryngol 20:93-96, 1991.
Canalicular Adenoma
Daley TD, Gardner DG, Smout MS: Canalicular adenoma: not a
basal cell adenoma, Oral Surg Oral Med Oral Pathol 57:181-
188, 1984.
Fantasia JE, Neville BW: Basal cell adenomas of the minor sali-
vary glands, Oral Surg Oral Med Oral Pathol 50:433-440,
1980.
Gardner DG, Daley TD: The use of the terms monomorphic
adenoma, basal cell adenoma, and canalicular adenoma as
applied to salivary gland tumors, Oral Surg Oral Med Oral
Pathol 56:608-615, 1983.
Nelson JF, Jacoway JR: Monomorphic adenoma (canalicular
type): report of 29 cases, Cancer 31:1511-1513, 1973.
Neville BW, Damm DD, Weir JC et al: Labial salivary gland
tumors: an analysis of 103 cases, Cancer 61:2113-2116,
1988.
Rousseau A, Mock D, Dover DG et al: Multiple canalicular ade-
nomas: a case report and review of the literature, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 87:346-350, 1999.
Suarez P, Hammond HL, Luna MA et al: Palatal canalicular
adenoma: report of 12 cases and review of the literature, Ann
Diagn Pathol 2:224-228, 1998.
Yoon AJ, Beller DE, Woo, VL et al: Bilateral canalicular adeno-
mas of the upper lip, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 102:341-343, 2006.
Basal Cell Adenoma
Batsakis JG, Brannon RB: Dermal analogue tumours of major
salivary glands, J Laryngol 95:155-164, 1981.
Ellis GL, Wiscovitch JG: Basal cell adenocarcinomas of the major
salivary glands, Oral Surg Oral Med Oral Pathol 69:461-469,
1990.
Fonseca I, Soares J: Basal cell adenocarcinoma of minor salivary
and seromucous glands of the head and neck region, Semin
Diagn Pathol 13:128-137, 1996.
Jayakrishnan A, Elmalah I, Hussain K et al: Basal cell adenocar-
cinoma in minor salivary glands, Histopathology 42:610-614,
2003.
Luna MA, Tortoledo ME, Allen M: Salivary dermal analogue
tumors arising in lymph nodes, Cancer 59:1165-1169,
1987.
Machado de Sousa SO, Soares de Araújo N, Corrêa L et al: Immu-
nohistochemical aspects of basal cell adenoma and canalicu-
lar adenoma of salivary glands, Oral Oncol 37:365-368,
2001.
Muller S, Barnes L: Basal cell adenocarcinoma of the salivary
glands: report of seven cases and review of the literature,
Cancer 78:2471-2477, 1996.
Parashar P, Baron E, Papadimitriou JC et al: Basal cell adenocar-
cinoma of the oral minor salivary glands: review of the litera-
ture and presentation of two cases, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 103:77-84, 2007.
Pogrel MA: The intraoral basal cell adenoma, J Craniomaxillofac
Surg 15:372-375, 1987.
Zarbo RJ, Prasad AR, Regezi JA et al: Salivary gland basal cell
and canalicular adenomas: immunohistochemical demon-
stration of myoepithelial cell participation and morphoge-
netic considerations, Arch Pathol Lab Med 124:401-405,
2000.
Salivary Papillomas
Abbey LM: Solitary intraductal papilloma of the minor
salivary glands, Oral Surg Oral Med Oral Pathol 40:135-140,
1975.
Abrams AM, Finck FM: Sialadenoma papilliferum: a previously
unreported salivary gland tumor, Cancer 24:1057-1063,
1969. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

504 ORAL AND MAXILLOFACIAL PATHOLOGY
Brannon RB, Sciubba JJ, Giulani M: Ductal papillomas of salivary
gland origin: a report of 19 cases and a review of the litera-
ture, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92:68-
77, 2001.
Cabov T, Macan D, Manojlovic S et al: Oral inverted ductal papil-
loma, Br J Oral Maxillofac Surg 42:75-77, 2004.
Fantasia JE, Nocco CE, Lally ET: Ultrastructure of sialadenoma
papilliferum, Arch Pathol Lab Med 110:523-527, 1986.
Gomes APN, Sobral APV, Loducca SVL et al: Sialadenoma papil-
liferum: immunohistochemical study, Int J Oral Maxillofac
Surg 33:621-624, 2004.
Hegarty DJ, Hopper C, Speight PM: Inverted ductal papilloma
of minor salivary glands, J Oral Pathol Med 23:334-336,
1994.
Iguchi H, Yamane H, Nasako Y et al: Intraductal papilloma in
the parotid duct, Acta Otolaryngol 122:314-317, 2002.
Maiorano E, Favia G, Ricco R: Sialadenoma papilliferum: an
immunohistochemical study of ﬁve cases, J Oral Pathol Med
25:336-342, 1996.
Nagao T, Sugano I, Matsuzaki O et al: Intraductal papillary
tumors of the major salivary glands. Case reports of benign
and malignant variants, Arch Pathol Lab Med 124:291-295,
2000.
de Sousa SO, Sesso A, de Araújo NS et al: Inverted ductal papil-
loma of minor salivary gland origin: morphological aspects
and cytokeratin expression, Eur Arch Otorhinolaryngol 252:
370-373, 1995.
White DK, Miller AS, McDaniel RK et al: Inverted ductal papil-
loma: a distinctive lesion of minor salivary gland, Cancer
49:519-524, 1982.
Mucoepidermoid Carcinoma
Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of
intraoral salivary glands, Cancer 69:2021-2030, 1992.
Batsakis JG, Luna MA: Histopathologic grading of salivary gland
neoplasms. I. Mucoepidermoid carcinomas, Ann Otol Rhinol
Laryngol 99:835-838, 1990.
Brandwein MS, Ivanov K, Wallace DI et al: Mucoepidermoid
carcinoma: a clinicopathologic study of 80 patients with
special reference to histological grading, Am J Surg Pathol
25:835-845, 2001.
Evans HL: Mucoepidermoid carcinoma of salivary glands: a
study of 69 cases with special attention to histologic grading,
Am J Clin Pathol 81:696-701, 1984.
Goode RK, Auclair PL, Ellis GL: Mucoepidermoid carcinoma of
the major salivary glands: clinical and histopathologic analy-
sis of 234 cases with evaluation of grading criteria, Cancer
82:1217-1224, 1998.
Guzzo M, Andreola S, Sirizzotti G et al: Mucoepidermoid carci-
noma of the salivary glands: clinicopathologic review of 108
patients treated at the National Cancer Institute of Milan, Ann
Surg Oncol 9:688-695, 2002.
Hicks J, Flaitz C: Mucoepidermoid carcinoma of salivary glands
in children and adolescents: assessment of proliferation
markers, Oral Oncol 36:454-460, 2000.
Luna MA: Salivary mucoepidermoid carcinoma: revisited, Adv
Anat Pathol 13:293-307, 2006.
Spiro RH, Huvos AG, Berk R et al: Mucoepidermoid carcinoma
of salivary gland origin: a clinicopathologic study of 367
cases, Am J Surg 136:461-468, 1978.
Stewart FW, Foote FW, Becker WF: Mucoepidermoid tumors of
salivary glands, Ann Surg 122:820-844, 1945.
Védrine PO, Cofﬁnet L, Temam S et al: Mucoepidermoid carci-
noma of salivary glands in the pediatric age group: 18 clinical
cases, including 11 second malignant neoplasms, Head Neck
28:827-833, 2006.
Whatley WS, Thompson JW, Rao B: Salivary gland tumors in
survivors of childhood cancer, Otolaryngol Head Neck Surg
134:385-388, 2006.
Intraosseous Mucoepidermoid Carcinoma
Bouquot JE, Gnepp DR, Dardick I et al: Intraosseous salivary
tissue: jawbone examples of choristomas, hamartomas,
embryonic rests, and inﬂammatory entrapment—another his-
togenetic source for intraosseous adenocarcinoma, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 90:205-217, 2000.
Brookstone MS, Huvos AG: Central salivary gland tumors of the
maxilla and mandible: a clinicopathologic study of 11 cases
with an analysis of the literature, J Oral Maxillofac Surg 50:229-
236, 1992.
Browand BC, Waldron CA: Central mucoepidermoid tumors of
the jaws, Oral Surg Oral Med Oral Pathol 40:631-643, 1975.
Inagaki M, Yuasa K, Nakayama E et al: Mucoepidermoid carci-
noma in the mandible. Findings of panoramic radiography
and computed tomography, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 85:613-618, 1998.
Martínez-Madrigal F, Pineda-Daboin K, Casiraghi O et al: Sali-
vary gland tumors of the mandible, Ann Diagn Pathol 4:347-
353, 2000.
Pires FR, Paes de Almeida O, Lopes MA et al: Central mucoepi-
dermoid carcinoma of the mandible: report of four cases with
long-term follow-up, Int J Oral Maxillofac Surg 32:378-382,
2003.
Waldron CA, Koh ML: Central mucoepidermoid carcinoma of
the jaws: report of four cases with analysis of the literature
and discussion of the relationship to mucoepidermoid, sialo-
dontogenic, and glandular odontogenic cysts, J Oral Maxillofac
Surg 48:871-877, 1990.
Acinic Cell Adenocarcinoma
Batsakis JG, Luna MA, El-Naggar AK: Histopathologic grading of
salivary gland neoplasms. II. Acinic cell carcinomas, Ann Otol
Rhinol Laryngol 99:929-933, 1990.
Chen S-Y, Brannon RB, Miller AS et al: Acinic cell adenocarci-
noma of minor salivary glands, Cancer 42:678-685, 1978.
Ellis GL, Corio RL: Acinic cell adenocarcinoma: a clinicopatho-
logic analysis of 294 cases, Cancer 52:542-549, 1983.
Hamper K, Mausch H-E, Caselitz J et al: Acinic cell carcinoma
of the salivary glands: the prognostic relevance of DNA cyto-
photometry in a retrospective study of long duration (1965-
1987), Oral Surg Oral Med Oral Pathol 69:68-75, 1990.
Hoffman HT, Karnell LH, Robinson RA et al: National Cancer
Data Base report on cancer of the head and neck: acinic cell
carcinoma, Head Neck 21:297-309, 1999.
Lewis JE, Olsen KD, Weiland LH: Acinic cell carcinoma: clinico-
pathologic review, Cancer 67:172-179, 1991.
Michal M, Skálová A, Simpson RHW et al: Well-differentiated
acinic cell carcinoma of salivary glands associated with lym-
phoid stroma, Hum Pathol 28:595-600, 1997.
Perzin KH, LiVolsi VA: Acinic cell carcinomas arising in salivary
glands: a clinicopathologic study, Cancer 44:1434-1457,
1979.
Malignant Mixed Tumor
Auclair PL, Ellis GL: Atypical features in salivary gland mixed
tumors: their relationship to malignant transformation, Mod
Pathol 9:652-657, 1996.
Bradley PJ: “Metastasizing pleomorphic salivary adenoma”
should now be considered a low-grade malignancy with a
lethal potential, Curr Opin Otolaryngol Head Neck Surg 13:123-
126, 2005.
Brandwein M, Huvos AG, Dardick I et al: Noninvasive and mini-
mally invasive carcinoma ex mixed tumor: a clinicopatho- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 11 SALIVARY GLAND PATHOLOGY 505
logic and ploidy study of 12 patients with major salivary
tumors of low (or no?) malignant potential, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 81:655-664, 1996.
Carson HJ, Tojo DP, Chow JM et al: Carcinosarcoma of salivary
glands with unusual stromal components: report of two cases
and review of the literature, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 79:738-746, 1995.
Gnepp DR: Malignant mixed tumors of the salivary glands: a
review, Pathol Annu 28(pt 1):279-328, 1993.
Klijanienko J, El-Naggar AK, Servois V et al: Clinically aggressive
metastasizing pleomorphic adenoma: report of two cases,
Head Neck 19:629-633, 1997.
Kwon MY, Gu M: True malignant mixed tumor (carcinosarcoma)
of parotid gland with unusual mesenchymal component: a
case report and review of the literature, Arch Pathol Lab Med
125:812-815, 2001.
Lewis JE, Olsen KD, Sebo TJ: Carcinoma ex pleomorphic
adenoma: pathologic analysis of 73 cases, Hum Pathol 32:596-
604, 2001.
LiVolsi VA, Perzin KH: Malignant mixed tumors arising in sali-
vary glands. I. Carcinomas arising in benign mixed tumor: a
clinicopathologic study, Cancer 39:2209-2230, 1977.
Nouraei SAR, Ferguson MS, Clarke PM et al: Metastasizing pleo-
morphic salivary adenoma, Arch Otolaryngol Head Neck Surg
132:788-793, 2006.
Nouraei SAR, Hope KL, Kelly CG et al: Carcinoma ex benign
pleomorphic adenoma of the parotid gland, Plast Reconstr
Surg 116:1206-1213, 2005.
Spiro RH, Huvos AG, Strong EW: Malignant mixed tumor of
salivary origin: a clinicopathologic study of 146 cases, Cancer
39:388-396, 1977.
Tortoledo ME, Luna MA, Batsakis JG: Carcinomas ex pleomor-
phic adenoma and malignant mixed tumors, Arch Otolaryngol
110:172-176, 1984.
Wenig BM, Hitchcock CL, Ellis GL et al: Metastasizing mixed
tumor of salivary glands. A clinicopathologic and ﬂow cyto-
metric analysis, Am J Surg Pathol 16:845-858, 1992.
Adenoid Cystic Carcinoma
Araújo VC, Loducca SVL, Sousa SOM et al: The cribriform fea-
tures of adenoid cystic carcinoma and polymorphous low-
grade adenocarcinoma: cytokeratin and integrin expression,
Ann Diagn Pathol 5:330-334, 2001.
Beltran D, Faquin WC, Gallagher G et al: Selective immunohis-
tochemical comparison of polymorphous low-grade adeno-
carcinoma and adenoid cystic carcinoma, J Oral Maxillofac
Surg 64:415-423, 2006.
Bradley PJ: Adenoid cystic carcinoma of the head and neck: a
review, Curr Opin Otolaryngol Head Neck Surg 12:127-132, 2004.
da Cruz Perez DE, de Abreu Alves F, Nobuko Nishimoto I et al:
Prognostic factors in head and neck adenoid cystic carci-
noma, Oral Oncol 42:139-146, 2006.
Darling MR, Schneider JW, Phillips VM: Polymorphous low-
grade adenocarcinoma and adenoid cystic carcinoma: a
review and comparison of immunohistochemical markers,
Oral Oncol 38:641-645, 2002.
Enamorado I, Lakhani R, Korkmaz H et al: Correlation of histo-
pathological variants, cellular DNA content, and clinical
outcome in adenoid cystic carcinoma of the salivary glands,
Otolaryngol Head Neck Surg 131:646-650, 2004.
Gurney TA, Eisele DW, Weinberg V et al: Adenoid cystic carci-
noma of the major salivary glands treated with surgery and
radiation, Laryngoscope 115:1278-1282, 2005.
Hamper K, Lazar F, Dietel M et al: Prognostic factors for adenoid
cystic carcinoma of the head and neck: a retrospective evalu-
ation of 96 cases, J Oral Pathol Med 19:101-107, 1990.
Jones AS, Hamilton JW, Rowley H et al: Adenoid cystic carci-
noma of the head and neck, Clin Otolaryngol 22:434-443,
1997.
Loducca SVL, Raitz R, Araújo NS et al: Polymorphous low-grade
adenocarcinoma and adenoid cystic carcinoma: distinct
architectural composition revealed by collagen IV, laminin
and their integrin ligands (α2β1 and α3β1), Histopathology
37:118-123, 2000.
Penner CR, Folpe AL, Budnick SD: C-kit expression distinguishes
salivary gland adenoid cystic carcinoma from polymorphous
low-grade adenocarcinoma, Mod Pathol 15:687-691, 2002.
Perzin KH, Gullane P, Clairmont AC: Adenoid cystic carcinomas
arising in salivary glands: a correlation of histologic features
and clinical course, Cancer 42:265-282, 1978.
Spiro RH: Distant metastasis in adenoid cystic carcinoma of sali-
vary origin, Am J Surg 174:495-498, 1997.
Szanto PA, Luna MA, Tortoledo ME et al: Histologic grading of
adenoid cystic carcinoma of the salivary glands, Cancer
54:1062-1069, 1984.
van der Wal JE, Snow GB, van der Waal I: Intraoral adenoid
cystic carcinoma: the presence of perineural spread in rela-
tion to site, size, local extension, and metastatic spread in 22
cases, Cancer 66:2031-2033, 1990.
Woo VL, Bhuiya T, Kelsch R: Assessment of CD43 expression in
adenoid cystic carcinomas, polymorphous low-grade adeno-
carcinomas, and monomorphic adenomas, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 102:495-500, 2006.
Polymorphous Low-Grade Adenocarcinoma
Araújo VC, Loducca SVL, Sousa SOM et al: The cribriform fea-
tures of adenoid cystic carcinoma and polymorphous low-
grade adenocarcinoma: cytokeratin and integrin expression,
Ann Diagn Pathol 5:330-334, 2001.
Araújo V, Sousa S, Jaeger M et al: Characterization of the cellular
component of polymorphous low-grade adenocarcinoma by
immunohistochemistry and electron microscopy, Oral Oncol
35:164-172, 1999.
Batsakis JG, Pinkston GR, Luna MA et al: Adenocarcinomas of
the oral cavity: a clinicopathologic study of terminal duct
carcinomas, J Laryngol Otol 97:825-835, 1983.
Beltran D, Faquin WC, Gallagher G et al: Selective immunohis-
tochemical comparison of polymorphous low-grade adeno-
carcinoma and adenoid cystic carcinoma, J Oral Maxillofac
Surg 64:415-423, 2006.
Castle JT, Thompson LDR, Frommelt RA et al: Polymorphous
low grade adenocarcinoma: a clinicopathologic study of 164
cases, Cancer 86:207-219, 1999.
Curran AE, White DK, Damm DD et al: Polymorphous low-
grade adenocarcinoma versus pleomorphic adenoma of
minor salivary glands: resolution of a diagnostic dilemma by
immunohistochemical analysis with glial ﬁbrillary acidic
protein, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
91:194-199, 2001.
Darling MR, Schneider JW, Phillips VM: Polymorphous low-
grade adenocarcinoma and adenoid cystic carcinoma: a
review and comparison of immunohistochemical markers,
Oral Oncol 38:641-645, 2002.
Evans HL, Luna MA: Polymorphous low-grade adenocarcinoma:
a study of 40 cases with long-term follow up and an evalua-
tion of the importance of papillary areas, Am J Surg Pathol
24:1319-1328, 2000.
Freedman PD, Lumerman H: Lobular carcinoma of intraoral
minor salivary glands, Oral Surg Oral Med Oral Pathol 56:157-
165, 1983.
Nagao T, Gaffey TA, Kay PA et al: Polymorphous low-grade ade-
nocarcinoma of the major salivary glands: report of three `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

506 ORAL AND MAXILLOFACIAL PATHOLOGY
cases in an unusual location, Histopathology 44:164-171,
2004.
Penner CR, Folpe AL, Budnick SD: C-kit expression distinguishes
salivary gland adenoid cystic carcinoma from polymorphous
low-grade adenocarcinoma, Mod Pathol 15:687-691, 2002.
Vincent SD, Hammond HL, Finkelstein MW: Clinical and thera-
peutic features of polymorphous low-grade adenocarcinoma,
Oral Surg Oral Med Oral Pathol 77:41-47, 1994.
Woo VL, Bhuiya T, Kelsch R: Assessment of CD43 expression in
adenoid cystic carcinomas, polymorphous low-grade adeno-
carcinomas, and monomorphic adenomas, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 102:495-500, 2006.
Salivary Adenocarcinoma, Not Otherwise Speciﬁed
Li J, Wang BY, Nelson M et al: Salivary adenocarcinoma, not
otherwise speciﬁed: a collection of orphans, Arch Pathol Lab
Med 128:1385-1394, 2004.
Matsuba HM, Mauney M, Simpson JR et al: Adenocarcinomas of
major and minor salivary gland origin: a histopathologic
review of treatment failure patterns, Laryngoscope 98:784-
788, 1988.
Spiro RH, Huvos AG, Strong EW: Adenocarcinoma of salivary
origin: clinicopathologic study of 204 patients, Am J Surg
144:423-431, 1982.
Stene T, Koppang HS: Intraoral adenocarcinomas, J Oral Pathol
10:216-225, 1981.
Wahlberg P, Anderson H, Biörklund A et al: Carcinoma of the
parotid and submandibular glands—a study of survival in
2465 patients, Oral Oncol 38:706-713, 2002. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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507
12
Soft Tissue Tumors
CHAPTER OUTLINE
Fibroma
Giant Cell Fibroma
Epulis Fissuratum
Inﬂammatory Papillary Hyperplasia
Fibrous Histiocytoma
Fibromatosis
Myoﬁbroma
Oral Focal Mucinosis
Pyogenic Granuloma
Peripheral Giant Cell Granuloma
Peripheral Ossifying Fibroma
Lipoma
Traumatic Neuroma
Palisaded Encapsulated Neuroma
Neurilemoma
Neuroﬁbroma
Neuroﬁbromatosis Type I
Multiple Endocrine Neoplasia Type 2B
Melanotic Neuroectodermal Tumor of Infancy
Paraganglioma
Granular Cell Tumor
Congenital Epulis
CLINICAL FEATURES
Although the irritation ﬁbroma can occur anywhere in
the mouth, the most common location is the buccal
mucosa along the bite line. Presumably, this is a con-
sequence of trauma from biting the cheek (Figs. 12-1
and 12-2). The labial mucosa, tongue, and gingiva also
are common sites (Figs. 12-3 and 12-4). It is likely
that many gingival ﬁbromas represent ﬁbrous matura-
tion of a preexisting pyogenic granuloma. The lesion
FIBROMA (IRRITATION FIBROMA;
TRAUMATIC FIBROMA; FOCAL
FIBROUS HYPERPLASIA;
FIBROUS NODULE)
The ﬁbroma is the most common “tumor” of the oral
cavity. However, it is doubtful that it represents a true
neoplasm in most instances; rather, it is a reactive
hyperplasia of ﬁbrous connective tissue in response to
local irritation or trauma.
Hemangioma and Vascular Malformations
Sturge-Weber Angiomatosis
Nasopharyngeal Angioﬁbroma
Hemangiopericytoma–Solitary Fibrous Tumor
Lymphangioma
Leiomyoma
Rhabdomyoma
Osseous and Cartilaginous Choristomas
SOFT TISSUE SARCOMAS
Fibrosarcoma
Malignant Fibrous Histiocytoma
Liposarcoma
Malignant Peripheral Nerve Sheath Tumor
Olfactory Neuroblastoma
Angiosarcoma
Kaposi’s Sarcoma
Leiomyosarcoma
Rhabdomyosarcoma
Synovial Sarcoma
Alveolar Soft-Part Sarcoma
Metastases to the Oral Soft Tissues `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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508 ORAL AND MAXILLOFACIAL PATHOLOGY
typically appears as a smooth-surfaced pink nodule
that is similar in color to the surrounding mucosa. In
black patients, the mass may demonstrate gray-brown
pigmentation. In some cases the surface may appear
white as a result of hyperkeratosis from continued irri-
tation. Most ﬁbromas are sessile, although some are
pedunculated. They range in size from tiny lesions that
are only a couple of millimeters in diameter to large
masses that are several centimeters across; however,
most ﬁbromas are 1.5 cm or less in diameter. The
lesion usually produces no symptoms, unless second-
ary traumatic ulceration of the surface has occurred.
Irritation ﬁbromas are most common in the fourth to
sixth decades of life, and the male-to-female ratio is
almost 1:2 for cases submitted for biopsy.
The frenal tag is a commonly observed type of
ﬁbrous hyperplasia, which most frequently occurs on
the maxillary labial frenum. Such lesions present as
small, asymptomatic, exophytic growths attached to
the thin frenum surface (Fig. 12-5).
Fig. 12-1 Fibroma. Pink nodule of the posterior buccal
mucosa near the level of the occlusal plane.
Fig. 12-2 Fibroma. Black patient with a smooth-surfaced
pigmented nodule on the buccal mucosa near the
commissure.
Fig. 12-3 Fibroma. Lesion on the lateral border of the
tongue.
Fig. 12-4 Fibroma. Smooth-surfaced, pink nodular mass of
the palatal gingiva between the cuspid and ﬁrst bicuspid.
Fig. 12-5 Frenal tag. A small ﬁngerlike projection of tissue
attached to the maxillary labial frenum. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 12 SOFT TISSUE TUMORS 509
HISTOPATHOLOGIC FEATURES
Microscopic examination of the irritation ﬁbroma
shows a nodular mass of ﬁbrous connective tissue
covered by stratiﬁed squamous epithelium (Figs. 12-6
and 12-7). This connective tissue is usually dense and
collagenized, although in some cases it is looser in
nature. The lesion is not encapsulated; the ﬁbrous
tissue instead blends gradually into the surrounding
connective tissues. The collagen bundles may be
arranged in a radiating, circular, or haphazard fashion.
The covering epithelium often demonstrates atrophy of
the rete ridges because of the underlying ﬁbrous mass.
However, the surface may exhibit hyperkeratosis from
secondary trauma. Scattered inﬂammation may be
seen, most often beneath the epithelial surface. Usually
this inﬂammation is chronic and consists mostly of
lymphocytes and plasma cells.
TREATMENT AND PROGNOSIS
The irritation ﬁbroma is treated by conservative surgical
excision; recurrence is extremely rare. However, it is
important to submit the excised tissue for microscopic
examination because other benign or malignant tumors
may mimic the clinical appearance of a ﬁbroma.
Because frenal tags are small, innocuous growths
that are easily diagnosed clinically, no treatment is
usually necessary.
GIANT CELL FIBROMA
The giant cell ﬁbroma is a ﬁbrous tumor with distinc-
tive clinicopathologic features. Unlike the traumatic
ﬁbroma, it does not appear to be associated with
chronic irritation. The giant cell ﬁbroma represents
approximately 2% to 5% of all oral ﬁbrous proliferations
submitted for biopsy.
CLINICAL FEATURES
The giant cell ﬁbroma is typically an asymptomatic
sessile or pedunculated nodule, usually less than 1 cm
in size (Fig. 12-8). The surface of the mass often appears
papillary; therefore, the lesion may be clinically mis-
taken for a papilloma. Compared with the common
irritation ﬁbroma, the lesion usually occurs at a younger
age. In about 60% of cases, the lesion is diagnosed
during the ﬁrst 3 decades of life. Some studies have
suggested a slight female predilection. Approximately
50% of all cases occur on the gingiva. The mandibular
gingiva is affected twice as often as the maxillary
gingiva. The tongue and palate also are common sites.
Fig. 12-6 Fibroma. Low-power view showing an exophytic
nodular mass of dense ﬁbrous connective tissue.
Fig. 12-7 Fibroma. Higher-power view demonstrating
dense collagen beneath the epithelial surface.
Fig. 12-8 Giant cell ﬁbroma. Exophytic nodule on the
dorsum of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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510 ORAL AND MAXILLOFACIAL PATHOLOGY
The retrocuspid papilla is a microscopically similar
developmental lesion that occurs on the gingiva lingual
to the mandibular cuspid. It is frequently bilateral and
typically appears as a small, pink papule that measures
less than 5 mm in diameter (Fig. 12-9). Retrocuspid
papillae are quite common, having been reported in
25% to 99% of children and young adults. The preva-
lence in older adults drops to 6% to 19%, suggesting that
the retrocuspid papilla represents a normal anatomic
variation that disappears with age.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the giant cell ﬁbroma
reveals a mass of vascular ﬁbrous connective tissue,
which is usually loosely arranged (Fig. 12-10). The hall-
mark is the presence of numerous large, stellate ﬁbro-
blasts within the superﬁcial connective tissue. These
cells may contain several nuclei. Frequently, the surface
of the lesion is pebbly. The covering epithelium often
is thin and atrophic, although the rete ridges may
appear narrow and elongated.
TREATMENT AND PROGNOSIS
The giant cell ﬁbroma is treated by conservative surgi-
cal excision. Recurrence is rare. Because of their char-
acteristic appearance, retrocuspid papillae should be
recognized clinically and do not need to be excised.
EPULIS FISSURATUM (INFLAMMATORY
FIBROUS HYPERPLASIA; DENTURE
INJURY TUMOR; DENTURE EPULIS)
The epulis ﬁssuratum is a tumorlike hyperplasia of
ﬁbrous connective tissue that develops in association
with the ﬂange of an ill-ﬁtting complete or partial
denture. Although the simple term epulis sometimes is
used synonymously for epulis ﬁssuratum, epulis is actu-
ally a generic term that can be applied to any tumor of
the gingiva or alveolar mucosa. Therefore, some authors
have advocated not using this term, preferring to call
these lesions inﬂammatory ﬁbrous hyperplasia or other
descriptive names. However, the term epulis ﬁssuratum
is still widely used today and is well understood by
virtually all clinicians. Other examples of epulides
include the giant cell epulis (peripheral giant cell
granuloma) (see page 520), ossifying ﬁbroid epulis
(peripheral ossifying ﬁbroma) (see page 521), and
congenital epulis (see page 537).
CLINICAL FEATURES
The epulis ﬁssuratum typically appears as a single or
multiple fold or folds of hyperplastic tissue in the alveo-
lar vestibule (Figs. 12-11 and 12-12). Most often, there
are two folds of tissue, and the ﬂange of the associated
denture ﬁts conveniently into the ﬁssure between the
folds. The redundant tissue is usually ﬁrm and ﬁbrous,
although some lesions appear erythematous and ulcer-
Fig. 12-9 Retrocuspid papilla. Bilateral papular lesions on
the gingiva lingual to the mandibular canines (arrows).
Fig. 12-10 Giant cell ﬁbroma. A, Low-power view
showing a nodular mass of ﬁbrous connective tissue covered
by stratiﬁed squamous epithelium. Note the elongation of the
rete ridges. B, High-power view showing multiple large
stellate-shaped and multinucleated ﬁbroblasts.
A
B `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 12 SOFT TISSUE TUMORS 511
vestibule. The epulis ﬁssuratum usually develops on
the facial aspect of the alveolar ridge, although occa-
sional lesions are seen lingual to the mandibular alveo-
lar ridge (Fig. 12-13).
The epulis ﬁssuratum most often occurs in middle-
aged and older adults, as would be expected with a
denture-related lesion. It may occur on either the
maxilla or mandible. The anterior portion of the jaws
is affected much more often than the posterior areas.
There is a pronounced female predilection; most
studies show that two thirds to three fourths of all cases
submitted for biopsy occur in women.
Another similar but less common ﬁbrous hyperpla-
sia, often called a ﬁbroepithelial polyp or leaﬂike
denture ﬁbroma, occurs on the hard palate beneath
a maxillary denture. This characteristic lesion is a ﬂat-
tened pink mass that is attached to the palate by a
narrow stalk (Fig. 12-14). Usually, the ﬂattened mass
is closely applied to the palate and sits in a slightly
cupped-out depression. However, it is easily lifted up
with a probe, which demonstrates its pedunculated
nature. The edge of the lesion often is serrated and
resembles a leaf.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the epulis ﬁssuratum
reveals hyperplasia of the ﬁbrous connective tissue.
Often multiple folds and grooves occur where the
denture impinges on the tissue (Fig. 12-15). The overly-
ing epithelium is frequently hyperparakeratotic and
demonstrates irregular hyperplasia of the rete ridges.
In some instances, the epithelium shows inﬂammatory
papillary hyperplasia (see page 513) or pseudoepithe-
liomatous (pseudocarcinomatous) hyperplasia. Focal
areas of ulceration are not unusual, especially at the
Fig. 12-11 Epulis ﬁssuratum. Hyperplastic folds of tissue
in the anterior maxillary vestibule.
A
B
Fig. 12-12 Epulis ﬁssuratum. A, Several folds of
hyperplastic tissue in the maxillary vestibule. B, An ill-ﬁtting
denture ﬁts into the ﬁssure between two of the folds. (Courtesy
of Dr. William Bruce.)
ated, similar to the appearance of a pyogenic granu-
loma. Occasional examples of epulis ﬁssuratum
demonstrate surface areas of inﬂammatory papillary
hyperplasia (see page 512). The size of the lesion can
vary from localized hyperplasias less than 1 cm in size
to massive lesions that involve most of the length of the
Fig. 12-13 Epulis ﬁssuratum. Redundant folds of tissue
arising in the ﬂoor of the mouth in association with a
mandibular denture. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

512 ORAL AND MAXILLOFACIAL PATHOLOGY
In rare instances, the formation of osteoid or chon-
droid is observed. This unusual-appearing product,
known as osseous and chondromatous metaplasia,
is a reactive phenomenon caused by chronic irritation
by the ill-ﬁtting denture (see page 318). The irregular
nature of this bone or cartilage can be microscopically
disturbing, and the pathologist should not mistake it for
a sarcoma.
The denture-related ﬁbroepithelial polyp has a
narrow core of dense ﬁbrous connective tissue
covered by stratiﬁed squamous epithelium. Like the
epulis ﬁssuratum, the overlying epithelium may be
hyperplastic.
TREATMENT AND PROGNOSIS
The treatment of the epulis ﬁssuratum or ﬁbroepithe-
lial polyp consists of surgical removal, with microscopic
examination of the excised tissue. The ill-ﬁtting denture
should be remade or relined to prevent a recurrence
of the lesion.
INFLAMMATORY PAPILLARY
HYPERPLASIA (DENTURE
PAPILLOMATOSIS)
Inﬂammatory papillary hyperplasia is a reactive
tissue growth that usually, although not always, devel-
ops beneath a denture. Some investigators classify this
lesion as part of the spectrum of denture stomatitis (see
page 216). Although the exact pathogenesis is unknown,
the condition most often appears to be related to the
following:
● An ill-ﬁtting denture
●Poor denture hygiene
●Wearing the denture 24 hours a day
Approximately 20% of patients who wear their den-
tures 24 hours a day have inﬂammatory papillary hyper-
plasia. Candida organisms also have been suggested as a
cause, but any possible role appears uncertain.
CLINICAL FEATURES
Inﬂammatory papillary hyperplasia usually occurs on
the hard palate beneath a denture base (Figs. 12-16
and 12-17). Early lesions may involve only the palatal
vault, although advanced cases cover most of the palate.
Less frequently, this hyperplasia develops on the eden-
tulous mandibular alveolar ridge or on the surface of
an epulis ﬁssuratum. On rare occasions, the condition
occurs on the palate of a patient without a denture,
especially in people who habitually breathe through
their mouth or have a high palatal vault. Candida-
associated palatal papillary hyperplasia also has been
Fig. 12-14 Fibroepithelial polyp. Flattened mass of tissue
arising on the hard palate beneath a maxillary denture; note
its pedunculated nature. Because of its serrated edge, this
lesion also is known as a leaﬂike denture ﬁbroma. Associated
inﬂammatory papillary hyperplasia is visible in the palatal
midline.
Fig. 12-15 Epulis ﬁssuratum. Low-power photomicrograph
demonstrating folds of hyperplastic ﬁbrovascular connective
tissue covered by stratiﬁed squamous epithelium.
base of the grooves between the folds. A variable
chronic inﬂammatory inﬁltrate is present; sometimes,
it may include eosinophils or show lymphoid follicles.
If minor salivary glands are included in the specimen,
then they usually show chronic sialadenitis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 513
reported in dentate patients with human immunodeﬁ-
ciency virus (HIV) infection.
Inﬂammatory papillary hyperplasia is usually
asymptomatic. The mucosa is erythematous and has a
pebbly or papillary surface. Many cases are associated
with denture stomatitis.
HISTOPATHOLOGIC FEATURES
The mucosa in inﬂammatory papillary hyperplasia
exhibits numerous papillary growths on the surface
that are covered by hyperplastic, stratiﬁed squamous
epithelium (Fig. 12-18). In advanced cases, this hyper-
plasia is pseudoepitheliomatous in appearance, and
the pathologist should not mistake it for carcinoma
(Fig. 12-19). The connective tissue can vary from loose
and edematous to densely collagenized. A chronic
inﬂammatory cell inﬁltrate is usually seen, which con-
sists of lymphocytes and plasma cells. Less frequently,
polymorphonuclear leukocytes are also present. If
underlying salivary glands are present, then they often
show sclerosing sialadenitis.
TREATMENT AND PROGNOSIS
For very early lesions of inﬂammatory papillary hyper-
plasia, removal of the denture may allow the erythema
and edema to subside, and the tissues may resume a
more normal appearance. The condition also may
show improvement after topical or systemic antifungal
therapy. For more advanced and collagenized lesions,
many clinicians prefer to excise the hyperplastic tissue
before fabricating a new denture. Various surgical
methods have been used, including the following:
Fig. 12-16 Inﬂammatory papillary hyperplasia.
Erythematous, pebbly appearance of the palatal vault.
Fig. 12-17 Inﬂammatory papillary hyperplasia. An
advanced case exhibiting more pronounced papular lesions
of the hard palate.
Fig. 12-18 Inﬂammatory papillary hyperplasia. Medium-
power view showing ﬁbrous and epithelial hyperplasia
resulting in papillary surface projections. Heavy chronic
inﬂammation is present.
Fig. 12-19 Inﬂammatory papillary hyperplasia. Higher-
power view showing pseudoepitheliomatous hyperplasia of
the epithelium. This epithelium has a bland appearance that
should not be mistaken for carcinoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

514 ORAL AND MAXILLOFACIAL PATHOLOGY
●Partial-thickness or full-thickness surgical blade
excision
● Curettage
● Electrosurgery
● Cryosurgery
● Laser surgery
After surgery, the existing denture can be lined with
a temporary tissue conditioner that acts as a palatal
dressing and promotes greater comfort. After healing,
the patient should be encouraged to leave the new
denture out at night and to keep it clean.
FIBROUS HISTIOCYTOMA
Fibrous histiocytomas are a diverse group of tumors
that exhibit ﬁbroblastic and histiocytic differentia-
tion. Although the cell of origin is still uncertain, it
may arise from the tissue histiocyte, which then
assumes ﬁbroblastic properties. Because of the variable
nature of these lesions, an array of terms has been used
for them, including dermatoﬁbroma, sclerosing
hemangioma, ﬁbroxanthoma, and nodular sub-
epidermal ﬁbrosis. Unlike other ﬁbrous growths
discussed previously in this chapter, the ﬁbrous
histiocytoma is generally considered to represent a
true neoplasm.
CLINICAL FEATURES
The ﬁbrous histiocytoma can develop almost anywhere
in the body. The most common site is the skin of the
extremities, where the lesion is called a dermatoﬁbroma.
Tumors of the oral and perioral region are uncommon.
Although oral tumors can occur at any site, the most
frequent location is the buccal mucosa and vestibule.
Rare intrabony lesions of the jaws have also been
reported. Oral ﬁbrous histiocytomas tend to occur in
middle-aged and older adults; cutaneous examples are
most frequent in young adults. The tumor is usually
a painless nodular mass and can vary in size from a
few millimeters to several centimeters in diameter
(Fig. 12-20). Deeper tumors tend to be larger.
HISTOPATHOLOGIC FEATURES
Microscopically, the ﬁbrous histiocytoma is character-
ized by a cellular proliferation of spindle-shaped ﬁbro-
blastic cells with vesicular nuclei (Figs. 12-21 and
12-22). The margins of the tumor often are not sharply
deﬁned. The tumor cells are arranged in short, inter-
secting fascicles, known as a storiform pattern because
of its resemblance to the irregular, whorled appear-
ance of a straw mat. Rounded histiocyte-like cells,
lipid-containing xanthoma cells, or multinucleated
giant cells can be seen occasionally, as may scattered
Fig. 12-20 Fibrous histiocytoma. Nodular mass on the
dorsum of the tongue.
Fig. 12-21 Fibrous histiocytoma. Low-power view
showing a moderately cellular nodular tumor of the tongue.
Fig. 12-22 Fibrous histiocytoma. High-power view
demonstrating storiform arrangement of spindle-shaped cells
with vesicular nuclei. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 515
lymphocytes. The stroma may demonstrate areas of
myxoid change or focal hyalinization.
TREATMENT AND PROGNOSIS
Local surgical excision is the treatment of choice.
Recurrence is uncommon, especially for superﬁcial
tumors. Larger lesions of the deeper soft tissues have a
greater potential to recur.
FIBROMATOSIS
The ﬁbromatoses are a broad group of ﬁbrous prolif-
erations that have a biologic behavior and histopatho-
logic pattern that is intermediate between those of
benign ﬁbrous lesions and ﬁbrosarcoma. A number of
different forms of ﬁbromatosis are recognized through-
out the body, and they often are named based on their
particular clinicopathologic features. In the soft tissues
of the head and neck, these lesions are frequently
called juvenile aggressive ﬁbromatoses or extraab-
dominal desmoids. Similar lesions within the bone
have been called desmoplastic ﬁbromas (see page
658). Individuals with familial adenomatous polyposis
and Gardner syndrome (see page 651) have a greatly
increased risk for developing aggressive ﬁbromatosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
Soft tissue ﬁbromatosis of the head and neck is a ﬁrm,
painless mass, which may exhibit rapid or insidious
growth (Fig. 12-23). The lesion most frequently occurs
in children or young adults; hence, the term juvenile
ﬁbromatosis. However, cases also have been seen in
middle-aged adults. The most common oral site is the
paramandibular soft tissue region, although the lesion
can occur almost anywhere. The tumor can grow to
considerable size, resulting in signiﬁcant facial disﬁg-
urement. Destruction of adjacent bone may be observed
on radiographs and other imaging studies.
HISTOPATHOLOGIC FEATURES
Soft tissue ﬁbromatosis is characterized by a cellular
proliferation of spindle-shaped cells that are arranged
in streaming fascicles and are associated with a vari-
able amount of collagen (Fig. 12-24). The lesion is
usually poorly circumscribed and inﬁltrates the adja-
cent tissues. Hyperchromatism and pleomorphism of
the cells should not be observed.
TREATMENT AND PROGNOSIS
Because of its locally aggressive nature, the preferred
treatment for soft tissue ﬁbromatosis is wide excision
that includes a generous margin of adjacent normal
tissues. Adjuvant chemotherapy or radiation therapy
sometimes has been used for incompletely resected or
recurrent tumors. A 23% recurrence rate has been
reported for oral and paraoral ﬁbromatosis, but a
higher recurrence rate has been noted for other head
and neck sites. Metastasis does not occur.
MYOFIBROMA (MYOFIBROMATOSIS)
Myoﬁbroma is a rare spindle cell neoplasm that con-
sists of myoﬁbroblasts (i.e., cells with both smooth
muscle and ﬁbroblastic features). Such cells are not
speciﬁc for this lesion, however, because they also can
be identiﬁed in other ﬁbrous proliferations. Most myo-
ﬁbromas occur as solitary lesions, but some patients
develop a multicentric tumor process known as
myoﬁbromatosis.
Fig. 12-23 Fibromatosis. Locally aggressive proliferation of
ﬁbrous connective tissue of the lingual mandibular gingival
mucosa.
Fig. 12-24 Fibromatosis. Streaming fascicles of ﬁbroblastic
cells that demonstrate little pleomorphism. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

516 ORAL AND MAXILLOFACIAL PATHOLOGY
CLINICAL AND RADIOGRAPHIC
FEATURES
Although myoﬁbromas are rare neoplasms, they dem-
onstrate a predilection for the head and neck region.
Solitary tumors develop most frequently in the ﬁrst 4
decades of life, with a mean age of 22 years. The most
common oral location is the mandible, followed by the
tongue and buccal mucosa. The tumor is typically a
painless mass that sometimes exhibits rapid enlarge-
ment. Intrabony tumors create radiolucent defects that
usually tend to be poorly deﬁned, although some may
be well deﬁned or multilocular (Fig. 12-25). Multicen-
tric myoﬁbromatosis primarily affects neonates and
infants who may have tumors of the skin, subcutaneous
tissue, muscle, bone, and viscera. The number of tumors
can vary from several to more than 100.
HISTOPATHOLOGIC FEATURES
Myoﬁbromas are composed of interlacing bundles of
spindle cells with tapered or blunt-ended nuclei and
eosinophilic cytoplasm (Fig. 12-26). Nodular fascicles
may alternate with more cellular zones, imparting a
biphasic appearance to the tumor. Scattered mitoses
are not uncommon. Centrally, the lesion is often more
vascular with a hemangiopericytoma-like appearance.
The tumor cells are positive for smooth muscle actin
and muscle-speciﬁc actin with immunohistochemistry,
but they are negative for desmin.
TREATMENT AND PROGNOSIS
Solitary myoﬁbromas are usually treated by surgical
excision. A small percentage of tumors will recur after
treatment, but typically, these can be controlled with
reexcision. Multifocal tumors arising in soft tissues and
bone rarely recur after surgical excision. Spontaneous
regression may occur in some cases. However, myoﬁ-
bromatosis involving the viscera or vital organs in
infants can act more aggressively and sometimes proves
to be fatal within a few days after birth.
ORAL FOCAL MUCINOSIS
Oral focal mucinosis is an uncommon tumorlike
mass that is believed to represent the oral counterpart
of cutaneous focal mucinosis or a cutaneous myxoid
cyst. The cause is unknown, although the lesion may
result from overproduction of hyaluronic acid by
ﬁbroblasts.
CLINICAL FEATURES
Oral focal mucinosis is most common in young adults
and shows a 2:1 female-to-male predilection. The
gingiva is the most common site; two thirds to three
fourths of all cases are found there. The hard palate is
the second most common location. The mass rarely
appears at other oral sites. The lesion usually presents
as a sessile or pedunculated, painless nodular mass that
is the same color as the surrounding mucosa (Fig.
12-27). The surface is typically smooth and nonulcer-
ated, although occasional cases exhibit a lobulated
appearance. The size varies from a few millimeters up
to 2 cm in diameter. The patient often has been aware
of the mass for many months or years before the diag-
nosis is made.
Fig. 12-25 Myoﬁbroma. Computed tomography (CT) scan
showing an expansile lytic mass of the posterior mandible on
the left side of the illustration. (Courtesy of Dr. Timothy Armanini.)
Fig. 12-26 Myoﬁbromatosis. Proliferation of spindle-
shaped cells with both ﬁbroblastic and smooth muscle
features. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 517
HISTOPATHOLOGIC FEATURES
Microscopic examination of oral focal mucinosis shows
a well-localized but nonencapsulated area of loose,
myxomatous connective tissue surrounded by denser,
normal collagenous connective tissue (Figs. 12-28 and
12-29). The lesion is usually found just beneath the
surface epithelium and often causes ﬂattening of the
rete ridges. The ﬁbroblasts within the mucinous area
can be ovoid, fusiform, or stellate, and they may dem-
onstrate delicate, ﬁbrillar processes. Few capillaries
are seen within the lesion, especially compared with
the surrounding denser collagen. Similarly, no signiﬁ-
cant inﬂammation is observed, although a perivascular
lymphocytic inﬁltrate often is noted within the sur-
rounding collagenous connective tissue. No apprecia-
ble reticulin is evident within the lesion, and special
stains suggest that the mucinous product is hyaluronic
acid.
TREATMENT AND PROGNOSIS
Oral focal mucinosis is treated by surgical excision and
does not tend to recur.
PYOGENIC GRANULOMA
The pyogenic granuloma is a common tumorlike
growth of the oral cavity that traditionally has been
considered to be nonneoplastic in nature.* Although it
was originally thought to be caused by pyogenic organ-
isms, it is now believed to be unrelated to infection.
Instead, the pyogenic granuloma is thought to repre-
sent an exuberant tissue response to local irritation
or trauma. In spite of its name, it is not a true
granuloma.
CLINICAL FEATURES
The pyogenic granuloma is a smooth or lobulated mass
that is usually pedunculated, although some lesions are
sessile (Figs. 12-30 to 12-32). The surface is character-
istically ulcerated and ranges from pink to red to
purple, depending on the age of the lesion. Young pyo-
genic granulomas are highly vascular in appearance;
older lesions tend to become more collagenized and
pink. They vary from small growths only a few millime-
ters in size to larger lesions that may measure several
centimeters in diameter. Typically, the mass is painless,
although it often bleeds easily because of its extreme
vascularity. Pyogenic granulomas may exhibit rapid
Fig. 12-27 Oral focal mucinosis. Nodular mass arising
from the gingiva between the mandibular ﬁrst and second
molars.
Fig. 12-28 Oral focal mucinosis. Low-power view showing
a nodular mass of loose, myxomatous connective tissue.
Fig. 12-29 Oral focal mucinosis. High-power view
demonstrating the myxomatous change.
*However, some pyogenic granulomas (also known as lobular capillary
hemangiomas) currently are categorized as vascular tumors under the clas-
siﬁcation scheme of the International Society for the Study of Vascular
Anomalies (see Box 12-2, page 539). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

518 ORAL AND MAXILLOFACIAL PATHOLOGY
Fig. 12-30 Pyogenic granuloma. Erythematous,
hemorrhagic mass arising from the maxillary anterior gingiva.
Fig. 12-31 Pyogenic granuloma. Ulcerated and lobulated
mass on the dorsum of the tongue.
Fig. 12-32 Pyogenic granuloma. Unusually large lesion
arising from the palatal gingiva in association with an
orthodontic band. The patient was pregnant.
growth, which may create alarm for both the patient
and the clinician, who may fear that the lesion might
be malignant.
Oral pyogenic granulomas show a striking predilec-
tion for the gingiva, which accounts for 75% of all
cases. Gingival irritation and inﬂammation that result
from poor oral hygiene may be a precipitating factor in
many patients. The lips, tongue, and buccal mucosa
are the next most common sites. A history of trauma
before the development of the lesion is not unusual,
especially for extragingival pyogenic granulomas.
Lesions are slightly more common on the maxillary
gingiva than the mandibular gingiva; anterior areas are
more frequently affected than posterior areas. These
lesions are much more common on the facial aspect of
the gingiva than the lingual aspect; some extend
between the teeth and involve both the facial and the
lingual gingiva.
Although the pyogenic granuloma can develop at
any age, it is most common in children and young
adults. Most studies also demonstrate a deﬁnite female
predilection, possibly because of the vascular effects of
female hormones. Pyogenic granulomas of the gingiva
frequently develop in pregnant women, so much so
that the terms pregnancy tumor or granuloma gravidarum
often are used. Such lesions may begin to develop
during the ﬁrst trimester, and their incidence increases
up through the seventh month of pregnancy. The
gradual rise in development of these lesions through-
out pregnancy may be related to the increasing levels
of estrogen and progesterone as the pregnancy pro-
gresses. After pregnancy and the return of normal
hormone levels, some of these pyogenic granulomas
resolve without treatment or undergo ﬁbrous matura-
tion and resemble a ﬁbroma (Fig. 12-33).
Epulis granulomatosa is a term used to describe
hyperplastic growths of granulation tissue that some-
times arise in healing extraction sockets (Fig. 12-34).
These lesions resemble pyogenic granulomas and
usually represent a granulation tissue reaction to bony
sequestra in the socket.
HISTOPATHOLOGIC FEATURES
Microscopic examination of pyogenic granulomas
shows a highly vascular proliferation that resembles
granulation tissue (Figs. 12-35 and 12-36). Numerous
small and larger endothelium-lined channels are
formed that are engorged with red blood cells. These
vessels sometimes are organized in lobular aggregates,
and some pathologists require this lobular arrange-
ment for the diagnosis (lobular capillary hemangioma).
The surface is usually ulcerated and replaced by a thick
ﬁbrinopurulent membrane. A mixed inﬂammatory cell
inﬁltrate of neutrophils, plasma cells, and lymphocytes `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 519
is evident. Neutrophils are most prevalent near the
ulcerated surface; chronic inﬂammatory cells are found
deeper in the specimen. Older lesions may have areas
with a more ﬁbrous appearance. In fact, many gingival
ﬁbromas probably represent pyogenic granulomas that
have undergone ﬁbrous maturation.
TREATMENT AND PROGNOSIS
The treatment of patients with pyogenic granuloma
consists of conservative surgical excision, which is
usually curative. The specimen should be submitted for
microscopic examination to rule out other more serious
diagnoses. For gingival lesions, the excision should
extend down to periosteum and the adjacent teeth
should be thoroughly scaled to remove any source of
continuing irritation. Occasionally, the lesion recurs
and reexcision is necessary. In rare instances, multiple
recurrences have been noted.
For lesions that develop during pregnancy, usually
treatment should be deferred unless signiﬁcant func-
tional or aesthetic problems develop. The recurrence
rate is higher for pyogenic granulomas removed during
pregnancy, and some lesions will resolve spontane-
ously after parturition.
A
B
Fig. 12-33 Pyogenic granuloma. A, Large gingival mass in
a pregnant woman just before childbirth. B, The mass has
decreased in size and undergone ﬁbrous maturation 3
months after childbirth. (Courtesy of Dr. George Blozis.)
Fig. 12-34 Epulis granulomatosa. Nodular mass of
granulation tissue that developed in a recent extraction site.
Fig. 12-35 Pyogenic granuloma. Low-power view showing
an exophytic mass of granulation-like tissue with an ulcerated
surface. Note the lobular endothelial proliferation in the
deeper connective tissue.
Fig. 12-36 Pyogenic granuloma. Higher-power view
showing capillary blood vessels and scattered inﬂammation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

520 ORAL AND MAXILLOFACIAL PATHOLOGY
PERIPHERAL GIANT CELL
GRANULOMA (GIANT CELL EPULIS)
The peripheral giant cell granuloma is a relatively
common tumorlike growth of the oral cavity. It proba-
bly does not represent a true neoplasm but rather is a
reactive lesion caused by local irritation or trauma. In
the past, it often was called a peripheral giant cell repara-
tive granuloma, but any reparative nature appears doubt-
ful. Some investigators believe that the giant cells show
immunohistochemical features of osteoclasts, whereas
other authors have suggested that the lesion is formed
by cells from the mononuclear phagocyte system. The
peripheral giant cell granuloma bears a close micro-
scopic resemblance to the central giant cell granu-
loma (see page 626), and some pathologists believe
that it may represent a soft tissue counterpart of this
central bony lesion.
CLINICAL AND RADIOGRAPHIC
FEATURES
The peripheral giant cell granuloma occurs exclusively
on the gingiva or edentulous alveolar ridge, presenting
as a red or red-blue nodular mass (Figs. 12-37 and
12-38). Most lesions are smaller than 2 cm in diameter,
although larger ones are seen occasionally. The lesion
can be sessile or pedunculated and may or may not be
ulcerated. The clinical appearance is similar to the
more common pyogenic granuloma of the gingiva (see
page 517), although the peripheral giant cell granu-
loma often is more blue-purple compared with the
bright red of a typical pyogenic granuloma.
Peripheral giant cell granulomas can develop at
almost any age, especially during the ﬁrst through
sixth decades of life. The mean age in several large
series ranges from 31 to 41 years. Approximately 60%
of cases occur in females. It may develop in either the
anterior or posterior regions of the gingiva or alveolar
mucosa, and the mandible is affected slightly more
often than the maxilla. Although the peripheral giant
cell granuloma develops within soft tissue, “cupping”
resorption of the underlying alveolar bone sometimes
is seen. On occasion, it may be difﬁcult to determine
whether the mass arose as a peripheral lesion or as a
central giant cell granuloma that eroded through the
cortical plate into the gingival soft tissues.
HISTOPATHOLOGIC FEATURES
Microscopic examination of a peripheral giant cell
granuloma shows a proliferation of multinucleated
giant cells within a background of plump ovoid and
spindle-shaped mesenchymal cells (Figs. 12-39 and
12-40). The giant cells may contain only a few nuclei
or up to several dozen. Some of these cells may have
large, vesicular nuclei; others demonstrate small, pyk-
notic nuclei. Mitotic ﬁgures are fairly common in the
background mesenchymal cells. Abundant hemor-
rhage is characteristically found throughout the mass,
which often results in deposits of hemosiderin pigment,
especially at the periphery of the lesion.
The overlying mucosal surface is ulcerated in about
50% of cases. A zone of dense ﬁbrous connective tissue
usually separates the giant cell proliferation from the
mucosal surface. Adjacent acute and chronic inﬂam-
matory cells are frequently present. Areas of reactive
bone formation or dystrophic calciﬁcations are not
unusual.
TREATMENT AND PROGNOSIS
The treatment of the peripheral giant cell granuloma
consists of local surgical excision down to the underly-
ing bone. The adjacent teeth should be carefully scaled
to remove any source of irritation and to minimize the
risk of recurrence. Approximately 10% of lesions are
reported to recur, and reexcision must be performed.
Fig. 12-37 Peripheral giant cell granuloma. Nodular
blue-purple mass of the mandibular gingiva.
Fig. 12-38 Peripheral giant cell granuloma. Ulcerated
mass of the mandibular gingiva. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 521
On rare occasions, lesions indistinguishable from
peripheral giant cell granulomas have been seen in
patients with hyperparathyroidism (see page 838).
They apparently represent the so-called osteoclastic
brown tumors associated with this endocrine disorder.
However, the brown tumors of hyperparathyroidism
are much more likely to be intraosseous in location and
mimic a central giant cell granuloma.
PERIPHERAL OSSIFYING FIBROMA
(OSSIFYING FIBROID EPULIS;
PERIPHERAL FIBROMA WITH
CALCIFICATION; CALCIFYING
FIBROBLASTIC GRANULOMA)
The peripheral ossifying ﬁbroma is a relatively
common gingival growth that is considered to be reac-
tive rather than neoplastic in nature. The pathogenesis
of this lesion is uncertain. Because of their clinical and
histopathologic similarities, researchers believe that
some peripheral ossifying ﬁbromas develop initially as
pyogenic granulomas that undergo ﬁbrous maturation
and subsequent calciﬁcation. However, not all periph-
eral ossifying ﬁbromas may develop in this manner.
The mineralized product probably has its origin from
cells of the periosteum or periodontal ligament.
Considerable confusion has existed over the nomen-
clature of this lesion, and several terms have been used
to describe its variable histopathologic features. In
the past, the terms peripheral odontogenic ﬁbroma (see
page 727) and peripheral ossifying ﬁbroma often were
used synonymously, but the peripheral odontogenic
ﬁbroma is now considered to be a distinct and separate
entity. In addition, in spite of the similarity in names,
the peripheral ossifying ﬁbroma does not represent the
soft tissue counterpart of the central ossifying ﬁbroma
(see page 646).
CLINICAL FEATURES
The peripheral ossifying ﬁbroma occurs exclusively on
the gingiva. It appears as a nodular mass, either pedun-
culated or sessile, that usually emanates from the inter-
dental papilla (Figs. 12-41 and 12-42). The color ranges
from red to pink, and the surface is frequently, but not
always, ulcerated. The growth probably begins as an
ulcerated lesion; older ones are more likely to demon-
strate healing of the ulcer and an intact surface. Red,
ulcerated lesions often are mistaken for pyogenic gran-
ulomas; the pink, nonulcerated ones are clinically
similar to irritation ﬁbromas. Most lesions are less than
2 cm in size, although larger ones occasionally occur.
The lesion often has been present for many weeks or
months before the diagnosis is made.
The peripheral ossifying ﬁbroma is predominantly a
lesion of teenagers and young adults, with peak preva-
lence between the ages of 10 and 19. Almost two thirds
Fig. 12-39 Peripheral giant cell granuloma. Low-power
view showing a nodular proliferation of multinucleated giant
cells within the gingiva.
Fig. 12-40 Peripheral giant cell granuloma. High-power
view showing scattered multinucleated giant cells within a
hemorrhagic background of ovoid and spindle-shaped
mesenchymal cells.
Fig. 12-41 Peripheral ossifying ﬁbroma. Red, ulcerated
mass of the maxillary gingiva. Such ulcerated lesions are
easily mistaken for a pyogenic granuloma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

522 ORAL AND MAXILLOFACIAL PATHOLOGY
of all cases occur in females. There is a slight predilec-
tion for the maxillary arch, and more than 50% of all
cases occur in the incisor-cuspid region. Usually, the
teeth are unaffected; rarely, there can be migration and
loosening of adjacent teeth.
HISTOPATHOLOGIC FEATURES
The basic microscopic pattern of the peripheral ossify-
ing ﬁbroma is one of a ﬁbrous proliferation associated
with the formation of a mineralized product (Figs.
12-43 and 12-44). If the epithelium is ulcerated, then
the surface is covered by a ﬁbrinopurulent membrane
with a subjacent zone of granulation tissue. The deeper
ﬁbroblastic component often is cellular, especially in
areas of mineralization. In some cases, the ﬁbroblastic
proliferation and associated mineralization is only a
small component of a larger mass that resembles a
ﬁbroma or pyogenic granuloma.
The type of mineralized component is variable and
may consist of bone, cementum-like material, or dys-
trophic calciﬁcations. Frequently, a combination of
products is formed. Usually, the bone is woven and
trabecular in type, although older lesions may demon-
strate mature lamellar bone. Trabeculae of unmineral-
ized osteoid are not unusual. Less frequently, ovoid
droplets of basophilic cementum-like material are
formed. Dystrophic calciﬁcations are characterized
by multiple granules, tiny globules, or large, irregular
masses of basophilic mineralized material. Such dys-
trophic calciﬁcations are more common in early, ulcer-
ated lesions; older, nonulcerated examples are more
likely to demonstrate well-formed bone or cementum.
In some cases, multinucleated giant cells may be found,
usually in association with the mineralized product.
TREATMENT AND PROGNOSIS
The treatment of choice for the peripheral ossifying
ﬁbroma is local surgical excision with submission of
the specimen for histopathologic examination. The
mass should be excised down to periosteum because
Fig. 12-42 Peripheral ossifying ﬁbroma. Pink,
nonulcerated mass arising from the maxillary gingiva. The
remaining roots of the ﬁrst molar are present.
A
B
Fig. 12-43 Peripheral ossifying ﬁbroma. Ulcerated
gingival mass demonstrating focal early mineralization
(arrow).
Fig. 12-44 Peripheral ossifying ﬁbroma. A, Nonulcerated
ﬁbrous mass of the gingiva showing central bone formation.
B, Higher-power view showing trabeculae of bone with
adjacent ﬁbrous connective tissue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 523
recurrence is more likely if the base of the lesion is
allowed to remain. In addition, the adjacent teeth
should be thoroughly scaled to eliminate any possible
irritants. Periodontal surgical techniques, such as repo-
sitioned ﬂaps or connective tissue grafts, may be neces-
sary to repair the gingival defect in an aesthetic manner.
Although excision is usually curative, a recurrence rate
of 8% to 16% has been reported.
LIPOMA
The lipoma is a benign tumor of fat. Although it rep-
resents by far the most common mesenchymal neo-
plasm, most examples occur on the trunk and proximal
portions of the extremities. Lipomas of the oral and
maxillofacial region are much less frequent. The patho-
genesis of lipomas is uncertain, but they appear to be
more common in obese people. However, the metabo-
lism of lipomas is completely independent of the
normal body fat. If the caloric intake is reduced, then
lipomas do not decrease in size, although normal body
fat may be lost.
CLINICAL FEATURES
Oral lipomas are usually soft, smooth-surfaced nodular
masses that can be sessile or pedunculated (Figs. 12-45
and 12-46). Typically, the tumor is asymptomatic and
often has been noted for many months or years before
diagnosis. Most are less than 3 cm in size, but occa-
sional lesions can become much larger. Although a
subtle or more obvious yellow hue often is detected
clinically, deeper examples may appear pink. The
buccal mucosa and buccal vestibule are the most
common intraoral sites and account for 50% of all
cases. Some buccal cases may not represent true
tumors, but rather herniation of the buccal fat pad
through the buccinator muscle, which may occur after
local trauma in young children or subsequent to surgi-
cal removal of third molars in older patients. Less
common sites include the tongue, ﬂoor of the mouth,
and lips. Most patients are 40 years of age or older;
lipomas are uncommon in children. Lipomas of the
oral and maxillofacial region have shown a fairly bal-
anced sex distribution in some studies, although one
recent large series demonstrated a marked male
predilection.
HISTOPATHOLOGIC FEATURES
Most oral lipomas are composed of mature fat cells that
differ little in microscopic appearance from the sur-
rounding normal fat (Figs. 12-47 and 12-48). The
tumor is usually well circumscribed and may demon-
strate a thin ﬁbrous capsule. A distinct lobular arrange-
ment of the cells often is seen. On rare occasions,
central cartilaginous or osseous metaplasia may occur
within an otherwise typical lipoma.
A number of microscopic variants have been
described. The most common of these is the ﬁbroli-
Fig. 12-45 Lipoma. Soft, yellow nodular mass in the ﬂoor
of the mouth. (Courtesy of Dr. Michael Tabor.)
Fig. 12-46 Lipoma. Nodular mass of the posterior buccal
mucosa.
Fig. 12-47 Lipoma. Low-power view of a tumor of the
tongue demonstrating a mass of mature adipose tissue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

524 ORAL AND MAXILLOFACIAL PATHOLOGY
poma, which is characterized by a signiﬁcant ﬁbrous
component intermixed with the lobules of fat cells. The
remaining variants are rare.
The angiolipoma consists of an admixture of mature
fat and numerous small blood vessels. The spindle
cell lipoma demonstrates variable amounts of uni-
form-appearing spindle cells in conjunction with a
more typical lipomatous component. Some spindle
cell lipomas exhibit a mucoid background (myxoid
lipoma) and may be confused with myxoid liposarco-
mas. Pleomorphic lipomas are characterized by the
presence of spindle cells plus bizarre, hyperchromatic
giant cells; they can be difﬁcult to distinguish from a
pleomorphic liposarcoma. Intramuscular (inﬁltrat-
ing) lipomas often are more deeply situated and have
an inﬁltrative growth pattern that extends between
skeletal muscle bundles.
TREATMENT AND PROGNOSIS
Lipomas are treated by conservative local excision, and
recurrence is rare. Most microscopic variants do not
affect the prognosis. Intramuscular lipomas have a
higher recurrence rate because of their inﬁltrative
growth pattern, but this variant is rare in the oral and
maxillofacial region.
TRAUMATIC NEUROMA
(AMPUTATION NEUROMA)
The traumatic neuroma is not a true neoplasm but a
reactive proliferation of neural tissue after transection
or other damage of a nerve bundle. After a nerve has
been damaged or severed, the proximal portion
attempts to regenerate and reestablish innervation of
the distal segment by the growth of axons through
tubes of proliferating Schwann cells. If these regenerat-
ing elements encounter scar tissue or otherwise cannot
reestablish innervation, then a tumorlike mass may
develop at the site of injury.
CLINICAL AND RADIOGRAPHIC
FEATURES
Traumatic neuromas of the oral mucosa are typically
smooth-surfaced, nonulcerated nodules. They can
develop at any location but are most common in the
mental foramen area, tongue, and lower lip (Figs.
12-49 and 12-50). A history of trauma often can be
elicited; some lesions arise subsequent to tooth extrac-
tion or other surgical procedures. Intraosseous trau-
matic neuromas may demonstrate a radiolucent
defect on oral radiographs. Examples also may occur
Fig. 12-48 Lipoma. High-power view showing the
similarity of the tumor cells to normal fat.
Fig. 12-49 Traumatic neuroma. Painful nodule of the
mental nerve as it exits the mental foramen (arrow).
Fig. 12-50 Traumatic neuroma. Note the irregular nodular
proliferation along the mental nerve that is being exposed at
the time of surgery. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 525
at other head and neck sites; it has been estimated
that traumatic neuromas of the greater auricular
nerve develop in 5% to 10% of patients undergoing
surgery for pleomorphic adenomas of the parotid
gland.
Traumatic neuromas can occur at any age, but they
are diagnosed most often in middle-aged adults. They
appear to be slightly more common in women. Many
traumatic neuromas are associated with altered nerve
sensations that can range from anesthesia to dysesthe-
sia to overt pain. Although pain has been traditionally
considered a hallmark of this lesion, studies indicate
that only one fourth to one third of oral traumatic
neuromas are painful. This pain can be intermittent or
constant and ranges from mild tenderness or burning
to severe radiating pain. Neuromas of the mental nerve
are frequently painful, especially when impinged on by
a denture or palpated.
HISTOPATHOLOGIC FEATURES
Microscopic examination of traumatic neuromas shows
a haphazard proliferation of mature, myelinated and
unmyelinated nerve bundles within a ﬁbrous connec-
tive tissue stroma that ranges from densely collage-
nized to myxomatous in nature (Figs. 12-51 and 12-52).
An associated mild chronic inﬂammatory cell inﬁltrate
may be present. Traumatic neuromas with inﬂamma-
tion are more likely to be painful than those without
signiﬁcant inﬂammation.
TREATMENT AND PROGNOSIS
The treatment of choice for the patient with a trau-
matic neuroma is surgical excision, including a small
portion of the involved nerve bundle. Most lesions do
not recur; in some cases, however, the pain persists or
returns at a later date.
PALISADED ENCAPSULATED
NEUROMA (SOLITARY
CIRCUMSCRIBED NEUROMA)
The palisaded encapsulated neuroma is a benign
neural tumor with distinctive clinical and histopatho-
logic features. Although it was ﬁrst recognized only
as recently as 1972, it represents one of the more
common superﬁcial nerve tumors, especially in the
head and neck region. The cause is uncertain, but some
authors have speculated that trauma may play an etio-
logic role; the tumor is generally considered to repre-
sent a reactive lesion rather than a true neoplasm.
CLINICAL FEATURES
The palisaded encapsulated neuroma shows a striking
predilection for the face, which accounts for approxi-
mately 90% of reported cases. The nose and cheek are
the most common speciﬁc sites. The lesion is most fre-
quently diagnosed between the ﬁfth and seventh
decades of life, although the tumor often has been
present for many months or years. It is a smooth-
surfaced, painless, dome-shaped papule or nodule that
is usually less than 1 cm in diameter. There is no sex
predilection.
Oral palisaded encapsulated neuromas are not
uncommon, although many are probably diagnosed
microscopically as neuroﬁbromas or neurilemomas.
The lesion appears most frequently on the hard palate
(Fig. 12-53) and maxillary labial mucosa, although it
also may occur in other oral locations.
HISTOPATHOLOGIC FEATURES
Palisaded encapsulated neuromas appear well circum-
scribed and often encapsulated (Fig. 12-54), although
this capsule may be incomplete, especially along the
Fig. 12-51 Traumatic neuroma. Low-power view showing
the haphazard arrangement of nerve bundles within the
background ﬁbrous connective tissue.
Fig. 12-52 Traumatic neuroma. High-power view showing
cross-sectioned nerve bundles within dense ﬁbrous
connective tissue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

526 ORAL AND MAXILLOFACIAL PATHOLOGY
superﬁcial aspect of the tumor. Some lesions have a
lobulated appearance. The tumor consists of moder-
ately cellular interlacing fascicles of spindle cells that
are consistent with Schwann cells. The nuclei are char-
acteristically wavy and pointed, with no signiﬁcant
pleomorphism or mitotic activity. Although the nuclei
show a similar parallel orientation within the fascicles,
the more deﬁnite palisading and Verocay bodies
typical of the Antoni A tissue of a neurilemoma are
usually not seen. Special stains reveal the presence of
numerous axons within the tumor and the cells show
a positive immunohistochemical reaction for S-100
protein (Fig. 12-55). Because the tumor is not always
encapsulated and the cells are usually not truly pali-
saded, some pathologists prefer solitary circum-
scribed neuroma as a better descriptive term for this
lesion.
TREATMENT AND PROGNOSIS
The treatment for the palisaded encapsulated neuroma
consists of conservative local surgical excision. Recur-
rence is rare. However, speciﬁc recognition of this
lesion is important because it is not associated with
neuroﬁbromatosis or multiple endocrine neoplasia
(MEN) type 2B.
NEURILEMOMA (SCHWANNOMA)
The neurilemoma is a benign neural neoplasm of
Schwann cell origin. It is relatively uncommon,
although 25% to 48% of all cases occur in the head and
neck region. Bilateral neurilemomas of the auditory-
vestibular nerve are a characteristic feature of the
hereditary condition, neuroﬁbromatosis type II
(NF2).
CLINICAL AND RADIOGRAPHIC
FEATURES
The solitary neurilemoma is a slow-growing, encapsu-
lated tumor that typically arises in association with a
nerve trunk. As it grows, it pushes the nerve aside.
Fig. 12-53 Palisaded encapsulated neuroma. Small,
painless nodule of the lateral hard palate.
A
B
Fig. 12-54 Palisaded encapsulated neuroma. A, Low-
power view showing a well-circumscribed, nodular
proliferation of neural tissue. B, Higher-power view
demonstrating spindle cells with wavy nuclei.
Fig. 12-55 Palisaded encapsulated neuroma.
Immunohistochemical reaction demonstrating spindle-shaped
cells that are strongly positive for S-100 protein. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 527
Usually, the mass is asymptomatic, although tender-
ness or pain may occur in some instances. The lesion
is most common in young and middle-aged adults and
can range from a few millimeters to several centime-
ters in size.
The tongue is the most common location for oral
neurilemomas, although the tumor can occur almost
anywhere in the mouth (Fig. 12-56). On occasion, the
tumor arises centrally within bone and may produce
bony expansion. Intraosseous examples are most
common in the posterior mandible and usually appear
as either unilocular or multilocular radiolucencies on
radiographs. Pain and paresthesia are not unusual for
intrabony tumors.
NF2 is an autosomal dominant condition caused by
a mutation of a tumor suppressor gene on chromosome
22, which codes for a protein known as merlin. In addi-
tion to bilateral neurilemomas (“acoustic neuromas”)
of the vestibular nerve, patients also develop neurile-
momas of peripheral nerves, plus meningiomas and
ependymomas of the central nervous system (CNS).
Characteristic symptoms include progressive sensori-
neural deafness, dizziness, and tinnitus.
HISTOPATHOLOGIC FEATURES
The neurilemoma is usually an encapsulated tumor
that demonstrates two microscopic patterns in varying
amounts: (1) Antoni A and (2) Antoni B. Streaming
fascicles of spindle-shaped Schwann cells characterize
Antoni A tissue. These cells often form a palisaded
arrangement around central acellular, eosinophilic
areas known as Verocay bodies (Fig. 12-57). These
Verocay bodies consist of reduplicated basement
membrane and cytoplasmic processes. Antoni B tissue
is less cellular and less organized; the spindle cells
are randomly arranged within a loose, myxomatous
stroma. Typically, neurites cannot be demonstrated
within the tumor mass. The tumor cells will show a
diffuse, positive immunohistochemical reaction for
S-100 protein.
Degenerative changes can be seen in some older
tumors (ancient neurilemomas). These changes consist
of hemorrhage, hemosiderin deposits, inﬂammation,
ﬁbrosis, and nuclear atypia. However, these tumors are
still benign, and the pathologist must be careful not to
mistake these alterations for evidence of a sarcoma.
TREATMENT AND PROGNOSIS
The solitary neurilemoma is treated by surgical exci-
sion, and the lesion should not recur. Malignant trans-
formation does not occur or is extremely rare.
Vestibular schwannomas in patients with NF2 are
difﬁcult to manage. Surgical removal is indicated for
Fig. 12-56 Neurilemoma. Nodular mass in the ﬂoor of the
mouth. (Courtesy of Dr. Art A. Gonty.)
A
B
Fig. 12-57 Neurilemoma. A, Low-power view showing
well-organized Antoni A tissue (right) with adjacent myxoid
and less organized Antoni B tissue (left). B, The Schwann cells
of the Antoni A tissue form a palisaded arrangement around
acellular zones known as Verocay bodies. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

528 ORAL AND MAXILLOFACIAL PATHOLOGY
large symptomatic tumors, but this almost always
results in total deafness and risks facial nerve damage.
Stereotactic radiosurgery may be considered for older
adult or frail patients, as well as for individuals who
decline traditional surgery.
NEUROFIBROMA
The neuroﬁbroma is the most common type of periph-
eral nerve neoplasm. It arises from a mixture of cell
types, including Schwann cells and perineural
ﬁbroblasts.
CLINICAL AND RADIOGRAPHIC
FEATURES
Neuroﬁbromas can arise as solitary tumors or be a
component of neuroﬁbromatosis (see page 529). Soli-
tary tumors are most common in young adults and
present as slow-growing, soft, painless lesions that
vary in size from small nodules to larger masses. The
skin is the most frequent location for neuroﬁbromas,
but lesions of the oral cavity are not uncommon (Figs.
12-58 and 12-59). The tongue and buccal mucosa are
the most common intraoral sites. On rare occasions,
the tumor can arise centrally within bone, where it may
produce a well-demarcated or poorly deﬁned unilocu-
lar or multilocular radiolucency (Fig. 12-60).
HISTOPATHOLOGIC FEATURES
The solitary neuroﬁbroma often is well circumscribed,
especially when the proliferation occurs within the
perineurium of the involved nerve. Tumors that prolif-
erate outside the perineurium may not appear well
demarcated and tend to blend with the adjacent con-
nective tissues.
The tumor is composed of interlacing bundles of
spindle-shaped cells that often exhibit wavy nuclei
(Figs. 12-61 and 12-62). These cells are associated with
delicate collagen bundles and variable amounts of
myxoid matrix. Mast cells tend to be numerous and can
be a helpful diagnostic feature. Sparsely distributed
small axons usually can be demonstrated within the
tumor tissue by using silver stains. Immunohistochemi-
cally, the tumor cells show a scattered, positive reac-
tion for S-100 protein.
TREATMENT AND PROGNOSIS
The treatment for solitary neuroﬁbromas is local surgi-
cal excision, and recurrence is rare. Any patient with a
lesion that is diagnosed as a neuroﬁbroma should be
evaluated clinically for the possibility of neuroﬁbro-
matosis (see next topic). Malignant transformation of
solitary neuroﬁbromas can occur, although the risk
Fig. 12-58 Neuroﬁbroma. Nodular mass of the anterior
ventral tongue. (Courtesy of Dr. Lindsey Douglas.)
Fig. 12-59 Neuroﬁbroma. Huge tumor involving the
maxillary gingiva and hard palate.
Fig. 12-60 Neuroﬁbroma. Intraosseous tumor ﬁlling the
right mandibular ramus. (Courtesy of Dr. Paul Allen.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 529
CLINICAL AND RADIOGRAPHIC
FEATURES
The diagnostic criteria for NF1 are summarized in Box
12-1. Patients have multiple neuroﬁbromas that can
occur anywhere in the body but are most common on
the skin. The clinical appearance can vary from small
papules to larger soft nodules to massive baggy, pendu-
lous masses (elephantiasis neuromatosa) on the skin
(Figs. 12-63 and 12-64). The plexiform variant of neu-
roﬁbroma, which feels like a “bag of worms,” is consid-
ered pathognomonic for NF1. The tumors may be
present at birth, but they often begin to appear during
puberty and may continue to develop slowly through-
out adulthood. Accelerated growth may be seen during
appears to be remote, especially compared with that in
patients with neuroﬁbromatosis.
NEUROFIBROMATOSIS TYPE I (VON
RECKLINGHAUSEN’S DISEASE OF
THE SKIN)
Neuroﬁbromatosis is a relatively common hereditary
condition that is estimated to occur in one of every
3000 births. At least eight forms of neuroﬁbromatosis
have been recognized, but the most common form is
neuroﬁbromatosis type I (NF1), which is discussed
here. This form of the disease, also known as von
Recklinghausen’s disease of the skin, accounts for
85% to 97% of cases and is inherited as an autosomal
dominant trait (although 50% of all patients have no
family history and apparently represent new muta-
tions). It is caused by a variety of mutations of the NF1
gene, which is located on chromosome region 17q11.2
and is responsible for a tumor suppressor protein
product known as neuroﬁbromin.
Fig. 12-61 Neuroﬁbroma. Low-power view showing a
cellular tumor mass below the epithelial surface.
Fig. 12-62 Neuroﬁbroma. High-power view showing
spindle-shaped cells with wavy nuclei.
Fig. 12-63 Neuroﬁbromatosis type I. Multiple tumors of
the trunk and arms.
Box 12-1
Diagnostic Criteria for
Neuroﬁbromatosis Type I (NF1)
The diagnostic criteria are met if a patient has two or
more of the following features:
1. Six or more café au lait macules more than 5 mm in
greatest diameter in prepubertal persons and more
than 15 mm in greatest diameter in postpubertal
persons
2.Two or more neuroﬁbromas of any type or one
plexiform neuroﬁbroma
3.Freckling in the axillary or inguinal regions
4.Optic glioma
5.Two or more Lisch nodules (iris hamartomas)
6.A distinctive osseous lesion such as sphenoid
dysplasia or thinning of long bone cortex with or
without pseudoarthrosis
7.A ﬁrst-degree relative (parent, sibling, or offspring)
with NF1, based on the previously mentioned
criteria `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

530 ORAL AND MAXILLOFACIAL PATHOLOGY
pregnancy. There is a wide variability in the expression
of the disease. Some patients have only a few neuroﬁ-
bromas; others have literally hundreds or thousands of
tumors. However, two thirds of patients have relatively
mild disease.
Another highly characteristic feature is the presence
of café au lait (coffee with milk) pigmentation on the
skin (Fig. 12-65). These spots are smooth-edged, yellow-
tan to dark-brown macules that vary in diameter from
1 to 2 mm to several centimeters. They are usually
present at birth or may develop during the ﬁrst year of
life. Axillary freckling (Crowe’s sign) is also a highly
suggestive sign.
Lisch nodules, translucent brown-pigmented spots
on the iris, are found in nearly all affected individuals.
The most common general medical problem is hyper-
tension, which may develop secondary to coarctation
of the aorta, pheochromocytoma, or renal artery steno-
Fig. 12-64 Neuroﬁbromatosis type I. Baggy, pendulous
neuroﬁbroma of the lower neck.
Fig. 12-65 Neuroﬁbromatosis type I. Same patient as
depicted in Fig. 12-63. Note the café au lait pigmentation on
the arm.
Fig. 12-66 Neuroﬁbromatosis type I. Intraoral
involvement characterized by unilateral enlargement of the
tongue.
sis. Other possible abnormalities include CNS tumors,
macrocephaly, mental deﬁciency, seizures, short
stature, and scoliosis.
In the past, oral lesions were estimated to occur in
4% to 7% of cases (Fig. 12-66). However, two studies
suggest that oral manifestations may occur in as many
as 72% to 92% of cases, especially if a detailed clinical
and radiographic examination is performed. The most
common reported ﬁnding is enlargement of the fungi-
form papillae (in about 50% of all affected patients);
however, the speciﬁcity of this ﬁnding for neuroﬁbro-
matosis is unknown. Only about 25% of patients exam-
ined in these two studies exhibited actual intraoral
neuroﬁbromas. Radiographic ﬁndings may include
enlargement of the mandibular foramen, enlargement
or branching of the mandibular canal, increased bone
density, concavity of the medial surface of the ramus,
and increase in dimension of the coronoid notch.
Several unusual clinical variants of NF1 have been
described. On occasion, the condition can include uni-
lateral enlargement that mimics hemifacial hyperpla-
sia (see page 38). In addition, several patients with NF1
have been described with associated Noonan syndrome
or with central giant cell granulomas of the jaw.
TREATMENT AND PROGNOSIS
There is no speciﬁc therapy for NF1, and treatment
often is directed toward prevention or management of
complications. Facial neuroﬁbromas can be removed `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 531
for cosmetic purposes. Carbon dioxide (CO
2) laser and
dermabrasion have been used successfully for exten-
sive lesions.
One of the most feared complications is the develop-
ment of cancer, most often a malignant peripheral
nerve sheath tumor (neuroﬁbrosarcoma; malig-
nant schwannoma), which has been reported to occur
in about 5% of cases. These tumors are most common
on the trunk and extremities, although head and neck
involvement is occasionally seen (Figs. 12-67 to
12-69). The prognosis for malignant peripheral nerve
sheath tumors associated with neuroﬁbromatosis is
poor, with a 5-year survival rate of only 15%. Other
malignancies also have been associated with neuroﬁ-
bromatosis, including CNS tumors, pheochromocy-
toma, leukemia, rhabdomyosarcoma, and Wilms’
tumor. The average lifespan of individuals with NF1 is
15 years less than the general population, mostly
related to vascular disease and malignant neoplasms.
In recent years, there has been considerable interest
in Joseph (not John) Merrick, the so-called Elephant
Man. Although Merrick once was mistakenly consid-
ered to have neuroﬁbromatosis, it is now generally
accepted that his horribly disﬁgured appearance was
not because of neuroﬁbromatosis, but that he most
likely had a rare condition known as Proteus syn-
drome. Because patients with neuroﬁbromatosis may
fear acquiring a similar clinical appearance, they
should be reassured that they have a different condi-
tion. The phrase “Elephant Man disease” is incorrect
and misleading, and it should be avoided. Genetic
counseling is extremely important for all patients with
neuroﬁbromatosis.
Fig. 12-67 Neuroﬁbromatosis type I. Malignant peripheral
nerve sheath tumor of the left cheek in a patient with type I
neuroﬁbromatosis. (From Neville BW, Hann J, Narang R et al: Oral
neuroﬁbrosarcoma associated with neuroﬁbromatosis type I, Oral Surg Oral
Med Oral Pathol 72:456-461, 1991.)
Fig. 12-68 Neuroﬁbromatosis type I. Same patient as
depicted in Fig. 12-67. Note the intraoral appearance of
malignant peripheral nerve sheath tumor of the mandibular
buccal vestibule. The patient eventually died of this tumor.
(From Neville BW, Hann J, Narang R et al: Oral neuroﬁbrosarcoma
associated with neuroﬁbromatosis type I, Oral Surg Oral Med Oral Pathol
72:456-461, 1991.)
Fig. 12-69 Malignant peripheral nerve sheath tumor.
High-power view of an intraoral tumor that developed in a
patient with neuroﬁbromatosis type I. There is a cellular
spindle cell proliferation with numerous mitotic ﬁgures. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

532 ORAL AND MAXILLOFACIAL PATHOLOGY
MULTIPLE ENDOCRINE NEOPLASIA
TYPE 2B (MULTIPLE ENDOCRINE
NEOPLASIA TYPE 3; MULTIPLE
MUCOSAL NEUROMA SYNDROME)
The multiple endocrine neoplasia (MEN) syn-
dromes are a group of rare conditions characterized by
tumors or hyperplasias of the neuroendocrine tissues.
For example, patients with MEN type 1 have benign
tumors of the pancreatic islets, adrenal cortex, parathy-
roid glands, and pituitary gland. MEN type 2A, also
known as Sipple syndrome. includes the development
of adrenal pheochromocytomas and medullary thyroid
carcinoma. In addition to pheochromocytomas and
medullary thyroid carcinoma, patients with MEN type
2B have mucosal neuromas that especially involve the
oral mucous membranes. Because oral manifestations
are most prominent in MEN type 2B, the remainder of
the discussion is limited to this condition.
Similar to the other MEN syndromes, MEN type 2B
is inherited as an autosomal dominant trait. However,
researchers believe that 50% of cases represent
spontaneous mutations. The condition is caused by a
mutation of the RET protooncogene on chromosome
10, which has been detected in 95% of affected
individuals.
CLINICAL FEATURES
Patients with MEN type 2B usually have a marfanoid
body build characterized by thin, elongated limbs with
muscle wasting. The face is narrow, but the lips are
characteristically thick and protuberant because of the
diffuse proliferation of nerve bundles. The upper eyelid
sometimes is everted because of thickening of the tarsal
plate (Fig. 12-70). Small, pedunculated neuromas may
be observable on the conjunctiva, eyelid margin, or
cornea.
Oral mucosal neuromas are usually the ﬁrst sign of
the condition. These neuromas appear as soft, painless
papules or nodules that principally affect the lips and
anterior tongue but also may be seen on the buccal
mucosa, gingiva, and palate (Fig. 12-71). Bilateral
neuromas of the commissural mucosa are highly
characteristic.
Pheochromocytomas of the adrenal glands develop
in at least 50% of all patients and become more preva-
lent with increasing age. These neuroendocrine tumors
are frequently bilateral or multifocal. The tumor cells
secrete catecholamines, which result in symptoms
such as profuse sweating, intractable diarrhea, head-
aches, ﬂushing, heart palpitations, and severe
hypertension.
The most signiﬁcant aspect of this condition is the
development of medullary carcinoma of the thyroid
gland, which occurs in more than 90% of cases. This
aggressive tumor arises from the parafollicular cells
(C cells), which are responsible for calcitonin produc-
tion. Medullary carcinoma most often is diagnosed in
patients between the ages of 18 and 25, and it shows
a marked propensity for metastasis. The average age at
death from this neoplasm is 21 years.
Fig. 12-70 Multiple endocrine neoplasia (MEN) type 2B.
Note the narrow face and eversion of the upper eyelids.
Fig. 12-71 Multiple endocrine neoplasia (MEN) type 2B.
Multiple neuromas along the anterior margin of the tongue
and bilaterally at the commissures. (Courtesy of Dr. Emmitt
Costich.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 533
LABORATORY VALUES
If medullary carcinoma of the thyroid gland is present,
then serum or urinary levels of calcitonin are elevated.
An increase in calcitonin levels may herald the onset
of the tumor, and calcitonin also can be monitored to
detect local recurrences or metastases after treatment.
Pheochromocytomas may result in increased levels of
urinary vanillylmandelic acid (VMA) and increased
epinephrine-to-norepinephrine ratios.
HISTOPATHOLOGIC FEATURES
The mucosal neuromas are characterized by marked
hyperplasia of nerve bundles in an otherwise normal
or loose connective tissue background (Figs. 12-72 and
12-73). Prominent thickening of the perineurium is
typically seen.
TREATMENT AND PROGNOSIS
The prognosis for patients with MEN type 2B centers
on early recognition of the oral features, given the
serious nature of the medullary thyroid carcinoma.
Some investigators advocate prophylactic removal of
the thyroid gland at an early age because medullary
carcinoma is almost certain to occur. Once it has devel-
oped, this tumor often exhibits an aggressive behavior
with a poor prognosis. The patient also should be
observed for the development of pheochromocytomas
because they may result in a life-threatening hyperten-
sive crisis, especially if surgery with general anesthesia
is performed.
MELANOTIC NEUROECTODERMAL
TUMOR OF INFANCY
The melanotic neuroectodermal tumor of infancy
is a rare pigmented neoplasm that usually occurs
during the ﬁrst year of life. It is generally accepted that
this lesion is of neural crest origin. In the past, however,
a number of tissues were suggested as possible sources
of this tumor. These included odontogenic epithelium
and retina, which resulted in various older terms for
this entity, such as pigmented ameloblastoma,
retinal anlage tumor, and melanotic progonoma.
Because these names are inaccurate, however, they
should no longer be used. Melanotic (pigmented) neuroec-
todermal tumor of infancy is the preferred term.
CLINICAL AND RADIOGRAPHIC
FEATURES
Melanotic neuroectodermal tumor of infancy almost
always develops in young children during the ﬁrst year
of life; only 9% of cases are diagnosed after the age of
12 months. There is a striking predilection for the
maxilla, which accounts for 61% of reported cases. Less
frequently reported sites include the skull (16%), epi-
didymis and testis (9%), mandible (6%), and brain (6%).
A slight male predilection has been noted.
The lesion is most common in the anterior region of
the maxilla, where it classically appears as a rapidly
expanding mass that is frequently blue or black (Fig.
12-74). The tumor often destroys the underlying bone
and may be associated with displacement of the devel-
oping teeth (Fig. 12-75). In some instances, there may
be an associated osteogenic reaction, which exhibits a
“sun ray” radiographic pattern that can be mistaken for
osteosarcoma.
Fig. 12-72 Multiple endocrine neoplasia (MEN) type 2B.
Low-power view of an oral mucosal neuroma showing
marked hyperplasia of nerve bundles.
Fig. 12-73 Multiple endocrine neoplasia (MEN) type 2B.
High-power view of the same neuroma as depicted in Fig.
12-72. Note the prominent thickening of the perineurium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

534 ORAL AND MAXILLOFACIAL PATHOLOGY
LABORATORY VALUES
High urinary levels of vanillylmandelic acid (VMA)
often are found in patients with melanotic neuroecto-
dermal tumor of infancy. These levels may return to
normal once the tumor has been resected. This ﬁnding
supports the hypothesis of neural crest origin because
other tumors from this tissue (e.g., pheochromocytoma,
neuroblastoma) often secrete norepinephrine-like hor-
mones that are metabolized to VMA and excreted in
the urine.
HISTOPATHOLOGIC FEATURES
The tumor consists of a biphasic population of cells that
form nests, tubules, or alveolar structures within a
dense, collagenous stroma (Figs. 12-76 and 12-77).
The alveolar and tubular structures are lined by
cuboidal epithelioid cells that demonstrate vesicular
nuclei and granules of dark-brown melanin pigment.
The second cell type is neuroblastic in appearance
and consists of small, round cells with hyperchro-
matic nuclei and little cytoplasm. These cells grow
in loose nests and are frequently surrounded by the
larger pigment-producing cells. Mitotic ﬁgures are
rare.
Because of the tumor’s characteristic microscopic
features, immunohistochemistry usually is not essen-
tial to establish the diagnosis. However, the larger epi-
thelioid cells typically are positive for cytokeratin and
also may express neuron-speciﬁc enolase. In addition,
the smaller cells usually are positive for neuron- speciﬁc
enolase and CD56, and sometimes they will express
Fig. 12-74 Melanotic neuroectodermal tumor of infancy.
Infant with an expansile mass of the anterior maxilla. (From
Steinberg B, Shuler C, Wilson S: Melanotic neuroectodermal tumor of
infancy: evidence for multicentricity, Oral Surg Oral Med Oral Pathol
66:666-669, 1988.)
Fig. 12-75 Melanotic neuroectodermal tumor of infancy.
Radiolucent destruction of the anterior maxilla associated
with displacement of the developing teeth. (Courtesy of Dr. Len
Morrow.)
Fig. 12-76 Melanotic neuroectodermal tumor of infancy.
Low-power view showing nests of epithelioid cells within a
ﬁbrous stroma.
Fig. 12-77 Melanotic neuroectodermal tumor of infancy.
High-power view of a tumor nest demonstrating two cell
types: (1) small, hyperchromatic round cells and (2) larger
epithelioid cells with vesicular nuclei. Some stippled melanin
pigment is also present. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 535
other neuroendocrine markers such as glial ﬁbrillary
acidic protein and synaptophysin.
TREATMENT AND PROGNOSIS
Despite their rapid growth and potential to destroy
bone, most melanotic neuroectodermal tumors of
infancy are benign. The lesion is best treated by surgi-
cal removal. Some clinicians prefer simple curettage,
although others advocate that a 5-mm margin of normal
tissue be included with the specimen. Recurrence of
the tumor has been reported in about 20% of cases. In
addition, about 6% of reported cases, mostly from the
brain or skull, have acted in a malignant fashion, result-
ing in metastasis and death. Although this estimation
of 6% is probably high (because unusual malignant
cases are more likely to be reported), it underscores the
potentially serious nature of this tumor and the need
for careful clinical evaluation and follow-up of affected
patients.
PARAGANGLIOMA (CAROTID BODY
TUMOR; CHEMODECTOMA; GLOMUS
JUGULARE TUMOR; GLOMUS
TYMPANICUM TUMOR)
The paraganglia are specialized tissues of neural crest
origin that are associated with the autonomic nerves
and ganglia throughout the body. Some of these cells
act as chemoreceptors, such as the carotid body (located
at the carotid bifurcation), which can detect changes in
blood pH or oxygen tension and subsequently cause
changes in respiration and heart rate. Tumors that
arise from these structures are collectively known as
paragangliomas, with the term preferably preceded
by the anatomic site at which they are located. There-
fore, tumors of the carotid body are appropriately
known as carotid body paragangliomas (carotid
body tumors); those that develop in the temporal
bone and middle ear are called jugulotympanic
paragangliomas. Jugulotympanic paragangliomas also
are commonly known as glomus jugulare tumors,
although some authors prefer to reserve this term only
for those examples that arise from the jugular bulb and
to use the term glomus tympanicum tumors for those
that arise in the middle ear.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although paragangliomas are rare, the head and
neck area is the most common site for these lesions.
The most common paraganglioma is the carotid body
tumor, which develops at the bifurcation of the internal
and external carotid arteries. This tumor usually occurs
in middle-aged adults. Most often it is a slowly enlarg-
ing, painless mass of the upper lateral neck below the
angle of the jaw. It is seen more frequently in patients
who live at high altitudes, indicating that some cases
may arise from chronic hyperplasia of the carotid body
in response to lower oxygen levels. Angiography can
help to localize the tumor and demonstrate its charac-
teristic vascular nature.
Jugulotympanic paragangliomas are the second most
common type of these tumors. They also are most
frequent in middle-aged individuals but show a 2:1
female predilection. The most common symptoms
include dizziness, tinnitus (a ringing or other noise in
the ear), hearing loss, and cranial nerve palsies. Imaging
studies, especially three-dimensional (3D) time-of-ﬂight
magnetic resonance angiography, can help to detect
and characterize such lesions. Other less common para-
gangliomas of the head and neck include vagal, naso-
pharyngeal, laryngeal, and orbital paragangliomas.
Approximately 10% to 20% of affected patients have
multifocal tumors. In 10% of all cases, there is a family
history of such tumors, with an autosomal dominant
pattern of inheritance that is modiﬁed by genomic
imprinting. The gene responsible for familial paragan-
gliomas has been mapped to chromosome 11q23. In
genomic imprinting, the gene is transmitted in a men-
delian manner, but expression of that gene is deter-
mined by the sex of the transmitting parent. Paternal
transmission results in development of tumors in the
offspring, even if the father is clinically unaffected.
Maternal transmission does not result in development
of tumors in the offspring, although these children will
carry the gene and have the ability to pass it down to
subsequent generations. Hereditary cases have an even
greater chance of being multicentric; about one third
of affected patients have more than one tumor.
HISTOPATHOLOGIC FEATURES
The paraganglioma is characterized by round or polyg-
onal epithelioid cells that are organized into nests
or zellballen (Fig. 12-78). The overall architecture is
similar to that of the normal paraganglia, except the
zellballen are usually larger and more irregular in shape.
These nests consist primarily of chief cells, which
demonstrate centrally located, vesicular nuclei and
somewhat granular, eosinophilic cytoplasm. The tumor
is typically vascular and may be surrounded by a thin
ﬁbrous capsule.
TREATMENT AND PROGNOSIS
The treatment of paragangliomas may include surgery,
radiation therapy, or both, depending on the extent
and location of the tumor. Localized carotid body para- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

536 ORAL AND MAXILLOFACIAL PATHOLOGY
gangliomas often can be treated by surgical excision
with maintenance of the vascular tree. If the carotid
artery is encased by tumor, it also may need to be
resected, followed by vascular grafting. Radiation
therapy may be used as adjunctive treatment or for
unresectable carotid body tumors.
Although most carotid body paragangliomas are
benign and can be controlled with surgery and radia-
tion therapy, vascular complications can lead to con-
siderable surgical morbidity or mortality. In addition,
6% to 9% of carotid body paragangliomas metastasize,
either to regional lymph nodes or distant sites. Unfor-
tunately, it is usually difﬁcult to predict which tumors
will act in a malignant fashion based on their micro-
scopic features. Because such metastases may develop
many years after the original diagnosis is made, long-
term follow-up is important.
Because of their location near the base of the brain,
jugulotympanic paragangliomas are more difﬁcult to
manage. Recent advances in both diagnostic radiology
and neurosurgery have greatly improved the potential
for resection of these tumors. Radiation therapy may
be used in conjunction with surgery or as a primary
treatment for unresectable tumors. Stereotactic radio-
surgery (gamma knife treatment) has shown promise
in the management of primary or recurrent glomus
jugulare tumors in patients who are poor surgical can-
didates. This technique allows the delivery of a focused,
large, single dose of radiation under stereotactic guid-
ance. Malignant behavior has been documented in
approximately 4% of jugulotympanic paragangliomas.
GRANULAR CELL TUMOR
The granular cell tumor is an uncommon benign soft
tissue neoplasm that shows a predilection for the oral
cavity. The histogenesis of this lesion has long been
debated. Originally, it was believed to be of skeletal
muscle origin and was called the granular cell myoblas-
toma. However, more recent investigations do not
support a muscle origin but point to a derivation from
Schwann cells (granular cell schwannoma) or neu-
roendocrine cells. At present, it seems best to use the
noncommittal term granular cell tumor for this
lesion.
CLINICAL FEATURES
Granular cell tumors are most common in the oral
cavity and on the skin. The single most common site is
the tongue, which accounts for one third to half of all
reported cases. Tongue lesions most often occur on the
dorsal surface. The buccal mucosa is the second most
common intraoral location. The tumor most frequently
occurs in the fourth to sixth decades of life and is rare
in children. There is a 2:1 female predilection.
The granular cell tumor is typically an asymptom-
atic sessile nodule that is usually 2 cm or less in size
(Figs. 12-79 and 12-80). The lesion often has been
noted for many months or years, although sometimes
the patient is unaware of its presence. The mass is typi-
cally pink, but occasional granular cell tumors appear
yellow. The granular cell tumor is usually solitary,
although multiple, separate tumors sometimes occur,
especially in black patients.
HISTOPATHOLOGIC FEATURES
The granular cell tumor is composed of large, polygo-
nal cells with abundant pale eosinophilic, granular
cytoplasm and small, vesicular nuclei (Fig. 12-81). The
cells are usually arranged in sheets, but they also may
be found in cords and nests. The cell borders often are
indistinct, which results in a syncytial appearance. The
lesion is not encapsulated and sometimes appears to
Fig. 12-78 Carotid body tumor. Nested arrangement of
tumor cells.
Fig. 12-79 Granular cell tumor. Submucosal nodule on
the dorsum of the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 537
inﬁltrate the adjacent connective tissues. Often, there
appears to be a transition from normal adjacent skele-
tal muscle ﬁbers to granular tumor cells; this ﬁnding
led earlier investigators to suggest a muscle origin for
this tumor. Less frequently, one may see groups of
granular cells that envelop small nerve bundles. Immu-
nohistochemical analysis reveals positivity for S-100
protein within the cells—a ﬁnding that is supportive,
but not diagnostic, of neural origin.
An unusual and signiﬁcant microscopic ﬁnding is
the presence of acanthosis or pseudoepitheliomatous
(pseudocarcinomatous) hyperplasia of the overlying
epithelium, which has been reported in up to 50% of
all cases (Fig. 12-82). Although this hyperplasia is
usually minor in degree, in some cases it may be so
striking that it results in a mistaken diagnosis of squa-
mous cell carcinoma and subsequent unnecessary
cancer surgery. The pathologist must be aware of this
possibility, especially when dealing with a superﬁcial
biopsy sample or a specimen from the dorsum of the
tongue—an unusual location for oral cancer.
TREATMENT AND PROGNOSIS
The granular cell tumor is best treated by conservative
local excision, and recurrence is uncommon. Extremely
rare examples of malignant granular cell tumor have
been reported.
CONGENITAL EPULIS (CONGENITAL
EPULIS OF THE NEWBORN;
CONGENITAL GRANULAR
CELL LESION)
The congenital epulis is an uncommon soft tissue
tumor that occurs almost exclusively on the alveolar
ridges of newborns. It is often known by the redundant
term, congenital epulis of the newborn. Rare exam-
ples also have been described on the tongue; therefore,
some authors prefer using the term congenital granu-
lar cell lesion, because not all cases present as an
epulis on the alveolar ridge. It also has been called
gingival granular cell tumor of the newborn, but
this term should be avoided. Although it bears a light
microscopic resemblance to the granular cell tumor
(discussed previously), it exhibits ultrastructural and
immunohistochemical differences that warrant its
classiﬁcation as a distinct and separate entity. However,
the histogenesis of this tumor is still uncertain.
CLINICAL FEATURES
The congenital epulis typically appears as a pink-to-
red, smooth-surfaced, polypoid mass on the alveolar
ridge of a newborn (Fig. 12-83). Most examples are
Fig. 12-80 Granular cell tumor. Nodular mass of the
buccal mucosa near the commissure.
Fig. 12-81 Granular cell tumor. Medium-high–power view
showing polygonal cells with abundant granular cytoplasm.
Fig. 12-82 Granular cell tumor. Marked pseudoepithelio-
matous hyperplasia overlying a granular cell tumor. Such
cases may easily be mistaken for squamous cell carcinoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

538 ORAL AND MAXILLOFACIAL PATHOLOGY
2 cm or less in size, although lesions as large as 7.5 cm
have been reported. On occasion, the tumor has been
detected in utero via ultrasound examination. Multiple
tumors develop in 10% of cases. A few rare examples
on the tongue have been described in infants who also
had alveolar tumors.
The tumor is two to three times more common on
the maxillary ridge than on the mandibular ridge. It
most frequently occurs lateral to the midline in the
area of the developing lateral incisor and canine teeth.
The congenital epulis shows a striking predilection
for females, which suggests a hormonal inﬂuence in
its development, although estrogen and progesterone
receptors have not been detected. Nearly 90% of cases
occur in females.
HISTOPATHOLOGIC FEATURES
The congenital epulis is characterized by large, rounded
cells with abundant granular, eosinophilic cytoplasm
and round to oval, lightly basophilic nuclei (Figs. 12-84
and 12-85). In older tumors, these cells may become
elongated and separated by ﬁbrous connective tissue.
In contrast to the granular cell tumor, the overlying
epithelium never shows pseudoepitheliomatous hyper-
plasia but typically demonstrates atrophy of the rete
ridges. In addition, in contradistinction to the granular
cell tumor, immunohistochemical analysis shows the
tumor cells to be negative for S-100 protein.
TREATMENT AND PROGNOSIS
The congenital epulis is usually treated by surgical exci-
sion. The lesion never has been reported to recur, even
with incomplete removal.
After birth, the tumor appears to stop growing and
may even diminish in size. Eventual complete regres-
sion has been reported in a few patients, even without
treatment (Fig. 12-86).
HEMANGIOMA AND VASCULAR
MALFORMATIONS
In recent years, great progress has been made in the
classiﬁcation and understanding of tumors and tumor-
like proliferations of vascular origin. A modiﬁed clas-
siﬁcation scheme for these vascular anomalies is
presented in Box 12-2.
The term hemangioma has traditionally been used
to describe a variety of developmental vascular anoma-
lies. Currently, hemangiomas are considered to be
benign tumors of infancy that display a rapid growth
phase with endothelial cell proliferation, followed by
gradual involution. Most hemangiomas cannot be rec-
ognized at birth, but arise subsequently during the ﬁrst
8 weeks of life. On the other hand, vascular malfor-
Fig. 12-83 Congenital epulis. Polypoid mass of the
anterior maxillary alveolar ridge in a newborn.
Fig. 12-84 Congenital epulis. Low-power photomicro-
graph showing a nodular tumor mass. Note the atrophy of
the rete ridges.
Fig. 12-85 Congenital epulis. High-power view of rounded
cells with abundant granular cytoplasm. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 539
dull-purple hue and the lesion feels less ﬁrm to palpa-
tion. By age 5, most of the red color is usually gone.
About half of all hemangiomas will show complete
resolution by 5 years of age, with 90% resolving by
age 9. After tumor regression is complete, normal
skin will be restored in about 50% of patients; however,
up to 40% of affected individuals will show perma-
nent changes such as atrophy, scarring, wrinkling, or
telangiectasias.
BA
mations are structural anomalies of blood vessels
without endothelial proliferation. By deﬁnition,
vascular malformations are present at birth and persist
throughout life. They can be categorized according to
the type of vessel involved (capillary, venous, arteriove-
nous) and according to hemodynamic features (low
ﬂow or high ﬂow).
CLINICAL AND RADIOGRAPHIC
FEATURES
HEMANGIOMA OF INFANCY
Hemangiomas are the most common tumors of infancy,
occurring in 5% to 10% of 1-year-old children. They are
much more common in females than in males (ratio:
3:1 to 5:1), and they occur more frequently in whites
than in other racial groups. The most common location
is the head and neck, which accounts for 60% of all
cases. Eighty percent of hemangiomas occur as single
lesions, but 20% of affected patients will have multiple
tumors.
Fully developed hemangiomas are rarely present at
birth, although a pale macule with threadlike telangi-
ectasias may be noted on the skin. During the ﬁrst few
weeks of life, the tumor will demonstrate rapid devel-
opment that occurs at a faster pace than the infant’s
overall growth. Superﬁcial tumors of the skin appear
raised and bosselated with a bright-red color (“straw-
berry” hemangioma) (Fig. 12-87). They are ﬁrm and
rubbery to palpation, and the blood cannot be evacu-
ated by applying pressure. Deeper tumors may appear
only slightly raised with a bluish hue.
The proliferative phase usually lasts for 6 to 10
months, after which the tumor slows in growth and
begins to involute. The color gradually changes to a
Fig. 12-86 Congenital epulis. A, Nodular mass on the maxillary alveolar ridge. Instead of
being excised, the lesion was monitored clinically. B, Clinical appearance of the child at 1 year
of age. The mass has disappeared without treatment. (Courtesy of Dr. Erwin Turner.)
Box 12-2
Classiﬁcation of Vascular Anomalies
VASCULAR TUMORS
Hemangiomas of Infancy
Superﬁcial
Deep
Mixed
Congenital Hemangiomas
Noninvoluting congenital hemangioma (NICH)
Rapidly involuting congenital hemangioma (RICH)
Kaposiform Hemangioendothelioma
Tufted Angioma
Pyogenic Granuloma (lobular capillary hemangioma)
VASCULAR MALFORMATIONS
Simple
Capillary malformation
Venous malformation
Lymphatic malformation
Arteriovenous malformation
Combined Malformations `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

540 ORAL AND MAXILLOFACIAL PATHOLOGY
Complications occur in about 20% of hemangiomas.
The most common problem is ulceration, which may
occur with or without secondary infection. Although
hemorrhage may be noted, signiﬁcant blood loss does
not usually occur. Hemangiomas that occur in crucial
areas can be associated with signiﬁcant morbidity.
Periocular tumors often result in amblyopia (dimness
of vision), strabismus, or astigmatism. Patients with
multiple cutaneous hemangiomas or large facial hem-
angiomas are at increased risk for concomitant visceral
hemangiomas. Tumors in the neck and laryngeal region
can lead to airway obstruction.
Large, segmental cervicofacial hemangioma can be
a component of a well-recognized hemangioma syn-
drome—PHACE(S) syndrome. This acronym stands
for the following:
●Posterior fossa brain anomalies (usually Dandy-
Walker malformation)
●Hemangioma (usually cervical segmental
hemangioma)
●Arterial anomalies
●Cardiac defects and Coarctation of the aorta
●Eye anomalies
●Sternal cleft or Supraumbilical raphe
Kasabach-Merritt phenomenon is a serious coag-
ulopathy that has been associated with two rare vascu-
lar tumors known as tufted hemangioma and kaposiform
hemangioendothelioma. This disorder is characterized by
severe thrombocytopenia and hemorrhage because of
platelet trapping within the tumor. The mortality rate
is as high as 20% to 30%.
VASCULAR MALFORMATIONS
In contrast to hemangiomas, vascular malformations
are present at birth and persist throughout life. Port
wine stains are relatively common capillary malforma-
tions that occur in 0.3% to 1.0% of newborns. They are
most common on the face, particularly along the distri-
bution of the trigeminal nerve. In Sturge-Weber angio-
matosis, associated intracranial lesions are present (see
page 543). Port wine stains are typically pink or purple
macular lesions that grow commensurately with the
patient. As the patient gets older, the lesion often
darkens and becomes nodular because of vascular
ectasia.
Low-ﬂow venous malformations encompass a
wide spectrum of lesions, from small isolated ectasias
to complex growths that involve multiple tissues and
organs. They are present at birth, although they may
not always be immediately apparent. Typically, venous
malformations are blue and are easily compressible
(Fig. 12-88). They often grow proportionately with the
patient, but they may swell when dependent or with
increased venous pressure. Secondary thrombosis and
phlebolith formation can occur.
Arteriovenous malformations are high-ﬂow
lesions that result from persistent direct arterial and
venous communication. Although they are present
from birth, they may not become noticeable until later
in childhood or adulthood. Because of the fast vascular
ﬂow through these lesions, a palpable thrill or bruit
often is noticeable. The overlying skin typically feels
warmer to touch. Presenting symptoms may include
pain, bleeding, and skin ulceration.
INTRABONY VASCULAR MALFORMATIONS
Intrabony “hemangiomas” also may occur and proba-
bly represent either venous or arteriovenous malfor-
mations. In the jaws, such lesions are detected most
often during the ﬁrst 3 decades of life. They are slightly
more common in females than in males and occur
three times more often in the mandible than the
Fig. 12-87 Hemangioma. Infant with two red, nodular
masses on the posterior scalp and neck (“strawberry”
hemangioma).
Fig. 12-88 Venous malformation. Blue-purple mass of the
anterior tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 541
maxilla. The lesion may be completely asymptomatic,
although some examples are associated with pain and
swelling. Mobility of teeth or bleeding from the gingival
sulcus may occur. A bruit or pulsation may be apparent
on auscultation and palpation.
The radiographic appearance of intrabony vascular
malformations is variable. Most commonly, the lesion
shows a multilocular radiolucent defect. The individual
loculations may be small (honeycomb appearance) or
large (soap bubble appearance). In other cases the
lesion may present as an ill-deﬁned radiolucent area
or a well-deﬁned, cystlike radiolucency (Fig. 12-89).
Large malformations may cause cortical expansion,
and occasionally a “sunburst” radiographic pattern is
produced (Fig. 12-90). Angiography can be helpful
in demonstrating the vascular nature of the lesion
(Fig. 12-91).
Fig. 12-89 Intrabony venous malformation. Well-
circumscribed radiolucency that contains ﬁne trabeculations.
Fig. 12-90 Intrabony venous malformation. Occlusal
radiograph demonstrating cortical destruction and a
“sunburst” periosteal reaction resembling osteosarcoma.
A B
Fig. 12-91 Intrabony arteriovenous malformation.
A, Periapical radiograph showing an expansile, mottled
radiolucency in the mandibular incisor region. Pulsatile
hemorrhage was encountered when a biopsy of this lesion
was attempted. B, Angiogram demonstrating a vascular
proliferation between the mandibular incisors. (Courtesy of Dr.
Larry Cunningham and Dr. Jason Ford.)
HISTOPATHOLOGIC FEATURES
Early hemangiomas of infancy are characterized by
numerous plump endothelial cells and often-indistinct
vascular lumina (Figs. 12-92 and 12-93). At this stage,
such lesions often are known microscopically as juve-
nile or cellular hemangiomas. Because of their cellular
nature, these lesions also have been called juvenile
Fig. 12-92 Juvenile (cellular) hemangioma. Low-power
photomicrograph showing a circumscribed cellular mass of
vascular endothelial cells arranged in lobular aggregates. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

542 ORAL AND MAXILLOFACIAL PATHOLOGY
hemangioendothelioma, although this term should
be avoided because hemangioendothelioma also is
used to designate other vascular tumors of intermedi-
ate malignant potential. As the lesion matures, the
endothelial cells become ﬂattened, and the small,
capillary-sized vascular spaces become more evident
(Fig. 12-94). As the hemangioma undergoes involution,
the vascular spaces become less prominent and are
replaced by ﬁbrous connective tissue.
Vascular malformations do not show active endo-
thelial cell proliferation, and the channels resemble
the vessels of origin. Therefore, capillary malforma-
tions may be similar to the capillary stage of hemangi-
oma (Fig. 12-95), whereas venous malformations
may show more dilated vessels (Fig. 12-96). Because of
their similar features, many vascular malformations
are incorrectly categorized as hemangiomas. Arterio-
venous malformations demonstrate a mixture of
thick-walled arteries and veins, along with capillary
vessels.
GLUT1 is an immunohistochemical marker that is
consistently positive in the hemangioma of infancy. In
contrast, this marker is negative in other developmen-
tal vascular tumors and anomalies listed in Box 12-2
(rapidly involuting congenital hemangioma [RICH],
noninvoluting congenital hemangioma [NICH], tufted
angioma, kaposiform hemangioendothelioma, pyo-
genic granuloma, and vascular malformations).
TREATMENT AND PROGNOSIS
Because most hemangiomas of infancy undergo invo-
lution, management often consists of “watchful neg-
lect.” It is important to educate parents that although
rapid growth may be seen, regression will occur. Surgi-
cal resection is rarely warranted during infancy. For
Fig. 12-93 Juvenile (cellular) hemangioma. High-power
view showing a highly cellular endothelial proliferation
forming occasional indistinct vascular lumina.
Fig. 12-94 Capillary hemangioma. High-power
photomicrograph demonstrating well-formed capillary-sized
vessels.
Fig. 12-95 Capillary malformation. Low-power view of a
vascular proliferation forming multiple capillary blood vessels.
Fig. 12-96 Venous malformation. Low-power
photomicrograph showing multiple large, dilated blood
vessels. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 543
problematic or life-threatening hemangiomas, phar-
macologic therapy may be indicated. Systemic cortico-
steroids may help to reduce the size of the lesion and
are associated with a 70% to 90% response rate. Intra-
lesional and topical corticosteroids also have been
used for smaller localized, problematic lesions. Intra-
venous (IV) vincristine is currently the drug of
choice for complicated tumors that are unresponsive
to systemic corticosteroid therapy. Interferon α-2a is
no longer widely used because of the reported risk of
permanent spastic diplegia.
Flashlamp pulsed dye lasers can be effective in the
treatment of port wine stains. The management of
venous malformations depends on the size, location,
and associated complications of the lesion. Small, stable
malformations may not require treatment. Larger,
problematic lesions may be treated with a combination
of sclerotherapy and surgical excision. Sclerotherapy
involves the injection of sclerosing agents, such as 95%
ethanol, directly into the lesion to induce ﬁbrosis.
Sclerotherapy alone may be sufﬁcient for smaller
lesions; for larger lesions, subsequent surgical resec-
tion can be accomplished with less risk of bleeding
after sclerotherapy.
The treatment of arteriovenous malformations is
more challenging and also depends on the size of the
lesion and degree of involvement of vital structures.
For cases that require resection, radiographic emboli-
zation often is performed 24 to 48 hours before surgery
to minimize blood loss.
Vascular malformations of the jaws are potentially
dangerous lesions because of the risk of severe bleed-
ing, which may occur spontaneously or during surgical
manipulation. Needle aspiration of any undiagnosed
intrabony lesion before biopsy is a wise precaution to
rule out the possibility of a vascular malformation.
Severe and even fatal hemorrhages have occurred after
incisional biopsy or extraction of teeth in the area of
such lesions.
STURGE-WEBER ANGIOMATOSIS
(ENCEPHALOTRIGEMINAL
ANGIOMATOSIS; STURGE-
WEBER SYNDROME)
Sturge-Weber angiomatosis is a rare, nonhereditary
developmental condition that is characterized by a
hamartomatous vascular proliferation involving the
tissues of the brain and face. It is believed to be caused
by the persistence of a vascular plexus around the
cephalic portion of the neural tube. This plexus devel-
ops during the sixth week of intrauterine development
but normally undergoes regression during the ninth
week.
CLINICAL AND RADIOGRAPHIC
FEATURES
Patients with Sturge-Weber angiomatosis are born
with a dermal capillary vascular malformation of the
face known as a port wine stain or nevus ﬂammeus
because of its deep-purple color. This port wine stain
usually has a unilateral distribution along one or more
segments of the trigeminal nerve. Occasionally, patients
have bilateral involvement or additional port wine
lesions elsewhere on the body. Not all patients with
facial port wine nevi have Sturge-Weber angiomatosis.
In one study of patients with facial port wine nevi, only
slightly more than 10% had Sturge-Weber angiomato-
sis. Only patients with involvement along the distribu-
tion of the ophthalmic branch of the trigeminal nerve
were at risk for the full condition (Figs. 12-97 and
12-98).
In addition to the facial port wine nevus, affected
individuals also have leptomeningeal angiomas that
overlie the ipsilateral cerebral cortex. This meningeal
angiomatosis is usually associated with a convulsive
disorder and often results in mental retardation or con-
tralateral hemiplegia. Imaging studies of the brain may
reveal gyriform “tramline” calciﬁcations on the affected
side (Fig. 12-99). Ocular involvement may be mani-
fested by glaucoma and vascular malformations of the
conjunctiva, episclera, choroid, and retina.
Intraoral involvement in Sturge-Weber angiomato-
sis is common, resulting in hypervascular changes to
the ipsilateral mucosa (Fig. 12-100). The gingiva may
exhibit slight vascular hyperplasia or a more massive
hemangiomatous proliferation that can resemble a
Fig. 12-97 Port wine stain. Nevus ﬂammeus of the malar
area in a patient without Sturge-Weber angiomatosis. Unless
the vascular lesion includes the region innervated by the
ophthalmic branch of the trigeminal nerve, usually the
patient does not have central nervous system (CNS)
involvement. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

544 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
The port wine nevus is characterized by excessive
numbers of dilated blood vessels in the middle and
deep dermis. The intraoral lesions show a similar vas-
cular dilatation. Proliferative gingival lesions may
resemble a pyogenic granuloma.
TREATMENT AND PROGNOSIS
The treatment and prognosis of Sturge-Weber angio-
matosis depend on the nature and severity of the pos-
sible clinical features. Usually, facial port wine nevi
can be improved by using the newer ﬂashlamp pulsed
dye lasers. Cortical excision of angiomatous meningeal
lesions may be necessary in some cases. Patients
with intractable epilepsy and progressive mental
retardation eventually may require more extensive
neuro surgical treatment, including lobectomy or
hemispherectomy.
Port wine nevi that affect the gingiva can make ﬂoss-
ing and dental prophylaxis difﬁcult. Great care must be
taken when performing surgical procedures in affected
areas of the mouth because severe hemorrhage may be
encountered. Lasers also may be helpful in the removal
of hyperplastic oral lesions.
NASOPHARYNGEAL ANGIOFIBROMA
The nasopharyngeal angioﬁbroma is a rare vascular
and ﬁbrous tumorlike lesion that occurs only in the
nasopharynx. Although microscopically benign, it fre-
quently exhibits locally destructive and aggressive
behavior. It may represent a vascular malformation
rather than a true neoplasm.
Fig. 12-98 Sturge-Weber angiomatosis. Port wine stain of
the left face, including involvement along the ophthalmic
branch of the trigeminal nerve. The patient also was mentally
retarded and had a seizure disorder.
pyogenic granuloma. Such gingival hyperplasia may be
attributable to the increased vascular component, phe-
nytoin therapy used to control the epileptic seizures, or
both. Destruction of the underlying alveolar bone has
been reported in rare instances.
Fig. 12-99 Sturge-Weber angiomatosis. Skull ﬁlm
showing “tramline” calciﬁcations (arrows). (Courtesy of Dr. Reg
Munden.)
Fig. 12-100 Sturge-Weber angiomatosis. Unilateral
vascular involvement of the soft palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 545
CLINICAL AND RADIOGRAPHIC
FEATURES
Nasopharyngeal angioﬁbromas occur almost exclu-
sively in males. The tumor is exceedingly rare in
females—so much so that the diagnosis in a female
patient should be viewed with skepticism and closely
scrutinized. The lesion also shows a striking predilec-
tion for adolescents between the ages of 10 and 17
and often has been called the juvenile nasopharyngeal
angioﬁbroma. However, rare examples also have been
reported in slightly younger and older patients. Because
of its almost exclusive occurrence in adolescent boys,
a hormonal inﬂuence seems likely, although no endo-
crine abnormalities have been detected.
Nasal obstruction and epistaxis are common early
symptoms. The lesion is currently presumed to arise in
the pterygopalatine fossa and expands medially into
the nasal cavity via the sphenopalatine foramen. Some
cases will show extension into the paranasal sinuses,
orbits, or middle cranial fossa. Invasion into the oral
cavity or cheek rarely has been reported. Computed
tomography (CT) scans and magnetic resonance
imaging (MRI) studies are helpful adjuncts in visualiz-
ing the extent of the lesion and degree of adjacent
tissue destruction. Anterior bowing of the posterior
wall of the maxillary sinus is a characteristic feature
(Fig. 12-101). Angiograms can be used to conﬁrm the
vascular nature of the lesion (Fig. 12-102).
HISTOPATHOLOGIC FEATURES
The nasopharyngeal angioﬁbroma consists of dense
ﬁbrous connective tissue that contains numerous
dilated, thin-walled blood vessels of variable size (Fig.
12-103). Typically, the vascular component is more
prominent at the periphery of the tumor, especially in
lesions from younger patients.
TREATMENT AND PROGNOSIS
The primary treatment of nasopharyngeal angioﬁ-
broma usually consists of surgical excision. Depending
on the extent of the lesion, this may be accomplished
via endoscopic surgery, lateral rhinotomy, midfacial
degloving procedure, infratemporal fossa approach, or
combined craniofacial resection. Preoperative emboli-
zation of the tumor is helpful in controlling blood loss.
Radiation therapy is usually reserved for recurrent
lesions and extensive tumors with unusual vascular
supplies or intracranial extension.
The recurrence rate varies from 20% to 40% in most
recent studies. Such recurrences are usually retreated
with further surgery or radiation therapy. Malignant
transformation into ﬁbrosarcoma has rarely been
Fig. 12-101 Nasopharyngeal angioﬁbroma. A contrasted
computed tomography (CT) scan showing a tumor of the
nasopharynx and pterygopalatine fossa, with characteristic
anterior bowing of the posterior wall of the right maxillary
sinus (arrow). (Courtesy of Dr. Pamela Van Tassel.)
Fig. 12-102 Nasopharyngeal angioﬁbroma. A digital
subtraction angiogram of the external carotid artery showing
the intense vascular blush of the tumor. (Courtesy of Dr. Pamela
Van Tassel.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

546 ORAL AND MAXILLOFACIAL PATHOLOGY
reported and is probably associated with prior radia-
tion therapy.
HEMANGIOPERICYTOMA–SOLITARY
FIBROUS TUMOR
As originally described, the hemangiopericytoma
(HPC) was a rare neoplasm that presumably was
derived from pericytes (i.e., cells with processes that
encircled endothelial cells of capillaries). However, in
many examples it was difﬁcult to conﬁrm pericytic dif-
ferentiation, making diagnostic reproducibility among
pathologists difﬁcult. The solitary ﬁbrous tumor (SFT)
was initially described as a pleural neoplasm that was
believed to be derived from either mesothelial cells or
submesothelial ﬁbroblasts. However, examples of this
tumor were later identiﬁed in a number of other ana-
tomic sites, including the head and neck region. Many
of these lesions exhibit microscopic features that
overlap those of HPC. In recent years, experts have
questioned the concept of the HPC, suggesting that
many purported examples should be reclassiﬁed as
SFTs or designated by the combined name, heman-
giopericytoma–solitary ﬁbrous tumor (HPC-SFT).
As more knowledge is gained, it appears likely that the
classiﬁcation and nomenclature of this spectrum of
tumors will undergo further revision.
In addition, a microscopically similar neoplasm
(hemangiopericytoma-like tumor) of the sinonasal
region is recognized, which is felt to represent a dis-
tinct, separate entity.
CLINICAL FEATURES
HPC-SFTs have been reported primarily in adults and
are rare in children. The tumor is usually described as
a slow-growing, painless, submucosal, or deep soft
tissue mass that is easily removed from the surround-
ing tissues. One of the most common oral locations is
the buccal mucosa, which accounts for 75% of cases
reported under the designation of SFT.
Hemangiopericytoma-like tumors of the nasal cavity
and paranasal sinuses primarily occur in middle-aged
and older adults. Common presenting symptoms
include nasal obstruction and epistaxis.
HISTOPATHOLOGIC FEATURES
HPC-SFTs are usually well-circumscribed lesions
that exhibit a variable microscopic appearance. At the
traditional HPC end of the spectrum, the tumor exhib-
its tightly packed cells that surround endothelium-
lined vascular channels. The cells are haphazardly
arranged and demonstrate round to ovoid nuclei
and indistinct cytoplasmic borders. The blood vessels
often show irregular branching, which results in a
characteristic “staghorn” and “antlerlike” appearance
(Fig. 12-104, A).
At the SFT end of the spectrum, the cells are more
spindled and arranged in either short fascicles or in
Fig. 12-103 Nasopharyngeal angioﬁbroma. Moderately
cellular ﬁbrous connective tissue with prominent blood
vessels.
Fig. 12-104 Hemangiopericytoma–solitary ﬁbrous tumor.
A, “Staghorn” blood vessels with surrounding pericytes.
B, Moderately cellular ﬁbrous proliferation (“patternless
pattern”) with prominent vascularity, slightly myxoid areas,
and scattered dense collagen bundles.
A
B `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 547
a disorganized fashion (“patternless pattern”) (Fig.
12-104, B). The tumor often demonstrates alternat-
ing hypercellular and hypocellular zones with a vari-
able degree or myxoid background change. Prominent
hyalinized collagen bundles are characteristically
observed in the hypocellular areas. Immunohisto-
chemical studies show the lesional cells to be positive
for CD34.
The identiﬁcation of four or more mitoses per 10
high-power ﬁelds suggests a rapidly growing tumor
that is capable of metastasis. The presence of necrosis
also suggests malignancy. However, it is difﬁcult to
predict microscopically whether a particular tumor
will act in a benign or malignant fashion.
Hemangiopericytoma-like tumors of the sinonasal
region have a more prominent spindle cell pattern,
with the cells arranged in a more orderly fashion.
Mitotic ﬁgures are rare or absent. The vascular compo-
nent is less intricate, and less interstitial collagen is
found among the tumor cells.
TREATMENT AND PROGNOSIS
For HPC-SFTs with a benign histopathologic appear-
ance, local excision is the treatment of choice.
More extensive surgery is required for tumors with
malignant characteristics. Oral examples usually
behave in a benign fashion, although up to 10% of
extraplural SFTs have been reported to show malig-
nant behavior. One recent paper reported a 5-year
survival rate of 86% for HPC. Therefore, long-term
follow-up of all patients with this tumor spectrum is
recommended.
Studies show that patients with hemangiopericy-
toma-like tumors of the sinonasal region have a better
prognosis than do those with tumors at other sites.
LYMPHANGIOMA
Lymphangiomas are benign, hamartomatous tumors
of lymphatic vessels. It is doubtful that they are true
neoplasms; instead, they most likely represent develop-
mental malformations that arise from sequestrations of
lymphatic tissue that do not communicate normally
with the rest of the lymphatic system.
There are three types of lymphangioma:
1. Lymphangioma simplex (capillary lymphan-
gioma), which consists of small, capillary-sized
vessels
2.Cavernous lymphangioma, which is composed
of larger, dilated lymphatic vessels
3.Cystic lymphangioma (cystic hygroma), which
exhibits large, macroscopic cystic spaces
However, this classiﬁcation system is rather arbitrary
because all three sizes of vessels often can be found
within the same lesion.
The subtypes are probably variants of the same
pathologic process, and the size of the vessels may
depend on the nature of the surrounding tissues. Cystic
lymphangiomas most often occur in the neck and
axilla, where the loose adjacent connective tissues
allow for more expansion of the vessels. Cavernous
lymphangiomas are more frequent in the mouth, where
the denser surrounding connective tissue and skeletal
muscle limit vessel expansion.
CLINICAL FEATURES
Lymphangiomas have a marked predilection for the
head and neck, which accounts for 50% to 75% of all
cases (Fig. 12-105). About half of all lesions are noted
at birth, and around 90% develop by 2 years of age.
Cervical lymphangiomas are more common in the
posterior triangle and are typically soft, ﬂuctuant
masses. They occur less frequently in the anterior tri-
angle, although lesions in this location are more likely
to result in respiratory difﬁculties or dysphagia if they
grow large. Occasionally, cervical lymphangiomas
extend into the mediastinum or upward into the oral
cavity. Such tumors can become massive and can
measure 15 cm or greater in size. Rapid tumor enlarge-
ment may occur secondary to an upper respiratory
tract infection, presumably because of increased lymph
Fig. 12-105 Lymphangioma. Young boy with a cystic
hygroma primarily involving the right side of the face.
(Courtesy of Dr. Frank Kendrick.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

548 ORAL AND MAXILLOFACIAL PATHOLOGY
production, blocked lymphatic drainage, or secondary
infection of the tumor.
Oral lymphangiomas may occur at various sites but
are most frequent on the anterior two thirds of the
tongue, where they often result in macroglossia (Figs.
12-106 and 12-107). Usually, the tumor is superﬁcial
in location and demonstrates a pebbly surface that
resembles a cluster of translucent vesicles. The surface
has been likened to the appearance of frog eggs or
tapioca pudding. Secondary hemorrhage into the lym-
phatic spaces may cause some of these “vesicles” to
become purple. Deeper tumors present as soft, ill-
deﬁned masses.
Small lymphangiomas less than 1 cm in size occur
on the alveolar ridge in around 4% of black neonates.
These lesions often occur bilaterally on the mandibular
ridge and show a 2:1 male-to-female distribution. Most
of these alveolar lymphangiomas apparently resolve
spontaneously because they are not observed in older
people.
HISTOPATHOLOGIC FEATURES
Lymphangiomas are composed of lymphatic vessels
that may show marked dilatation (cavernous lymphan-
gioma) (Figs. 12-108 and 12-109) or macroscopic cyst-
like structures (cystic hygroma) (Fig. 12-110). The
vessels often diffusely inﬁltrate the adjacent soft tissues
and may demonstrate lymphoid aggregates in their
walls. The lining endothelium is typically thin, and the
spaces contain proteinaceous ﬂuid and occasional lym-
phocytes. Some channels also may contain red blood
cells, which creates uncertainty as to whether they are
lymphatic or blood vessels. Although many of these
likely represent secondary hemorrhage into a lym-
phatic vessel, some actually may be examples of mixed
lymphangioma and hemangioma.
In intraoral tumors, the lymphatic vessels are char-
acteristically located just beneath the epithelial surface
and often replace the connective tissue papillae. This
superﬁcial location results in the translucent, vesicle-
Fig. 12-106 Lymphangioma. Pebbly, vesicle-like
appearance of a tumor of the right lateral tongue.
Fig. 12-107 Lymphangioma. Dorsal tongue lesion
demonstrating a purple color, which can be caused by
secondary hemorrhage or an associated hemangiomatous
component.
Fig. 12-108 Cavernous lymphangioma. Lesion of the
tongue showing dilated lymphatic vessels beneath the
epithelium and in the deeper connective tissues.
Fig. 12-109 Cavernous lymphangioma. High-power
photomicrograph showing dilated, lymph-ﬁlled vessels
immediately below the atrophic surface epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 549
like clinical appearance. However, extension of these
vessels into the deeper connective tissue and skeletal
muscle also may be seen.
TREATMENT AND PROGNOSIS
The treatment of lymphangiomas usually consists of
surgical excision, although total removal may not be
possible in all cases because of large size or involve-
ment of vital structures. Recurrence is common, espe-
cially for cavernous lymphangiomas of the oral cavity,
because of their inﬁltrative nature. Some clinicians do
not recommend treatment for nonenlarging lymphan-
giomas of the tongue because of the difﬁculty in removal
and high recurrence rate. Cystic lymphangiomas of the
cervical region are often well circumscribed and have
a lower rate of recurrence. Spontaneous regression of
lymphangiomas is rare.
Unfortunately, lymphangiomas do not respond to
sclerosing agents as do hemangiomas. However, some
success with sclerosant therapy for unresectable lymph-
angiomas has been reported using OK-432, a lyophi-
lized incubation mixture of a low-virulent strain of
Streptococcus pyogenes with penicillin G potassium,
which has lost its streptolysin S–producing ability.
The prognosis is good for most patients, although
large tumors of the neck or tongue may result in airway
obstruction and death. The mortality rate for cystic
hygromas ranges from 2% to 5% in most series.
LEIOMYOMA
Leiomyomas are benign tumors of smooth muscle that
most commonly occur in the uterus, gastrointestinal
tract, and skin. Leiomyomas of the oral cavity are rare.
Most of these probably have their origin from vascular
smooth muscle.
The three types are as follows:
1. Solid leiomyomas
2. Vascular leiomyomas (angiomyomas or angio-
leiomyomas)
3. Epithelioid leiomyomas (leiomyoblastomas)
Almost all oral leiomyomas are either solid or vascular
in type; angiomyomas account for nearly 75% of all oral
cases.
CLINICAL AND RADIOGRAPHIC
FEATURES
The oral leiomyoma can occur at any age and is usually
a slow-growing, ﬁrm, mucosal nodule (Fig. 12-111).
Most lesions are asymptomatic, although occasional
tumors can be painful. Solid leiomyomas are typically
normal in color, although angiomyomas may exhibit a
bluish hue. The most common sites are the lips, tongue,
palate, and cheek, which together account for 80% of
cases. Extremely rare intraosseous examples may
present as unilocular radiolucencies of the jaws.
HISTOPATHOLOGIC FEATURES
Solid leiomyomas are well-circumscribed tumors that
consist of interlacing bundles of spindle-shaped smooth
muscle cells (Figs. 12-112 and 12-113). The nuclei are
elongated, pale staining, and blunt ended. Mitotic
ﬁgures are uncommon. Angiomyomas also are well-
circumscribed lesions that demonstrate multiple tortu-
ous blood vessels with thickened walls caused by
hyperplasia of their smooth muscle coats (Fig. 12-114).
Intertwining bundles of smooth muscle may be found
between the vessels, sometimes with intermixed
adipose tissue. As its name implies, the epithelioid leio-
myoma is composed primarily of epithelioid cells
rather than spindle cells.
Fig. 12-110 Cystic hygroma. Lesion from the neck
showing markedly dilated lymphatic vessels.
Fig. 12-111 Leiomyoma. Small, pink-red nodule on the
posterior hard palate lateral to the midline. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

550 ORAL AND MAXILLOFACIAL PATHOLOGY
Special stains and immunohistochemistry may be
helpful to conﬁrm the smooth muscle origin if the diag-
nosis is in doubt. The smooth muscle stains bright red
with the Masson trichrome stain (Fig. 12-115). Immu-
nohistochemical analysis usually reveals the tumor
cells to be positive for vimentin, smooth muscle actin,
and muscle-speciﬁc actin; desmin positivity also may
be seen.
TREATMENT AND PROGNOSIS
Oral leiomyomas are treated by local surgical excision.
The lesion should not recur.
RHABDOMYOMA
Benign neoplasms of skeletal muscle are called rhab-
domyomas. The term rhabdomyoma also is used to
describe a hamartomatous lesion of the heart that often
is associated with tuberous sclerosis (see page 757).
Despite the great amount of skeletal muscle through-
out the body, benign skeletal muscle tumors are
extremely rare. However, these extracardiac rhabdo-
myomas show a striking predilection for the head and
neck. Rhabdomyomas of the head and neck can be
subclassiﬁed into two major categories: (1) adult rhab-
domyomas and (2) fetal rhabdomyomas.
CLINICAL FEATURES
ADULT RHABDOMYOMAS
Adult rhabdomyomas of the head and neck occur pri-
marily in middle-aged and older patients, with about
70% of cases found in men. The most frequent sites are
the pharynx, oral cavity, and larynx; intraoral lesions
are most common in the ﬂoor of the mouth, soft palate,
Fig. 12-112 Leiomyoma. Low-power view showing a well-
circumscribed cellular mass of spindle-shaped smooth muscle
cells.
Fig. 12-113 Leiomyoma. High-power view showing
spindle-shaped cells with blunt-ended nuclei. Immuno-
histochemical analysis shows strong positivity for smooth
muscle actin (inset).
Fig. 12-114 Angiomyoma. Well-circumscribed tumor
exhibiting prominent blood vessels surrounded by smooth
muscle.
Fig. 12-115 Angiomyoma. Masson trichrome stain
demonstrating bundles of smooth muscle (red) with adjacent
normal collagen (blue). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 551
and base of tongue. The tumor appears as a nodule or
mass that can grow to many centimeters before discov-
ery (Figs. 12-116 and 12-117). Laryngeal and pharyn-
geal lesions often lead to airway obstruction. Sometimes,
the tumor is multinodular in nature, with two or more
discrete nodules found in the same anatomic location.
Occasional cases are multicentric, with separate, dis-
tinct tumors at different sites.
FETAL RHABDOMYOMAS
Fetal rhabdomyomas usually occur in young children,
although some also develop in adults. A similar male
predilection is noted. The most common locations are
the face and periauricular region.
HISTOPATHOLOGIC FEATURES
ADULT RHABDOMYOMAS
The adult rhabdomyoma is composed of well-circum-
scribed lobules of large, polygonal cells, which exhibit
abundant granular, eosinophilic cytoplasm (Fig.
12-118). These cells often demonstrate peripheral
vacuolization that results in a “spider web” appearance
of the cytoplasm. Focal cells with cross striations can
be identiﬁed in most cases (Fig. 12-119). Although
rarely necessary for the diagnosis, immunohistochemi-
cal examination will show the tumor cells to be positive
for myoglobin, desmin, and muscle-speciﬁc actin.
FETAL RHABDOMYOMAS
The fetal rhabdomyoma has a less mature appearance
and consists of a haphazard arrangement of spindle-
Fig. 12-116 Adult rhabdomyoma. Nodular mass (arrow) in
the left cheek. (Courtesy of Dr. Craig Little.)
Fig. 12-117 Adult rhabdomyoma. Computed tomography
(CT) scan of the same tumor depicted in Fig. 12-116. Note
the mass (arrow) lateral to the left body of the mandible.
(Courtesy of Dr. Craig Little.)
Fig. 12-118 Adult rhabdomyoma. Medium-power view
showing a uniform tumor composed of rounded and
polygonal cells with focal vacuolization.
Fig. 12-119 Adult rhabdomyoma. Phosphotungstic acid
hematoxylin (PTAH) stain that demonstrates focal cross
striations in some cells (arrow). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

552 ORAL AND MAXILLOFACIAL PATHOLOGY
shaped muscle cells that sometimes are found within
a myxoid stroma. Some tumors may show considerable
cellularity and mild pleomorphism, which makes them
easily mistaken for rhabdomyosarcomas.
TREATMENT AND PROGNOSIS
The treatment of both variants of rhabdomyoma con-
sists of local surgical excision. Recurrence is uncom-
mon but has been reported in a few cases.
OSSEOUS AND CARTILAGINOUS
CHORISTOMAS
A choristoma is a tumorlike growth of microscopically
normal tissue in an abnormal location. Several differ-
ent tissue types may occur in the mouth as choristomas.
These include gastric mucosa, glial tissue, and tumor-
like masses of sebaceous glands. However, the most
frequently observed choristomas of the oral cavity are
those that consist of bone, cartilage, or both. These
lesions sometimes have been called soft tissue osteo-
mas or soft tissue chondromas, but choristoma is a
better term because they do not appear to be true
neoplasms.
CLINICAL FEATURES
Osseous and cartilaginous choristomas show a striking
predilection for the tongue, which accounts for 85% of
cases. The most common location is the posterior
tongue near the foramen cecum, although rare exam-
ples also have been reported elsewhere on the tongue
and at other oral locations. The lesion is usually a ﬁrm,
smooth-surfaced, sessile or pedunculated nodule
between 0.5 and 2.0 cm in diameter (Fig. 12-120).
Many patients are unaware of the lesion, although
some complain of gagging or dysphagia. More than
70% of osseous choristomas have been reported in
women.
HISTOPATHOLOGIC FEATURES
Microscopic examination of choristomas shows a well-
circumscribed mass of dense lamellar bone or mature
cartilage that is surrounded by dense ﬁbrous connec-
tive tissue (Fig. 12-121). Sometimes a combination of
bone and cartilage is formed. The bone has a well-
developed haversian canal system and occasionally
demonstrates central fatty or hematopoietic marrow.
TREATMENT AND PROGNOSIS
Osseous and cartilaginous choristomas are best treated
by local surgical excision. Recurrence has not been
reported.
Soft Tissue Sarcomas
Fortunately, soft tissue sarcomas are rare in the oral
and maxillofacial region and account for less than 1%
of the cancers in this area. Because of their relative
rarity, it is beyond the scope of this book to give a com-
plete, detailed discussion of each of these tumors.
However, a review of these entities is included in the
following section.
Fig. 12-120 Osseous choristoma. Hard pedunculated
nodule on the posterior dorsum of the tongue. (Courtesy of Dr.
Michael Meyrowitz.)
Fig. 12-121 Osseous choristoma. Mass of dense lamellar
bone beneath the surface epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 553
Over the past two decades, clinicians have seen a
radical shift in the classiﬁcation and nomenclature of
many soft tissue sarcomas on the basis of detailed
histochemical, immunohistochemical, and ultrastruc-
tural studies. Because of this, a number of previous
tumor concepts have changed or are being critically
reevaluated.
FIBROSARCOMA
The ﬁbrosarcoma is a malignant tumor of ﬁbroblasts.
At one time, it was considered one of the most common
soft tissue sarcomas. However, the diagnosis of ﬁbro-
sarcoma is made much less frequently today because
of the recognition and separate classiﬁcation of other
spindle cell lesions that have similar microscopic fea-
tures. The tumor is most common in the extremities;
only 10% occur in the head and neck region.
CLINICAL FEATURES
Fibrosarcomas most often present as slow-growing
masses that may reach considerable size before they
produce pain (Fig. 12-122). They can occur anywhere
in the head and neck region. A number of cases have
been reported in the nose and paranasal sinuses, where
they often result in obstructive symptoms. They can
occur at any age but are most common in young adults
and children.
HISTOPATHOLOGIC FEATURES
Well-differentiated ﬁbrosarcomas consist of fascicles
of spindle-shaped cells that classically form a “herring-
bone” pattern (Fig. 12-123). The cells often show little
variation in size and shape, although variable numbers
of mitotic ﬁgures can usually be identiﬁed. In poorly
differentiated tumors, the cells are less organized and
may appear rounder or ovoid. Mild pleomorphism
along with more frequent mitotic activity may be seen.
Poorly differentiated tumors tend to produce less col-
lagen than do well-differentiated tumors.
TREATMENT AND PROGNOSIS
The treatment of choice is usually surgical excision,
including a wide margin of adjacent normal tissue.
Recurrence is noted in about half of cases, and 5-year
survival rates range from 40% to 70%.
MALIGNANT FIBROUS HISTIOCYTOMA
The malignant ﬁbrous histiocytoma is considered to
be a sarcoma with both ﬁbroblastic and histiocytic fea-
tures. After the introduction of this term in 1963, this
tumor concept rapidly gained acceptance and became
the most common soft tissue sarcoma diagnosed in
adults. However, some experts today question the
concept of malignant ﬁbrous histiocytoma and now
favor reclassiﬁcation of the various tumors in this
family into other categories, including undifferentiated
pleomorphic sarcoma, liposarcoma, myxoﬁbrosar-
coma, melanoma, and anaplastic carcinoma. On the
other hand, other authors still support the concept of
this neoplasm. The following brief discussion reviews
the traditional features of malignant ﬁbrous histiocy-
toma, although it is possible that use of this term may
fall further out of favor in the future.
CLINICAL FEATURES
The malignant ﬁbrous histiocytoma is primarily con-
sidered to be a tumor of older age groups. The most
common complaint is an expanding mass that may or
Fig. 12-122 Fibrosarcoma. Child with a large mass of the
hard palate and maxillary alveolar ridge. (Courtesy of Dr. John
McDonald.)
Fig. 12-123 Fibrosarcoma. Cellular mass of spindle-
shaped cells demonstrating mild pleomorphism. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

554 ORAL AND MAXILLOFACIAL PATHOLOGY
may not be painful or ulcerated. Tumors of the nasal
cavity and paranasal sinuses produce obstructive
symptoms.
HISTOPATHOLOGIC FEATURES
Several histopathologic subtypes have been described.
The storiform-pleomorphic type is the most common.
This pattern is characterized by short fascicles of plump
spindle cells arranged in a storiform pattern, admixed
with areas of pleomorphic giant cells (Fig. 12-124).
Myxoid, giant cell, inﬂammatory, and angiomatoid sub-
types also have been recognized.
TREATMENT AND PROGNOSIS
The malignant ﬁbrous histiocytoma is considered to be
an aggressive tumor that is usually treated by radical
surgical resection. Approximately 40% of patients have
had local recurrences. A similar percentage has devel-
oped metastases, usually within 2 years of the initial
diagnosis. The survival rate for patients with oral tumors
appears to be worse than for those with tumors at other
body sites.
LIPOSARCOMA
The liposarcoma is a malignant neoplasm of fatty
origin. It currently is considered to be the most common
soft tissue sarcoma and accounts for 20% of all soft
tissue malignancies in adults. The most common sites
are the thigh, retroperitoneum, and inguinal region.
Liposarcomas of the head and neck are rare.
CLINICAL FEATURES
Liposarcomas are primarily seen in adults, with peak
prevalence between the ages of 40 and 60. The tumor
is typically a soft, slow-growing, ill-deﬁned mass that
may appear normal in color or yellow. Pain or tender-
ness is uncommon; when present, it is usually a late
feature. The neck is the most common site for liposar-
comas of the head and neck region. The most frequent
oral locations are the tongue and cheek.
HISTOPATHOLOGIC FEATURES
Most liposarcomas can be divided into three major
categories:
1.Well-differentiated liposarcoma/atypical lipo-
matous tumor
2.Myxoid/round cell liposarcoma
3.Pleomorphic liposarcoma
The most common of these variants in the oral cavity
is the well-differentiated liposarcoma, which ac-
counts for 55% to 90% of all cases. These tumors
resemble benign lipomas but demonstrate scattered
lipoblasts and atypical, hyperchromatic stromal cells
(Fig. 12-125).
Myxoid liposarcomas demonstrate proliferating
lipoblasts within a myxoid stroma that contains a rich
capillary network. The round cell liposarcoma is a
more aggressive form of myxoid liposarcoma with less
differentiated, rounded cells.
Pleomorphic liposarcomas exhibit extreme cellu-
lar pleomorphism and bizarre giant cells. Dedifferen-
tiated liposarcomas are characterized by the
combination of well-differentiated liposarcoma with
poorly differentiated, nonlipogenic sarcomatous
changes. These features may coexist in the same neo-
plasm, or the dedifferentiated changes may develop in
a recurrent tumor or metastasis.
TREATMENT AND PROGNOSIS
Radical excision is the treatment of choice for most
liposarcomas throughout the body. In spite of this,
around 50% of all tumors recur. The overall 5-year
Fig. 12-124 Malignant ﬁbrous histiocytoma. Spindle cell
neoplasm demonstrating marked pleomorphism of some of
the larger histiocytic cells.
Fig. 12-125 Liposarcoma. High-power view showing
vacuolated lipoblasts with pleomorphic nuclei. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 555
survival rate ranges from 59% to 70%. There is a 10-
year survival rate of approximately 50%. The histopath-
ologic subtype is extremely important in predicting the
prognosis; the outlook for pleomorphic liposarcomas is
much worse than for myxoid and well-differentiated
tumors.
In contrast, the prognosis for oral liposarcoma is
more favorable because of the predominance of well-
differentiated subtypes and because most tumors are
small when diagnosed. Local recurrence has been
reported in 15% to 20% of cases, but metastasis and
death as a result of tumor is rare.
MALIGNANT PERIPHERAL NERVE
SHEATH TUMOR (MALIGNANT
SCHWANNOMA;
NEUROFIBROSARCOMA;
NEUROGENIC SARCOMA)
The principal malignancy of peripheral nerve origin is
preferably called a malignant peripheral nerve
sheath tumor. These tumors account for 5% of all soft
tissue sarcomas, with about half of such cases occur-
ring in patients with neuroﬁbromatosis type I (see page
529). The lesion is most common on the proximal por-
tions of the extremities and the trunk; only 10% to 15%
of cases occur in the head and neck.
CLINICAL AND RADIOGRAPHIC
FEATURES
Malignant peripheral nerve sheath tumors are most
common in young adults. The mean age in patients
with neuroﬁbromatosis (29 to 36 years) is about one
decade younger than in those without this condition
(40 to 46 years). The tumor is an enlarging mass that
sometimes exhibits rapid growth. Associated pain or a
nerve deﬁcit is common.
Oral tumors may occur anywhere, but the most
common sites are the mandible, lips, and buccal
mucosa (see Figs. 12-67 and 12-68, page 531). Radio-
graphic examination of intraosseous tumors of the
mandible may reveal widening of the mandibular canal
or the mental foramen, with or without irregular
destruction of the surrounding bone.
HISTOPATHOLOGIC FEATURES
The malignant peripheral nerve sheath tumor shows
fascicles of atypical spindle-shaped cells, which often
resemble the cells of ﬁbrosarcoma (see Fig. 12-69,
page 531). However, these cells are frequently more
irregular in shape with wavy or comma-shaped nuclei.
In addition to streaming fascicles, less cellular myxoid
areas also may be present. With some tumors, there
can be heterologous elements, which include skeletal
muscle differentiation (malignant Triton tumor), car-
tilage, bone, or glandular structures.
A deﬁnitive diagnosis of neural origin is often difﬁ-
cult, especially in the absence of neuroﬁbromatosis.
Positive immunostaining for S-100 protein is a helpful
clue, but this is found in only about 50% of all cases.
TREATMENT AND PROGNOSIS
The treatment of malignant peripheral nerve sheath
tumors consists primarily of radical surgical excision,
possibly along with adjuvant radiation therapy and
chemotherapy. The prognosis is poor, especially in
patients with neuroﬁbromatosis. One study showed the
5-year survival rate in individuals with neuroﬁbroma-
tosis type I to be only 16%. For other patients, the
5-year survival rate was 53%; this rate dropped to 38%
at 10 years. However, another study showed an overall
5-year survival rate of 44%, which was nearly equal
between both groups.
OLFACTORY NEUROBLASTOMA
(ESTHESIONEUROBLASTOMA)
The olfactory neuroblastoma is a rare neuroectoder-
mal neoplasm of the upper nasal vault that shows some
similarities to neuroblastomas seen elsewhere in the
body. Traditionally, it is believed to arise from the olfac-
tory epithelium.
CLINICAL AND RADIOGRAPHIC
FEATURES
Unlike the usual neuroblastoma, the olfactory neuro-
blastoma is rare in patients younger than the age of 10
years. Instead, it is more common in adults and occurs
over a wide age range. The tumor arises high in the nasal
cavity close to the cribriform plate. From there it may
extend into the adjacent paranasal sinuses (especially
the ethmoid sinus), the orbit, and the anterior cranial
fossa (Fig. 12-126). The most common symptoms are
nasal obstruction, anosmia, epistaxis, and pain.
HISTOPATHOLOGIC FEATURES
Olfactory neuroblastomas consist of small, round to
ovoid basophilic cells that are arranged in sheets and
lobules (Fig. 12-127). Rosette and pseudorosette for-
mation and areas of delicate neuroﬁbrillary material
may be seen.
TREATMENT AND PROGNOSIS
The treatment of olfactory neuroblastoma consists of
surgical excision, often with adjuvant radiation therapy.
A combined craniofacial surgical approach frequently `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

556 ORAL AND MAXILLOFACIAL PATHOLOGY
is used. Chemotherapy also has been administered,
especially in advanced cases.
The prognosis depends on the stage of the disease.
For patients with stage A lesions (tumor conﬁned to the
nasal cavity), the 5-year survival rate ranges from 72%
to nearly 90%. The 5-year survival rate drops to 59% to
70% for stage B disease (tumor extending into the para-
nasal sinuses). For stage C disease (tumor extending
beyond the nasal cavity and sinuses), the 5-year sur-
vival rate has improved to nearly 50% or even greater
with newer treatment regimens. Death is usually a
result of local recurrence; metastasis occurs in approxi-
mately 20% to 37% of cases.
ANGIOSARCOMA
Angiosarcoma is a rare malignancy of vascular endo-
thelium, which may arise from either blood or lym-
phatic vessels. More than 50% of all cases occur in the
head and neck region, with the scalp and forehead
being the most common sites. Oral lesions are quite
rare.
The term hemangioendothelioma is used to
describe vascular tumors with microscopic features
intermediate between those of hemangiomas and
angiosarcomas. Such tumors also are rare and are con-
sidered to be of intermediate malignancy.
CLINICAL FEATURES
Cutaneous angiosarcomas of the head and neck are
most common in older adult patients. Early lesions
often resemble a simple bruise, which may lead to a
delay in diagnosis. However, the lesion continues to
enlarge, which results in an elevated, nodular, or ulcer-
ated surface. Many examples appear multifocal in
nature. Oral angiosarcomas have been reported in
various locations; the tongue and mandible are two of
the more common sites (Fig. 12-128).
Fig. 12-126 Olfactory neuroblastoma. A T1-weighted
sagittal magnetic resonance image (MRI) showing a tumor
ﬁlling the superior nasal cavity and ethmoid sinus, with
extension into the anterior cranial fossa (arrows). (Courtesy of
Dr. Pamela Van Tassel.)
Fig. 12-127 Olfactory neuroblastoma. Sheet of small,
basophilic cells adjacent to the sinonasal epithelium (top).
Fig. 12-128 Angiosarcoma. Occlusal radiograph showing a
destructive, expansile tumor of the anterior mandible.
(Courtesy of Dr. W.C. John.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 557
HISTOPATHOLOGIC FEATURES
Angiosarcoma is characterized by an inﬁltrative prolif-
eration of endothelium-lined blood vessels that form
an anastomosing network (Fig. 12-129). The endothe-
lial cells appear hyperchromatic and atypical; they
often tend to pile up within the vascular lumina.
Increased mitotic activity may be seen. Immunohisto-
chemical studies show the tumor cells to be positive for
CD31 and factor VIII–related antigen in most cases,
whereas CD34 positivity is observed less consistently.
TREATMENT AND PROGNOSIS
Treatment usually consists of radical surgical excision,
radiation therapy, or both. The prognosis for angiosar-
coma of the face and scalp is poor, with a reported 10-
year survival rate of only 21%. However, angiosarcomas
of the oral cavity and salivary glands appear to have a
better outcome. One recent study showed 11 of 14
patients with oral and salivary angiosarcoma to be free
of tumor on follow-up (mean follow-up period: 8.6
years).
KAPOSI’S SARCOMA
Kaposi’s sarcoma is an unusual vascular neoplasm
that was ﬁrst described in 1872 by Moritz Kaposi, a
Hungarian dermatologist. Before the advent of the
acquired immunodeﬁciency syndrome (AIDS) epi-
demic, it was a rare tumor; however, beginning in the
early 1980s, Kaposi’s sarcoma became quite common
because of its propensity to develop in individuals
infected by the human immunodeﬁciency virus (HIV).
Since the introduction of highly active antiretroviral
therapy (HAART) in the mid- to late 1990s, the preva-
lence of AIDS-related Kaposi’s sarcoma in the Western
world has declined. Unfortunately, however, the fre-
quency of this tumor still appears to be increasing in
certain developing African nations.
Current evidence suggests that Kaposi’s sarcoma is
caused by human herpesvirus 8 (HHV-8; Kaposi’s
sarcoma–associated herpesvirus [KSHV]). The lesion
most likely arises from endothelial cells, with some
evidence of lymphatic origin. Four clinical presenta-
tions are recognized:
1.Classic
2.Endemic (African)
3.Iatrogenic immunosuppression associated
4.AIDS related
The ﬁrst three forms are discussed here; AIDS-related
Kaposi’s sarcoma is covered in the section on HIV
disease (see page 270).
CLINICAL FEATURES
CLASSIC TYPE
Classic (chronic) Kaposi’s sarcoma is primarily a
disease of late adult life, and 70% to 90% of cases occur
in men. It mostly affects individuals of Italian, Jewish,
or Slavic ancestry. Multiple blue-purple macules and
plaques are present on the skin of the lower extremities
(Fig. 12-130). These lesions grow slowly over many
years and develop into painless tumor nodules. Oral
lesions are rare and most frequently involve the palate.
Some earlier reports suggested that patients with classic
Kaposi’s sarcoma had an increased prevalence of lym-
phoreticular malignancies, but more recent analysis
has questioned any signiﬁcant association.
Fig. 12-129 Angiosarcoma. Sinusoidal vascular spaces
lined by pleomorphic endothelial cells.
Fig. 12-130 Kaposi’s sarcoma. Classic Kaposi’s sarcoma in
an older man presenting as multiple purple macules and
plaques on the lower leg. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

558 ORAL AND MAXILLOFACIAL PATHOLOGY
ENDEMIC TYPE
Endemic Kaposi’s sarcoma in Africa has been divided
into four subtypes:
1.A benign nodular type, similar to classic
Kaposi’s sarcoma
2.An aggressive or inﬁltrative type, characterized
by progressive development of locally invasive
lesions that involve the underlying soft tissues
and bone
3.A ﬂorid form, characterized by rapidly progres-
sive and widely disseminated, aggressive lesions
with frequent visceral involvement
4.A unique lymphadenopathic type, occurring
primarily in young black children and exhibiting
generalized, rapidly growing tumors of the lymph
nodes, occasional visceral organ lesions, and
sparse skin involvement
IATROGENIC TYPE
Iatrogenic immunosuppression-associated Kapo-
si’s sarcoma most often occurs in recipients of organ
transplants. It affects 0.5% of renal transplant patients,
usually several months to a few years after the trans-
plant. It is probably related to the loss of cellular immu-
nity, which occurs as a result of immunosuppressive
drugs. Like classic Kaposi’s sarcoma, iatrogenic immu-
nosuppression-associated cases are most common in
individuals of Italian, Jewish, and Slavic ancestry;
however, the disease may run a more aggressive
course.
HISTOPATHOLOGIC FEATURES
Kaposi’s sarcoma typically evolves through three
stages:
1. Patch (macular)
2. Plaque
3. Nodular
A proliferation of miniature vessels characterizes
the patch stage. This results in an irregular, jagged
vascular network that surrounds preexisting vessels.
Sometimes normal structures, such as hair follicles or
preexisting blood vessels, may appear to protrude into
these new vessels (promontory sign). The lesional
endothelial cells have a bland appearance and may be
associated with scattered lymphocytes and plasma
cells.
The plaque stage demonstrates further prolifera-
tion of these vascular channels along with the develop-
ment of a signiﬁcant spindle cell component.
In the nodular stage, the spindle cells increase to
form a nodular tumorlike mass that may resemble a
ﬁbrosarcoma or other spindle cell sarcomas (Figs.
12-131 and 12-132). However, numerous extrava-
sated erythrocytes are present, and slitlike vascular
spaces may be discerned.
TREATMENT AND PROGNOSIS
The treatment of Kaposi’s sarcoma depends on the
clinical subtype and stage of the disease. For skin
lesions in the classic form of the disease, radiation
therapy (especially electron beam) often is used. Radia-
tion therapy for oral lesions must be approached with
caution, because an unusually severe mucositis can
develop. Surgical excision can be performed for the
control of individual lesions of the skin or mucosa.
Systemic chemotherapy, especially vinblastine, also
may be helpful. Intralesional injection of chemothera-
peutic agents is used to control individual lesions.
The prognosis is variable, depending on the form of
the disease and the patient’s immune status. The classic
form of the disease is slowly progressive; only 10% to
Fig. 12-131 Kaposi’s sarcoma. Low-power
photomicrograph showing a cellular spindle cell tumor within
the connective tissue.
Fig. 12-132 Kaposi’s sarcoma. High-power
photomicrograph showing spindle cells and poorly deﬁned
vascular slits. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 559
20% of patients develop disseminated lesions. The mean
survival time is 10 to 15 years, and patients often die
from unrelated causes. The benign nodular, endemic
African form of the disease is similar in behavior to
classic non-African Kaposi’s sarcoma. However, the
other endemic African forms are more aggressive and
the prognosis is poorer. The lymphadenopathic form
runs a particularly fulminant course, usually resulting
in the death of the patient within 2 to 3 years. In trans-
plant patients, the disease also may be somewhat more
aggressive, although the tumors may regress if immu-
nosuppressive therapy is discontinued or reduced.
LEIOMYOSARCOMA
The leiomyosarcoma is a malignant neoplasm of
smooth muscle differentiation, which accounts for 5%
to 10% of all soft tissue sarcomas. The most common
sites are the uterine wall and gastrointestinal tract.
Leiomyosarcomas of the oral cavity are rare.
CLINICAL FEATURES
In general, leiomyosarcomas are most common in
middle-aged and older adults. However, tumors in the
oral and maxillofacial region occur over a wide age
range without a predilection for any age group. They
have been reported at various sites, but half of all oral
cases occur in the jawbones. The clinical appearance
is nonspeciﬁc; there is usually an enlarging mass that
may or may not be painful (Fig. 12-133). Secondary
ulceration of the mucosal surface may occur.
HISTOPATHOLOGIC FEATURES
The microscopic examination of a leiomyosarcoma
shows fascicles of spindle-shaped cells with abundant
eosinophilic cytoplasm and blunt-ended, cigar-shaped
nuclei (Fig. 12-134). Some tumors may be composed
primarily of rounded epithelioid cells that have either
eosinophilic or clear cytoplasm (epithelioid leiomyo-
sarcoma). The degree of pleomorphism varies from
one tumor to the next, but smooth muscle tumors with
the presence of ﬁve or more mitoses per 10 high-power
ﬁelds should be considered malignant. Glycogen can
usually be demonstrated within the cells with a peri-
odic acid-Schiff (PAS) stain, and the cell cytoplasm
appears bright red with a Masson trichrome stain.
Immunohistochemical analysis usually reveals the
presence of one or more of the following myogenic
markers: desmin, muscle-speciﬁc actin (HHF 35),
smooth muscle myosin (SMMS), and smooth muscle
actin.
TREATMENT AND PROGNOSIS
The treatment of leiomyosarcoma primarily consists of
radical surgical excision, sometimes with adjunctive
chemotherapy or radiation therapy. The prognosis for
oral tumors is guarded, with the potential for local
recurrence and distant metastasis. Although few cases
are available for analysis, a 5-year survival rate of 62%
has been estimated.
RHABDOMYOSARCOMA
Rhabdomyosarcoma is a malignant neoplasm that is
characterized by skeletal muscle differentiation. These
tumors are much more common in young children,
accounting for 60% of soft tissue sarcomas in child-
hood. In contrast, rhabdomyosarcoma comprises only
2% to 5% of soft tissue sarcomas in adults. The most
frequent site is the head and neck, which accounts for
35% of all cases. The genitourinary tract is the second
most common location. Several microscopic patterns
Fig. 12-133 Leiomyosarcoma. Ulcerated mass of the
anterior maxillary alveolar ridge. (Courtesy of Dr. Jim Weir.)
Fig. 12-134 Leiomyosarcoma. Medium-high–power view
of a pleomorphic spindle cell proliferation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

560 ORAL AND MAXILLOFACIAL PATHOLOGY
of pediatric rhabdomyosarcoma are recognized (Table
12-1), although discussion here will be limited primar-
ily to the embryonal and alveolar subtypes.
CLINICAL FEATURES
Rhabdomyosarcoma primarily occurs during the ﬁrst
decade of life but also may occur in teenagers
and young adults. It is rare in people older than 45
years, and approximately 60% of all cases occur in
males. Embryonal rhabdomyosarcomas are most
common in the ﬁrst 10 years of life and account for
about 60% of all cases. Alveolar rhabdomyosarcomas
occur most often in persons between 10 and 25 years
of age; they account for 20% to 30% of all tumors.
Pleomorphic rhabdomyosarcomas represent less
than 5% of all cases and show a peak prevalence in
patients older than 40 years of age. Most head and
neck lesions are embryonal or alveolar types; pleomor-
phic rhabdomyosarcomas primarily occur on the
extremities.
The tumor is most often a painless, inﬁltrative mass
that may grow rapidly (Figs. 12-135 and 12-136). In
the head and neck region, the face and orbit are the
most frequent locations, followed by the nasal cavity.
The palate is the most frequent intraoral site, and some
lesions may appear to arise in the maxillary sinus and
break through into the oral cavity. Some embryonal
rhabdomyosarcomas that arise within a cavity, such as
the vagina or oropharynx, demonstrate an exophytic,
polypoid growth pattern that resembles a cluster of
grapes. The term botryoid (grapelike) rhabdomyosarcoma
has been used for these lesions.
HISTOPATHOLOGIC FEATURES
EMBRYONAL TYPE
The embryonal rhabdomyosarcoma resembles various
stages in the embryogenesis of skeletal muscle. Poorly
differentiated examples may be difﬁcult to diagnose
and consist of small round or oval cells with hyperchro-
matic nuclei and indistinct cytoplasm (Fig. 12-137).
Table 12-1 Pediatric Rhabdomyosarcomas
Major Types Distribution Five-Year Survival Relative Prognosis
Embryonal rhabdomyosarcoma
NOS
Botryoid
Spindle
49%
6%
3%
66%
95%
88%
Intermediate
Excellent
Excellent
Alveolar rhabdomyosarcoma 31% 53% Poor
Undifferentiated sarcoma 3% 44% Poor
Anaplastic rhabdomyosarcoma 2% 45% Poor
Adapted from Hicks J, Flaitz C: Rhabdomyosarcoma of the head and neck in children, Oral Oncol 38:450-459, 2002.
NOS, Not otherwise speciﬁed.
Fig. 12-135 Embryonal rhabdomyosarcoma. Young child
with a mass of the right maxilla. (Courtesy of Dr. Robert Achterberg.)
Fig. 12-136 Embryonal rhabdomyosarcoma. Computed
tomography (CT) scan of patient from Fig. 12-135 showing
expansile lytic lesion of the maxilla. (Courtesy of Dr. Robert
Achterberg.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 561
Alternating hypercellular and myxoid zones may
be seen. Better-differentiated lesions show round to
ovoid rhabdomyoblasts with distinctly eosinophilic
cytoplasm and ﬁbrillar material around the nucleus.
Cross striations are rarely found. Some tumors
show better-differentiated, elongated, strap-shaped
rhabdomyoblasts.
The botryoid subtype of embryonal rhabdomyosar-
coma is sparsely cellular and has a pronounced myxoid
stroma. Increased cellularity, or a so-called cambium
layer, is usually seen just beneath the mucosal
surface.
Immunohistochemical analysis for the presence of
desmin, myogenin, and muscle-speciﬁc actin can be
helpful in supporting the muscular nature of the tumor.
However, the intensity of the immunostaining can
vary depending on the degree of rhabdomyoblastic
differentiation.
ALVEOLAR TYPE
Both classic and solid variants of alveolar rhabdomyo-
sarcoma are recognized. The classic pattern is charac-
terized by aggregates of poorly differentiated round to
oval cells separated by ﬁbrous septa. These cells dem-
onstrate a central loss of cohesiveness, which results in
an alveolar pattern. The peripheral cells of these aggre-
gates adhere to the septal walls in a single layer. The
central cells appear to ﬂoat freely within the alveolar
spaces. Mitoses are common, and multinucleated giant
cells also may be seen. In contrast, solid alveolar rhab-
domyosarcoma demonstrates cellular ﬁelds of small
round basophilic cells without ﬁbrovascular septa.
Cytogenetic and molecular studies play an impor-
tant role in the diagnosis of rhabdomyosarcoma. Two
distinct translocations have been identiﬁed in alveolar
rhabdomyosarcoma (PAX3-FKHR and PAX7-FKHR).
Embryonal rhabdomyosarcoma is characterized by a
consistent loss of heterozygosity or loss of imprinting at
chromosome 11p15.
TREATMENT AND PROGNOSIS
Before 1960 the prognosis for a patient with rhabdo-
myosarcoma was extremely poor, with more than 90%
of patients dying. With the advent of multimodal
therapy during the past several decades, the prognosis
has improved dramatically.
Treatment typically consists of local surgical exci-
sion followed by multiagent chemotherapy (vincristine,
actinomycin D, and cyclophosphamide). Postoperative
radiation therapy also is used, except for localized
tumors that have been completely resected at initial
surgery. The 5-year survival rate for embryonal rhab-
domyosarcoma (not otherwise speciﬁed [NOS]) is
around 66%, although the ﬁgures for botryoid (95%)
and spindle cell variants (88%) are much better. The
5-year survival rate for alveolar rhabdomyosarcoma is
only 53%, and survival drops to slightly less than 50%
for anaplastic rhabdomyosarcoma and undifferenti-
ated sarcomas.
SYNOVIAL SARCOMA
Synovial sarcoma is an uncommon malignancy that
represents 5% to 10% of all soft tissue sarcomas. The
tumor occurs primarily near large joints and bursae,
especially in the extremities, but most authorities now
agree that this lesion probably does not arise from the
synovium. Although it is often para-articular in loca-
tion, the tumor rarely occurs within the joint capsule.
In some instances, it arises in areas without any obvious
relationship to synovial structures. Synovial sarcomas
of the head and neck are rare (only 4% to 9% of all
cases), and many of these apparently are unrelated to
joint areas.
Over 90% of synovial sarcomas exhibit a speciﬁc
balanced reciprocal translocation between the X chro-
mosome and chromosome 18: t(X;18)(p11.2;q11.2).
Detection of this translocation can be helpful in making
the diagnosis, evaluating tumor margins, and conﬁrm-
ing the presence of metastatic disease.
CLINICAL FEATURES
Synovial sarcomas most frequently occur in teenagers
and young adults, and there is a slight male predilec-
tion. The most common presentation is a gradually
enlarging mass that often is associated with pain or
tenderness. Tumors in the head and neck region are
most common in the paravertebral and parapharyn-
geal areas. Often, they produce symptoms of dyspha-
gia, dyspnea, or hoarseness. Oral tumors most often
have been reported in the tongue and cheek.
Fig. 12-137 Embryonal rhabdomyosarcoma. Medium-
power view showing a sheet of small, round cells with
hyperchromatic nuclei. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

562 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Classic synovial sarcoma is a biphasic tumor that con-
sists of a combination of spindle cells and epithelial
cells (Fig. 12-138). The spindle cells usually predomi-
nate and produce a pattern that is similar to ﬁbrosar-
coma. Within this spindle cell background are groups
of cuboidal to columnar epithelial cells that surround
glandlike spaces or form nests, cords, or whorls. Calci-
ﬁcations are seen in around 30% of cases.
Less frequently, the tumor is monophasic and con-
sists primarily or entirely of spindle cells. The diagnosis
of these tumors is difﬁcult, but most lesions demon-
strate at least focal positive immunostaining of spindle
cells for cytokeratin or epithelial membrane antigen.
Rare examples of monophasic epithelial synovial sar-
comas also have been reported.
TREATMENT AND PROGNOSIS
Treatment of synovial sarcoma usually consists of
radical surgical excision, possibly with adjunctive radi-
ation therapy or chemotherapy. The prognosis is poor
because the tumor has a high rate of recurrence and
metastasis. The reported 5-year survival rate ranges
from 36% to 64%. However, the 10-year survival rate
drops to 20% to 38% because of the high rate of late
metastases.
ALVEOLAR SOFT-PART SARCOMA
The alveolar soft-part sarcoma is a rare neoplasm of
uncertain histogenesis. About 25% of all cases occur in
the head and neck.
CLINICAL FEATURES
The alveolar soft-part sarcoma is usually a slow-growing,
painless mass. The tumor is most common in young
adults and children. In adults, the lower extremity is
the most frequent location; in younger patients, the
head and neck region is the most common site. The
orbit and tongue are the most common head and neck
locations, and the median age for lingual tumors is
only 5 to 8 years. During the ﬁrst 2 decades of life, the
tumor shows nearly a 2:1 female predilection. However,
cases that develop after the age of 30 are more common
in men.
HISTOPATHOLOGIC FEATURES
Alveolar soft-part sarcomas are composed of groups of
large, polygonal cells that are arranged around central
alveolar spaces (Fig. 12-139). These cells have abun-
dant granular, eosinophilic cytoplasm and one to
several vesicular nuclei. Mitoses are rare. Special stains
will reveal PAS-positive, diastase-resistant crystals that
are highly characteristic for this tumor. Under the elec-
tron microscope, these crystals appear as rhomboid,
polygonal, or rod-shaped structures with a regular lat-
ticework pattern.
Immunohistochemistry has played a limited role in
the speciﬁc diagnosis of alveolar soft-part sarcoma,
except to rule out other tumors with more characteris-
tic staining patterns. However, molecular analysis of
fresh tissue may be helpful in difﬁcult cases because
the tumor shows a characteristic genetic translocation,
der(17)t(X;17)(p11.2;q25), which results in an ASPL-
TFE3 fusion gene. Recently, an antibody against the
C-terminus of the ASPL-TFE3 fusion protein has been
created, allowing the development of a sensitive immu-
nohistochemical marker for this tumor.
Fig. 12-138 Synovial sarcoma. Biphasic tumor consisting
of spindle cells intermixed with cuboidal to columnar
epithelial cells that line glandlike spaces.
Fig. 12-139 Alveolar soft-part sarcoma. Alveolar
collections of large, polygonal cells containing abundant
granular cytoplasm. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 563
TREATMENT AND PROGNOSIS
Most patients with alveolar soft-part sarcomas are
treated by radical surgical excision, possibly in con-
junction with radiation therapy and chemotherapy.
The prognosis is poor, often as a result of late metasta-
sis. One study reported a 5-year survival rate of 60%,
but the 20-year survival rate dropped to only 15%.
Another series showed a 5-year disease-free survival of
71% for patients with localized disease, compared with
only 20% for patients who presented with metastatic
disease. However, the prognosis for children appears
to be better than for adults. Lingual and orbital tumors
have very high survival rates, possibly because of
smaller tumor size at diagnosis and younger patient
age.
METASTASES TO THE ORAL
SOFT TISSUES
Metastatic tumors to the oral cavity are uncommon and
represent approximately 1% of all oral malignancies.
Such metastases can occur to bone (see page 669) or
to the oral soft tissues. The mechanism by which tumors
can spread to the oral cavity is poorly understood.
Primary malignancies from immediately adjacent
tissues might be able to spread by a lymphatic route;
however, such a mechanism cannot explain metastases
from tumors from lower parts of the body, which are
almost certainly blood-borne and should be ﬁltered out
by the lungs. One possible explanation for blood-borne
metastases to the head and neck, especially in the
absence of pulmonary metastases, is Batson’s plexus,
a valveless vertebral venous plexus that might allow
retrograde spread of tumor cells, bypassing ﬁltration
through the lungs.
CLINICAL FEATURES
The most common site for oral soft tissue metastases is
the gingiva, which accounts for slightly more than 50%
of all cases. The next most common site is the tongue,
which accounts for 25% of cases. The lesion usually
appears as a nodular mass that often resembles a
hyperplastic or reactive growth, such as a pyogenic
granuloma (Figs. 12-140 to 12-142). Occasionally, the
lesion appears as a surface ulceration. Adjacent teeth
may become loosened by an underlying destruction of
the alveolar bone. The presence of teeth may play an
important role in the preference of metastases for the
gingiva. Once malignant cells reach the oral cavity, the
rich vascular network of inﬂamed gingival tissues may
serve as a fertile site for further growth.
Oral soft tissue metastases are more common in
males and are seen most frequently in middle-aged
and older adults. Almost any malignancy from any
body site is capable of metastasis to the oral cavity, and
a wide variety of tumors have been reported to spread
to the mouth. (However, there is probably a bias in the
literature toward reporting more unusual cases.) In the
cases reported, lung cancer is responsible for more
than one third of all oral soft tissue metastases in men,
followed by renal carcinoma and melanoma. Although
prostate cancer is common in men, metastases from
these tumors have an afﬁnity for bone and rarely occur
in soft tissues. For women, breast cancer accounts
for 25% of all cases, followed by malignancies of the
genital organs, lung, bone, and kidney. It is probable
that in the future we will see an increased number of
metastatic lung cancers in women (today this is the
most common cancer killer of women in the United
States).
In most cases the primary tumor already is known
when the metastatic lesion is discovered. In some cases,
Fig. 12-140 Metastatic melanoma. Pigmented nodule of
the mandibular gingiva.
Fig. 12-141 Metastatic renal carcinoma. Nodular mass of
the left lateral border of the tongue. (Courtesy of Dr. Mark
Bowden.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

564 ORAL AND MAXILLOFACIAL PATHOLOGY
however, the oral lesion is the ﬁrst sign of the malig-
nant disease.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of the metastatic neo-
plasm should resemble the tumor of origin (Fig.
12-143). Most cases represent carcinomas; metastatic
sarcomas to the oral region are rare.
TREATMENT AND PROGNOSIS
The prognosis for patients with metastatic tumors is
generally poor because other metastatic sites also are
frequently present. Management of the oral lesion is
usually palliative and should be coordinated with the
patient’s overall treatment.
BIBLIOGRAPHY
Fibroma and Giant Cell Fibroma
Barker DS, Lucas RB: Localised ﬁbrous overgrowth of the oral
mucosa, Br J Oral Surg 5:86-92, 1967.
Brannon RB, Pousson RR: The retrocuspid papillae: a clinical
evaluation of 51 cases, J Dent Hyg 77:180-184, 2003.
Buchner A, Merrell PW, Hansen LS et al: The retrocuspid papilla
of the mandibular lingual gingiva, J Periodontol 61:586-590,
1990.
Gonsalves WC, Chi AC, Neville BW: Common oral lesions: part
II. Masses and neoplasia, Am Fam Physician 75:509-512,
2007.
Houston GD: The giant cell ﬁbroma: a review of 464 cases, Oral
Surg Oral Med Oral Pathol 53:582-587, 1982.
Magnusson BC, Rasmusson LG: The giant cell ﬁbroma: a review
of 103 cases with immunohistochemical ﬁndings, Acta
Odontol Scand 53:293-296, 1995.
Savage NW, Monsour PA: Oral ﬁbrous hyperplasias and the
giant cell ﬁbroma, Aust Dent J 30:405-409, 1985.
Souza LB, Andrade ES, Miguel MC et al: Origin of stellate giant
cells in oral ﬁbrous lesions determined by immunohisto-
chemical expression of vimentin, HHF-35, CD68 and factor
XIIIa, Pathology 36:316-320, 2004.
Weathers DR, Callihan MD: Giant cell ﬁbroma, Oral Surg Oral
Med Oral Pathol 37:374-384, 1974.
Epulis Fissuratum
Buchner A, Begleiter A, Hansen LS: The predominance of epulis
ﬁssuratum in females, Quintessence Int 15:699-702, 1984.
Cutright DE: Osseous and chondromatous metaplasia caused
by dentures, Oral Surg Oral Med Oral Pathol 34:625-633,
1972.
Cutright DE: The histopathologic ﬁndings in 583 cases of epulis
ﬁssuratum, Oral Surg Oral Med Oral Pathol 37:401-411,
1974.
Inﬂammatory Papillary Hyperplasia
Antonelli JR, Panno FV, Witko A: Inﬂammatory papillary hyper-
plasia: supraperiosteal excision by the blade-loop technique,
Gen Dent 46:390-397, 1998.
Bergendal T, Heimdahl A, Isacsson G: Surgery in the treatment
of denture-related inﬂammatory papillary hyperplasia of the
palate, Int J Oral Surg 9:312-319, 1980.
BA
Fig. 12-142 Metastatic adenocarcinoma of the colon. A, Focal swelling of the left
retromolar pad area. B, Same patient 4 weeks later. Note the marked enlargement of the
lesion. (Courtesy of Dr. George Blozis.)
Fig. 12-143 Metastatic carcinoma of the lung. Aggregates
of malignant epithelial cells below the surface epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 12 SOFT TISSUE TUMORS 565
Bhaskar SN, Beasley JD III, Cutright DE: Inﬂammatory papillary
hyperplasia of the oral mucosa: report of 341 cases, J Am Dent
Assoc 81:949-952, 1970.
Budtz-Jørgensen E: Oral mucosal lesions associated with the
wearing of removable dentures, J Oral Pathol 10:65-80,
1981.
Cutright DE: Morphogenesis of inﬂammatory papillary hyper-
plasia, J Prosthet Dent 33:380-385, 1975.
Infante-Cossio P, Martinez-de-Fuentes R, Torres-Carranza E
et al: Inﬂammatory papillary hyperplasia of the palate: treat-
ment with carbon dioxide laser, followed by restoration with
an implant-supported prosthesis, Br J Oral Maxillofac Surg
45:658-660, 2007.
Reichart PA, Schmidt-Westhausen A, Samaranayake LP et al:
Candida-associated palatal papillary hyperplasia in HIV infec-
tion, J Oral Pathol Med 23:403-405, 1994.
Salonen MAM, Raustia AM, Oikarinen KS: Effect of treatment of
palatal inﬂammatory papillary hyperplasia with local and
systemic antifungal agents accompanied by renewal of com-
plete dentures, Acta Odontol Scand 54:87-91, 1996.
Fibrous Histiocytoma
Alves FA, Vargas PA, Siqueira SA et al: Benign ﬁbrous histiocy-
toma of the buccal mucosa: case report with immunohisto-
chemical features, J Oral Maxillofac Surg 61:269-271, 2003.
Gray PB, Miller AS, Loftus MJ: Benign ﬁbrous histiocytoma of the
oral/perioral regions: report of a case and review of 17 addi-
tional cases, J Oral Maxillofac Surg 50:1239-1242, 1992.
Harsanyi BB, Larsson A: Xanthomatous lesions of the mandible:
osseous expression of non-X histiocytosis and benign ﬁbrous
histiocytoma, Oral Surg Oral Med Oral Pathol 65:551-566,
1988.
Heo M-S, Cho H-J, Kwon K-J et al: Benign ﬁbrous histiocytoma
in the mandible, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 97:276-280, 2004.
Thompson SH, Shear M: Fibrous histiocytomas of the oral and
maxillofacial regions, J Oral Pathol 13:282-294, 1984.
Fibromatosis
Buitendijk S, van de Ven CP, Dumans TG et al: Pediatric aggres-
sive ﬁbromatosis: a retrospective analysis of 13 patients and
review of the literature, Cancer 104:1090-1099, 2005.
Dormans JP, Spiegel D, Meyer J et al: Fibromatoses in childhood:
the desmoid/ﬁbromatosis complex, Med Pediatr Oncol 37:126-
131, 2001.
Fowler CB, Hartman KS, Brannon RB: Fibromatosis of the oral
and paraoral region, Oral Surg Oral Med Oral Pathol 77:373-
386, 1994.
Gnepp DR, Henley J, Weiss S et al: Desmoid ﬁbromatosis of the
sinonasal tract and nasopharynx: a clinicopathologic study of
25 cases, Cancer 78:2572-2579, 1996.
Vally IM, Altini M: Fibromatoses of the oral and paraoral soft
tissues and jaws: review of the literature and report of 12
new cases, Oral Surg Oral Med Oral Pathol 69:191-198,
1990.
Myoﬁbroma (Myoﬁbromatosis)
Allon I, Vered M, Buchner A et al: Central (intraosseous) myoﬁ-
broma of the mandible: clinical, radiologic, and histopatho-
logic features of a rare lesion, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 103:e45-e53, 2007.
Foss RD, Ellis GL: Myoﬁbromas and myoﬁbromatosis of the oral
region: a clinicopathologic analysis of 79 cases, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 89:57-65, 2000.
Jones AC, Freedman PD, Kerpel SM: Oral myoﬁbromas: a report
of 13 cases and review of the literature, J Oral Maxillofac Surg
52:870-875, 1994.
Lingen MW, Mostoﬁ RS, Solt DB: Myoﬁbromas of the oral cavity,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 80:297-302,
1995.
Matthews MS, Tabor MW, Thompson SH et al: Infantile myoﬁ-
bromatosis of the mandible, J Oral Maxillofac Surg 48:884-
889, 1990.
Sedghizadeh PP, Allen CM, Kalmar JR et al: Solitary central
myoﬁbroma presenting in the gnathic region, Ann Diagn
Pathol 8:284-289, 2004.
Vered M, Allon I, Buchner A et al: Clinico-pathologic correla-
tions of myoﬁbroblastic tumor of the oral cavity. II. Myoﬁ-
broma and myoﬁbromatosis of the oral soft tissues, J Oral
Pathol Med 36:304-314, 2007.
Oral Focal Mucinosis
Aldred MJ, Talacko AA, Ruljancich K et al: Oral focal mucinosis:
report of 15 cases and review of the literature, Pathology
35:393-396, 2003.
Buchner A, Merrell PW, Leider AS et al: Oral focal mucinosis,
Int J Oral Maxillofac Surg 19:337-340, 1990.
Soda G, Baiocchini A, Bosco D et al: Oral focal mucinosis of the
tongue, Pathol Oncol Res 4:304-307, 1998.
Tomich CE: Oral focal mucinosis: a clinicopathologic and histo-
chemical study of eight cases, Oral Surg Oral Med Oral Pathol
38:714-724, 1974.
Pyogenic Granuloma
Bhaskar SN, Jacoway JR: Pyogenic granuloma—clinical features,
incidence, histology, and result of treatment: report of 242
cases, J Oral Surg 24:391-398, 1966.
Daley TD, Nartey NO, Wysocki GP: Pregnancy tumor: an analy-
sis, Oral Surg Oral Med Oral Pathol 72:196-199, 1991.
Epivatianos A, Antoniades D, Zaraboukas T et al: Pyogenic granu-
loma of the oral cavity: comparative study of its clinicopatho-
logical and immunohistochemical features, Pathol Int 55:
391-397, 2005.
Kerr DA: Granuloma pyogenicum, Oral Surg Oral Med Oral Pathol
4:158-176, 1951.
Mills SE, Cooper PH, Fechner RE: Lobular capillary hemangi-
oma: the underlying lesion of pyogenic granuloma: a study of
73 cases from the oral and nasal mucous membranes, Am J
Surg Pathol 4:471-479, 1980.
Patrice SJ, Wiss K, Mulliken JB: Pyogenic granuloma (lobular
capillary hemangioma): a clinicopathologic study of 178
cases, Pediatr Dermatol 8:267-276, 1991.
Toida M, Hasegawa T, Watanabe F et al: Lobular capillary
hemangioma of the oral mucosa: clinicopathological study of
43 cases with a special reference to immunohistochemical
characterization of the vascular elements, Pathol Int 53:1-7,
2003.
Zain RB, Khoo SP, Yeo JF: Oral pyogenic granuloma (excluding
pregnancy tumor)—a clinical analysis of 304 cases, Singapore
Dent J 20:8-10, 1995.
Peripheral Giant Cell Granuloma
Carvalho YR, Loyola AM, Gomez RS et al: Peripheral giant cell
granuloma. An immunohistochemical and ultrastructural
study, Oral Dis 1:20-25, 1995.
Flanagan AM, Tinkler SMB, Horton MA et al: The multinucleate
cells in giant cell granulomas of the jaw are osteoclasts, Cancer
62:1139-1145, 1988.
Giansanti JS, Waldron CA: Peripheral giant cell granuloma:
review of 720 cases, J Oral Surg 17:787-791, 1969.
Katsikeris N, Kakarantza-Angelopoulou E, Angelopoulos AP:
Peripheral giant cell granuloma: clinicopathologic study of
224 new cases and review of 956 reported cases, Int J Oral
Maxillofac Surg 17:94-99, 1988. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

566 ORAL AND MAXILLOFACIAL PATHOLOGY
Motamedi MHK, Eshghyar N, Jafari SM et al: Peripheral and
central giant cell granulomas of the jaws: a demographic
study, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:
e39-e43, 2007.
Smith BR, Fowler CB, Svane TJ: Primary hyperparathyroidism
presenting as a “peripheral” giant cell granuloma, J Oral Max-
illofac Surg 46:65-69, 1988.
Peripheral Ossifying Fibroma
Buchner A, Hansen LS: The histomorphologic spectrum of
peripheral ossifying ﬁbroma, Oral Surg Oral Med Oral Pathol
63:452-461, 1987.
Cuisia ZE, Brannon RB: Peripheral ossifying ﬁbroma—a clinical
evaluation of 134 pediatric cases, Pediatr Dent 23:245-248,
2001.
Kendrick F, Waggoner WF: Managing a peripheral ossifying
ﬁbroma, ASDC J Dent Child 63:135-138, 1996.
Kenney JN, Kaugars GE, Abbey LM: Comparison between the
peripheral ossifying ﬁbroma and peripheral odontogenic
ﬁbroma, J Oral Maxillofac Surg 47:378-382, 1989.
Walters JD, Will JK, Hatﬁeld RD et al: Excision and repair of the
peripheral ossifying ﬁbroma: a report of 3 cases, J Periodontol
72:939-944, 2001.
Zain RB, Fei YJ: Fibrous lesions of the gingiva: a histopathologic
analysis of 204 cases, Oral Surg Oral Med Oral Pathol 70:466-
470, 1990.
Lipoma
Bataineh AB, Mansour MJ, Abalkhail A: Oral inﬁltrating lipomas,
Br J Oral Maxillofac Surg 34:520-523, 1996.
Billings SD, Henley JD, Summerlin D-J et al: Spindle cell lipoma
of the oral cavity, Am J Dermatopathol 28:28-31, 2006.
Chen S-Y, Fantasia JE, Miller AS: Myxoid lipoma of oral soft
tissue: a clinical and ultrastructural study, Oral Surg Oral Med
Oral Pathol 57:300-307, 1984.
Darling MR, Daley TD: Intraoral chondroid lipoma: a case report
and immunohistochemical investigation, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 99:331-333, 2005.
Epivatianos A, Markopoulos AK, Papanayotou P: Benign
tumors of adipose tissue of the oral cavity: a clinicopathologic
study of 13 cases, J Oral Maxillofac Surg 58:1113-1117,
2000.
Fregnani ER, Pires FR, Falzoni R et al: Lipomas of the oral cavity:
clinical ﬁndings, histological classiﬁcation and proliferative
activity of 46 cases, Int J Oral Maxillofac Surg 32:49-53,
2003.
Furlong MA, Fanburg-Smith JC, Childers ELB: Lipoma of the
oral and maxillofacial region: site and subclassiﬁcation of 125
cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98:441-
450, 2004.
Garavaglia J, Gnepp DR: Intramuscular (inﬁltrating) lipoma of
the tongue, Oral Surg Oral Med Oral Pathol 63:348-350,
1987.
Horie N, Shimoyama T, Kaneko T et al: Traumatic herniation of
the buccal fat pad, Pediatr Dent 23:249-252, 2001.
Traumatic Neuroma
Lee EJ, Calcaterra TC, Zuckerbraun L: Traumatic neuromas of
the head and neck, Ear Nose Throat J 77:670-676, 1998.
Peszkowski MJ, Larsson Å: Extraosseous and intraosseous oral
traumatic neuromas and their association with tooth extrac-
tion, J Oral Maxillofac Surg 48:963-967, 1990.
Sist TC Jr, Greene GW: Traumatic neuroma of the oral cavity:
report of thirty-one new cases and review of the literature,
Oral Surg Oral Med Oral Pathol 51:394-402, 1981.
Vora AR, Loescher AR, Craig GT et al: A light microscopical
study on the structure of traumatic neuromas of the human
lingual nerve, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 99:395-403, 2005.
Palisaded Encapsulated Neuroma
Chauvin PJ, Wysocki GP, Daley TD et al: Palisaded encapsulated
neuroma of oral mucosa, Oral Surg Oral Med Oral Pathol
73:71-74, 1992.
Dakin MC, Leppard B, Theaker JM: The palisaded, encapsulated
neuroma (solitary circumscribed neuroma), Histopathology
20:405-410, 1992.
Dover JS, From L, Lewis A: Palisaded encapsulated neuromas:
a clinicopathologic study, Arch Dermatol 125:386-389,
1989.
Fletcher CDM: Solitary circumscribed neuroma of the skin (so-
called palisaded, encapsulated neuroma): a clinicopathologic
and immunohistochemical study, Am J Surg Pathol 13:574-
580, 1989.
Magnusson B: Palisaded encapsulated neuroma (solitary circum-
scribed neuroma) of the oral mucosa, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 82:302-304, 1996.
Neurilemoma and Neuroﬁbroma
Chi AC, Carey J, Muller S: Intraosseous schwannoma of the
mandible: a case report and review of the literature, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 96:54-65, 2003.
Colreavy MP, Lacy PD, Hughes J et al: Head and neck
schwannomas—a 10 year review, J Laryngol Otol 114:119-
124, 2000.
Ellis GL, Abrams AM, Melrose RJ: Intraosseous benign neural
sheath neoplasms of the jaws: report of seven new cases and
review of the literature, Oral Surg Oral Med Oral Pathol 44:731-
743, 1977.
Ferner RE: Neuroﬁbromatosis 1 and neuroﬁbromatosis 2: a
twenty-ﬁrst century perspective, Lancet Neurol 6:340-351,
2007.
Hanemann CO, Evans DG: News on the genetics, epidemiology,
medical care and translational research of schwannomas,
J Neurol 253:1533-1541, 2006.
Marocchio LS, Oliveira DT, Pereira MC et al: Sporadic and mul-
tiple neuroﬁbromas in the head and neck region: a retrospec-
tive study of 33 years, Clin Oral Invest 11:165-169, 2007.
Muramatsu T, Hashimoto S, Inoue T et al: Melanotic schwannoma
arising in the ﬂoor of the mouth, J Oral Maxillofac Surg 63:703-
706, 2005.
Williams HK, Cannell H, Silvester K et al: Neurilemmoma of the
head and neck, Br J Oral Maxillofac Surg 31:32-35, 1993.
Woodruff JM: The pathology and treatment of peripheral nerve
tumors and tumor-like conditions, CA Cancer J Clin 43:290-
308, 1993.
Wright BA, Jackson D: Neural tumors of the oral cavity, Oral Surg
Oral Med Oral Pathol 49:509-522, 1980.
Neuroﬁbromatosis Type I
D’Ambrosio JA, Langlais RP, Young RS: Jaw and skull changes
in neuroﬁbromatosis, Oral Surg Oral Med Oral Pathol 66:391-
396, 1988.
Edwards PC, Fantasia JE, Saini T et al: Clinically aggressive
central giant cell granulomas in two patients with neuroﬁbro-
matosis 1, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
102:765-772, 2006.
Ferner RE: Neuroﬁbromatosis 1 and neuroﬁbromatosis 2: a
twenty-ﬁrst century perspective, Lancet Neurol 6:340-351,
2007.
Lee L, Yan Y-H, Pharoah MJ: Radiographic features of the man-
dible in neuroﬁbromatosis. A report of 10 cases and review
of the literature, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 81:361-367, 1996. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 12 SOFT TISSUE TUMORS 567
Neville BW, Hann J, Narang R et al: Oral neuroﬁbrosarcoma
associated with neuroﬁbromatosis type I, Oral Surg Oral Med
Oral Pathol 72:456-461, 1991.
Overdiek A, Feifel H, Schaper J et al: Diagnostic delay of NF1 in
hemifacial hypertrophy due to plexiform neuroﬁbromas,
Brain Dev 28:275-280, 2006.
Rasmussen SA, Yang Q, Friedman JM: Mortality in neuroﬁbro-
matosis 1: an analysis using U.S. death certiﬁcates, Am J Hum
Genet 68:1110-1118, 2001.
Riccardi VM: Neuroﬁbromatosis: phenotype, natural history, and path-
ogenesis, ed 2, Baltimore, 1992, Johns Hopkins University Press.
Ruggieri M: The different forms of neuroﬁbromatosis, Childs Nerv
Syst 15:295-308, 1999.
Shapiro SD, Abramovitch K, Van Dis ML et al: Neuroﬁbromato-
sis: oral and radiographic manifestations, Oral Surg Oral Med
Oral Pathol 58:493-498, 1984.
Yazdizadeh M, Tapia JL, Baharvand M et al: A case of neuroﬁ-
bromatosis-Noonan syndrome with a central giant cell granu-
loma, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
98:316-320, 2004.
Multiple Endocrine Neoplasia Type 2B
Calender A, Giraud S, Schuffenecker I et al: Genetic testing in
presymptomatic diagnosis of multiple endocrine neoplasia,
Horm Res 47:199-210, 1997.
Carney JA: Familial multiple endocrine neoplasia: the ﬁrst 100
years, Am J Surg Pathol 29:254-274, 2005.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Multiple endocrine
neoplasia, type 2B (multiple mucosal neuroma syndrome,
MEN type 3). In Syndromes of the head and neck, ed 4, pp 462-
468, New York, 2001, Oxford University Press.
Kahn MA, Cote GJ, Gagel RF: RET protooncogene mutational
analysis in multiple endocrine neoplasia syndrome type 2B.
Case report and review of the literature, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 82:288-294, 1996.
Lakhani VT, You YN, Wells SA: The multiple endocrine neopla-
sia syndromes, Annu Rev Med 58:253-265, 2007.
Melanotic Neuroectodermal Tumor of Infancy
Barrett AW, Morgan M, Ramsay AD et al: A clinicopathologic
and immunohistochemical analysis of melanotic neuroecto-
dermal tumor of infancy, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 93:688-698, 2002.
Bouckaert MMR, Raubenheimer EJ: Gigantiform melanotic neu-
roectodermal tumor of infancy, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 86:569-572, 1998.
Kapadia SB, Frisman DM, Hitchcock CL et al: Melanotic neuro-
ectodermal tumor of infancy: clinicopathological, immuno-
histochemical, and ﬂow cytometric study, Am J Surg Pathol
17:566-573, 1993.
Kruse-Lösler B, Gaertner C, Bürger H et al: Melanotic neuroec-
todermal tumor of infancy: systematic review of the literature
and presentation of a case, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 102:204-216, 2006.
Pettinato G, Manivel C, d’Amore ESG et al: Melanotic neuroec-
todermal tumor of infancy: a reexamination of a histogenetic
problem based on immunohistochemical, ﬂow cytometric,
and ultrastructural study of 10 cases, Am J Surg Pathol 15:233-
245, 1991.
Paraganglioma
Hodge KM, Byers RM, Peters LJ: Paragangliomas of the head
and neck, Arch Otolaryngol Head Neck Surg 114:872-877,
1988.
Jordan JA, Roland PS, McManus C et al: Stereotactic radiosur-
gery for glomus jugulare tumors, Laryngoscope 110:35-38,
2000.
LaMuraglia GM, Fabian RL, Brewster DC et al: The current surgi-
cal management of carotid body paragangliomas, J Vasc Surg
15:1038-1045, 1992.
Pellitteri PK, Rinaldo A, Myssiorek D et al: Paragangliomas of
the head and neck, Oral Oncol 40:563-575, 2004.
Robertson JH, Gardner G, Cocke EW Jr: Glomus jugulare tumors,
Clin Neurosurg 41:39-61, 1994.
van den Berg, R: Imaging and management of head and neck
paragangliomas, Eur Radiol 15:1310-1318, 2005.
Granular Cell Tumor
Brannon RB, Anand PM: Oral granular cell tumors: an analysis
of 10 new pediatric and adolescent cases and a review of the
literature, J Clin Pediatr Dent 29:69-74, 2004.
Collins BM, Jones AC: Multiple granular cell tumors of the oral
cavity: report of a case and review of the literature, J Oral
Maxillofac Surg 53:707-711, 1995.
Fliss DM, Puterman M, Zirkin H et al: Granular cell lesions in
head and neck: a clinicopathological study, J Surg Oncol
42:154-160, 1989.
Mirchandani R, Sciubba JJ, Mir R: Granular cell lesions of the
jaws and oral cavity: a clinicopathologic, immunohistochemi-
cal, and ultrastructural study, J Oral Maxillofac Surg 47:1248-
1255, 1989.
Stewart CM, Watson RE, Eversole LR et al: Oral granular cell
tumors: a clinicopathologic and immunocytochemical study,
Oral Surg Oral Med Oral Pathol 65:427-435, 1988.
Williams HK, Williams DM: Oral granular cell tumours: a histo-
logical and immunocytochemical study, J Oral Pathol Med
26:164-169, 1997.
Congenital Epulis
Damm DD, Cibull ML, Geissler RH et al: Investigation into the
histogenesis of congenital epulis of the newborn, Oral Surg
Oral Med Oral Pathol 76:205- 212, 1993.
Kumar P, Kim HHS, Zahtz GD et al: Obstructive congenital
epulis: prenatal diagnosis and perinatal management, Laryn-
goscope 112:1935-1939, 2002.
Lack EE, Worsham GF, Callihan MD et al: Gingival granular cell
tumors of the newborn (congenital “epulis”): a clinical and
pathologic study of 21 patients, Am J Surg Pathol 5:37-46,
1981.
Loyola AM, Gatti AF, Santos Pinto D Jr et al: Alveolar and extra-
alveolar granular cell lesions of the newborn: report of case
and review of literature, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 84:668-671, 1997.
O’Brien FV, Pielou WD: Congenital epulis: its natural history,
Arch Dis Child 46:559-560, 1971.
Hemangioma and Vascular Malformations
Adams DM, Lucky AW: Cervicofacial vascular anomalies. I.
Hemangiomas and other benign vascular tumors, Semin
Pediatr Surg 15:124-132, 2006.
Bunel K, Sindet-Pederson S: Central hemangioma of the mandi-
ble, Oral Surg Oral Med Oral Pathol 75:565-570, 1993.
Chang MW: Updated classiﬁcation of hemangiomas and other
vascular anomalies, Lymphat Res Biol 1:259-265, 2003.
Drolet BA, Esterly NB, Frieden IJ: Hemangiomas in children, N
Engl J Med 341:173-181, 1999.
Elluru RG, Azizkhan RG: Cervicofacial vascular anomalies. II. Vas-
cular malformations, Semin Pediatr Surg 15:133-139, 2006.
Ethunandan M, Mellor TK: Haemangiomas and vascular malfor-
mations of the maxillofacial region—a review, Br J Oral Maxil-
lofac Surg 44:263-272, 2006.
Fishman SJ, Mulliken JB: Hemangiomas and vascular malforma-
tions of infancy and childhood, Pediatr Clin North Am 40:1177-
1200, 1993. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

568 ORAL AND MAXILLOFACIAL PATHOLOGY
Greene LA, Freedman PD, Friedman JM et al: Capillary heman-
gioma of the maxilla. A report of two cases in which angiog-
raphy and embolization were used, Oral Surg Oral Med Oral
Pathol 70:268-273, 1990.
Kaban LB, Mulliken JB: Vascular anomalies of the maxillofacial
region, J Oral Maxillofac Surg 44:203-213, 1986.
MacArthur CJ: Head and neck hemangiomas of infancy, Curr
Opin Otolaryngol Head Neck Surg 14:397-405, 2006.
Sadan N, Wolach B: Treatment of hemangiomas of infants with
high doses of prednisone, J Pediatr 128:141-146, 1996.
Zlotogorski A, Buchner A, Kaffe I et al: Radiological features of
central haemangioma of the jaws, Dentomaxillofac Radiol
34:292-296, 2005.
Sturge-Weber Angiomatosis
Di Rocco C, Tamburrini G: Sturge-Weber syndrome, Childs Nerv
Syst 22:909-921, 2006.
Hylton RP: Use of CO2 laser for gingivectomy in a patient with
Sturge-Weber disease complicated by Dilantin hyperplasia,
J Oral Maxillofac Surg 44:646-648, 1986.
Sujansky E, Conradi S: Outcome of Sturge-Weber syndrome in
52 adults, Am J Med Genet 57:35-45, 1995.
Sullivan TJ, Clarke MP, Morin JD: The ocular manifestations of
the Sturge-Weber syndrome, J Pediatr Ophthalmol Strabismus
29:349-356, 1992.
Yukna RA, Cassingham RJ, Carr RF: Periodontal manifestations
and treatment in a case of Sturge-Weber syndrome, Oral Surg
Oral Med Oral Pathol 47:408-415, 1979.
Nasopharyngeal Angioﬁbroma
Bales C, Kotapka M, Loevner LA et al: Craniofacial resection of
advanced juvenile nasopharyngeal angioﬁbroma, Arch Otolar-
yngol Head Neck Surg 128:1071-1078, 2002.
Beham A, Beham-Schmid C, Regauer S et al: Nasopharyngeal
angioﬁbroma: true neoplasm or vascular malformation? Adv
Anat Pathol 7:36-46, 2000.
Douglas R, Wormald P-J: Endoscopic surgery for juvenile naso-
pharyngeal angioﬁbroma: Where are the limits? Curr Opin
Otolaryngol Head Neck Surg 14:1-5, 2006.
Lee JT, Chen P, Safa A et al: The role of radiation in the treatment
of advanced juvenile angioﬁbroma, Laryngoscope 112:1213-
1220, 2002.
Lloyd G, Howard D, Phelps P et al: Juvenile angioﬁbroma: the
lessons of 20 years of modern imaging, J Laryngol Otol
113:127-134, 1999.
Makek MS, Andrews JC, Fisch U: Malignant transformation of a
nasopharyngeal angioﬁbroma, Laryngoscope 99:1088-1092,
1989.
Marshall AH, Bradley PJ: Management dilemmas in the treat-
ment and follow-up of advanced juvenile nasopharyngeal
angioﬁbroma, ORL J Otorhinolaryngol Relat Spec 68:273-278,
2006.
McDaniel RK, Houston GD: Juvenile nasopharyngeal angioﬁ-
broma with lateral extension into the cheek: report of case,
J Oral Maxillofac Surg 53:473-476, 1995.
Hemangiopericytoma–Solitary Fibrous Tumor
Alawi F, Stratton D, Freedman PD: Solitary ﬁbrous tumor of the
oral soft tissues, Am J Surg Pathol 25:900-910, 2001.
Carew JF, Singh B, Kraus DH: Hemangiopericytoma of the head
and neck, Laryngoscope 109:1409-1411, 1999.
Compagno J: Hemangiopericytoma-like tumors of the nasal
cavity: a comparison with hemangiopericytoma of soft tissues,
Laryngoscope 88:460-469, 1978.
Eichhorn JH, Dickersin R, Bhan AK et al: Sinonasal hemangio-
pericytoma: a reassessment with electron microscopy, immu-
nohistochemistry, and long-term follow-up, Am J Surg Pathol
14:856-866, 1990.
Espat NJ, Lewis JJ, Leung D et al: Conventional hemangiopericy-
toma. Modern analysis of outcome, Cancer 95:1746-1751,
2002.
Fletcher CD: Hemangiopericytoma—a dying breed? Reappraisal
of an entity and its variants, Curr Opin Pathol 1:19-23,
1994.
Gengler C, Guillou L: Solitary ﬁbrous tumour and haemangio-
pericytoma: evolution of a concept, Histopathology 48:63-74,
2006.
Veltrini VC, Etges A, Magalhães MHCG et al: Solitary ﬁbrous
tumor of the oral mucosa—morphological and immunohisto-
chemical proﬁle in the differential diagnosis with hemangio-
pericytoma, Oral Oncol 39:420-426, 2003.
Watanabe K, Saito A, Suzuki M et al: True hemangiopericytoma
of the nasal cavity. Immunohistochemical and electron
microscopic study of 2 cases and a review of the literature on
sinonasal hemangiopericytomas, Arch Pathol Lab Med 125:686-
690, 2001.
Weiss SW, Goldblum JR: Hemangiopericytoma–solitary ﬁbrous
tumor. In Weiss SW, Goldblum JR, editors: Enzinger and
Weiss’s soft tissue tumors, ed 5, pp 1120-1134, Philadelphia,
2008, Elsevier.
Lymphangioma
Brennan TD, Miller AS, Chen S-Y: Lymphangiomas of the oral
cavity: a clinicopathologic, immunohistochemical, and elec-
tron-microscopic study, J Oral Maxillofac Surg 55:932-935,
1997.
Jian X-C: Surgical management of lymphangiomatous or
lymphangiohemangiomatous macroglossia, J Oral Maxillofac
Surg 63:15-19, 2005.
Levin LS, Jorgenson RJ, Jarvey BA: Lymphangiomas of the alveo-
lar ridges in neonates, Pediatrics 58:881-884, 1976.
Ogita S, Tsuto T, Deguchi E et al: OK-432 therapy for unresect-
able lymphangiomas in children, J Pediatr Surg 26:263-270,
1991.
Okazaki T, Iwatani S, Yanai T et al: Treatment of lymphangioma
in children: our experience of 128 cases, J Pediatr Surg
42:386-389, 2007.
Osborne TE, Levin LS, Tilghman DM et al: Surgical correction
of mandibulofacial deformities secondary to large cervical
cystic hygromas, J Oral Maxillofac Surg 45:1015-1021,
1987.
Wilson S, Gould AR, Wolff C: Multiple lymphangiomas of the
alveolar ridge in a neonate: case study, Pediatr Dent 8:231-
234, 1986.
Leiomyoma
Baden E, Doyle JL, Lederman DA: Leiomyoma of the oral cavity:
a light microscopic and immunohistochemical study with
review of the literature from 1884 to 1992, Eur J Cancer B
Oral Oncol 30B:1-7, 1994.
Damm DD, Neville BW: Oral leiomyomas, Oral Surg Oral Med
Oral Pathol 47:343-348, 1979.
Koutlas IG, Manivel JC: Epithelioid leiomyoma of the oral
mucosa, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
82:670-673, 1996.
Liang H, Frederiksen NL, Binnie WH et al: Intraosseous leiomy-
oma: systematic review and report of one case, Dentomaxillo-
fac Radiol 32:285-290, 2003.
Loyola AM, Araújo NS, Zanetta-Barbosa D et al: Intraosseous
leiomyoma of the mandible, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 87:78-82, 1999.
Rhabdomyoma
Cleveland DB, Chen SY, Allen CM et al: Adult rhabdomyoma: a
light microscopic, ultrastructural, virologic, and immunologic
analysis, Oral Surg Oral Med Oral Pathol 77:147-153, 1994. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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Chapter 12 SOFT TISSUE TUMORS 569
Corio RL, Lewis DM: Intraoral rhabdomyomas, Oral Surg Oral
Med Oral Pathol 48:525-531, 1979.
Kapadia SB, Meis JM, Frisman DM et al: Adult rhabdomyoma of
the head and neck: a clinicopathologic and immunopheno-
typic study, Hum Pathol 24:608-617, 1993.
Kapadia SB, Meis JM, Frisman DM et al: Fetal rhabdomyoma of
the head and neck: a clinicopathologic and immunopheno-
typic study of 24 cases, Hum Pathol 24:754-765, 1993.
Sørensen KB, Godballe C, Østergaard B et al: Adult extracardiac
rhabdomyoma: light and immunohistochemical studies of
two cases in the parapharyngeal space, Head Neck 28:275-
279, 2006.
Willis J, Abdul-Karim FW, di Sant’Agnese PA: Extracardiac rhab-
domyomas, Semin Diagn Pathol 11:15-25, 1994.
Osseous and Cartilaginous Choristomas
Abdelsayed RA, Wetherington RW, Bent JP III et al: Glial cho-
ristoma of the tongue. A case report and review of the litera-
ture, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
87:215-222, 1999.
Chou L, Hansen LS, Daniels TE: Choristomas of the oral cavity:
a review, Oral Surg Oral Med Oral Pathol 72:584-593, 1991.
Supiyaphun P, Sampatanakul P, Kerekhanjanarong V et al:
Lingual osseous choristoma: a study of eight cases and review
of the literature, Ear Nose Throat J 77:316-318, 320, 325,
1998.
Toida M, Sugiyama T, Kato Y: Cartilaginous choristoma of the
tongue, J Oral Maxillofac Surg 61:393-396, 2003.
Ünal T, Ertürk S: Cartilaginous choristoma of the gingiva. Report
of two cases: review of the literature of both gingival choris-
tomas and intraoral chondromas, Ann Dent 53:19-27, 1994.
Soft Tissue Sarcomas
Fletcher CDM: The evolving classiﬁcation of soft tissue tumours:
an update based on the new WHO classiﬁcation, Histopathol-
ogy 48:3-12, 2006.
Fletcher CDM, Unni KK, Mertens F: World Health Organization
classiﬁcation of tumours: pathology and genetics of tumours of soft
tissue and bone, Lyon, France, 2002, IARC Press.
Freedman AM, Reiman HM, Woods JE: Soft tissue sarcomas of
the head and neck, Am J Surg 158:367-372, 1989.
Mendenhall WM, Mendenhall CM, Werning JW et al: Adult
head and neck soft tissue sarcomas, Head Neck 27:916-922,
2005.
Wanebo HJ, Koness RJ, MacFarlane JK et al: Head and neck
sarcoma: report of the Head and Neck Sarcoma Registry,
Head Neck 14:1-7, 1992.
Weiss SW, Goldblum J: Enzinger and Weiss’s soft tissue tumors, ed
5, Philadelphia, 2008, Elsevier.
Fibrosarcoma
Frankenthaler R, Ayala AG, Hartwick RW et al: Fibrosarcoma of
the head and neck, Laryngoscope 100:799-802, 1990.
Greager JA, Reichard K, Campana JP et al: Fibrosarcoma of the
head and neck, Am J Surg 167:437-439, 1994.
Mark RJ, Sercarz JA, Tran L et al: Fibrosarcoma of the head and
neck: the UCLA experience, Arch Otolaryngol Head Neck Surg
117:396-401, 1991.
Malignant Fibrous Histiocytoma
Barnes L, Kanbour A: Malignant ﬁbrous histiocytoma of the head
and neck: a report of 12 cases, Arch Otolaryngol Head Neck Surg
114:1149-1156, 1988.
Bras J, Batsakis JG, Luna MA: Malignant ﬁbrous histiocytoma of
the oral soft tissues, Oral Surg Oral Med Oral Pathol 64:57-67,
1987.
Erlandson RA, Antonescu CR: The rise and fall of malignant
ﬁbrous histiocytoma, Ultrastruct Pathol 28:283-289, 2004.
Liposarcoma
Fanburg-Smith JC, Furlong MA, Childers ELB: Liposarcoma of
the oral and salivary gland region: a clinicopathologic study
of 18 cases with emphasis on speciﬁc sites, morphologic sub-
types, and clinical outcome, Mod Pathol 15:1020-1031,
2002.
Nascimento AF, McMenamin ME, Fletcher CDM: Liposarcomas/
atypical lipomatous tumors of the oral cavity: a clinicopatho-
logic study of 23 cases, Ann Diagn Pathol 6:83-93, 2002.
Malignant Peripheral Nerve Sheath Tumor
Bailet JW, Abemayor E, Andrews JC et al: Malignant nerve
sheath tumors of the head and neck: a combined experience
from two university hospitals, Laryngoscope 101:1044-1049,
1991.
Ducatman BS, Scheithauer BW, Piepgras DG et al: Malignant
peripheral nerve sheath tumors: a clinicopathologic study of
120 cases, Cancer 57:2006-2021, 1986.
Martinez Devesa P, Mitchell TE, Scott I et al: Malignant periph-
eral nerve sheath tumors of the head and neck: two cases and
a review of the literature, Ear Nose Throat J 85:392-396,
2006.
Minovi A, Basten O, Hunter B et al: Malignant peripheral nerve
sheath tumors of the head and neck: management of 10 cases
and literature review, Head Neck 29:439-445, 2007.
Wanebo JE, Malik JM, VandenBerg SR et al: Malignant periph-
eral nerve sheath tumors: a clinicopathologic study of 28
cases, Cancer 71:1247-1253, 1993.
Olfactory Neuroblastoma
Bradley PJ, Jones NS, Robertson I: Diagnosis and management
of esthesioneuroblastoma, Curr Opin Otolaryngol Head Neck
Surg 11:112-118, 2003.
Dulgnerov P, Calcaterra T: Esthesioneuroblastoma: the UCLA
experience 1970-1990, Laryngoscope 102:843-849, 1992.
Levine PA, Gallagher R, Cantrell RW: Esthesioneuroblastoma:
reﬂections of a 21-year experience, Laryngoscope 109:1539-
1543, 1999.
Oskouian RJ Jr, Jane JA Sr, Dumont AS et al: Esthesioneuroblas-
toma: clinical presentation, radiological, and pathological
features, treatment, review of the literature, and the Univer-
sity of Virginia experience, Neurosurg Focus 12:e4, 2002.
Zappia JJ, Carroll WR, Wolf GT et al: Olfactory neuroblastoma:
the results of modern treatment approaches at the University
of Michigan, Head Neck 15:190-196, 1993.
Angiosarcoma
Chi AC, Weathers DR, Folpe AL et al: Epithelioid hemangioen-
dothelioma of the oral cavity: report of two cases and review
of the literature, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 100:717-724, 2005.
Fanburg-Smith JC, Furlong MA, Childers ELB: Oral and salivary
gland angiosarcoma: a clinicopathologic study of 29 cases,
Mod Pathol 16:263-271, 2003.
Favia G, Lo Muzio L, Serpico R et al: Angiosarcoma of the head
and neck with intra-oral presentation. A clinico-pathological
study of four cases, Oral Oncol 38:757-762, 2002.
Fedok FG, Levin RJ, Maloney ME et al: Angiosarcoma: current
review, Am J Otolaryngol 20:223-231, 1999.
Loudon JA, Billy ML, DeYoung BR et al: Angiosarcoma of
the mandible: a case report and review of the literature, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 89:471-476,
2000.
Mark RJ, Poen JC, Tran LM et al: Angiosarcoma. A report of 67
patients and a review of the literature, Cancer 77:2400-2406,
1996.
Morrison WH, Byers RM, Garden AS et al: Cutaneous angiosar-
coma of the head and neck, Cancer 76:319-327, 1995. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

570 ORAL AND MAXILLOFACIAL PATHOLOGY
Kaposi’s Sarcoma
Brenner B, Weissmann-Brenner A, Rakowsky E et al: Classical
Kaposi sarcoma. Prognostic factor analysis of 248 patients,
Cancer 95:1982-1987, 2002.
Cohen A, Wolf DG, Guttman-Yassky et al: Kaposi’s sarcoma-
associated herpesvirus: clinical, diagnostic, and epidemiologi-
cal aspects, Crit Rev Clin Lab Sci 42:101-153, 2005.
Ficarra G, Berson AM, Silverman S Jr et al: Kaposi’s sarcoma of
the oral cavity: a study of 134 patients with a review of the
pathogenesis, epidemiology, clinical aspects, and treatment,
Oral Surg Oral Med Oral Pathol 66:543-550, 1988.
Flaitz CM, Jin Y-T, Hicks MJ et al: Kaposi’s sarcoma-associated
herpesvirus-like DNA sequences (KSHV/HHV-8) in oral
AIDS-Kaposi’s sarcoma: a PCR and clinicopathologic study,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:259-264,
1997.
Fossati S, Boneschi V, Ferrucci S et al: Human immunodeﬁ-
ciency virus negative Kaposi sarcoma and lymphoprolifera-
tive disorders, Cancer 85:1611-1615, 1999.
Friedman-Kien AE, Saltzman BR: Clinical manifestations of clas-
sical, endemic African, and epidemic AIDS-associated Kapo-
si’s sarcoma, J Am Acad Dermatol 22:1237-1250, 1990.
Lager I, Altini M, Coleman H et al: Oral Kaposi’s sarcoma: a
clinicopathologic study from South Africa, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 96:701-710, 2003.
Stein ME, Spencer D, Ruff P et al: Endemic African Kaposi’s
sarcoma: clinical and therapeutic implications. 10-year expe-
rience in the Johannesburg Hospital (1980-1990), Oncology
51:63-69, 1994.
Tappero JW, Conant MA, Wolfe SF et al: Kaposi’s sarcoma.
Epidemiology, pathogenesis, histology, clinical spectrum,
staging criteria and therapy, J Am Acad Dermatol 28:371-395,
1993.
Leiomyosarcoma
Dry SM, Jorgensen JL, Fletcher CDM: Leiomyosarcomas of the
oral cavity: an unusual topographic subset easily mistaken for
nonmesenchymal tumours, Histopathology 36:210-220,
2000.
Freedman PD, Jones AC, Kerpel SM: Epithelioid leiomyosar-
coma of the oral cavity: report of two cases and review of the
literature, J Oral Maxillofac Surg 51:928-932, 1993.
Nikitakis NG, Lopes MA, Bailey JS et al: Oral leiomyosarcoma:
review of the literature and report of two cases with assess-
ment of the prognostic and diagnostic signiﬁcance of immu-
nohistochemical and molecular markers, Oral Oncol
38:201-208, 2002.
Sedghizadeh PP, Angiero F, Allen CM et al: Post-irradiation leio-
myosarcoma of the maxilla: report of a case in a patient with
prior radiation treatment for retinoblastoma, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 97:726-731, 2004.
Vilos GA, Rapidis AD, Lagogiannis GD et al: Leiomyosarcomas
of the oral tissues: clinicopathologic analysis of 50 cases,
J Oral Maxillofac Surg 63:1461-1477, 2005.
Rhabdomyosarcoma
Bras J, Batsakis JG, Luna MA: Rhabdomyosarcoma of the oral soft
tissues, Oral Surg Oral Med Oral Pathol 64:585-596, 1987.
Dagher R, Helman L: Rhabdomyosarcoma: an overview, Oncolo-
gist 4:34-44, 1999.
Hicks J, Flaitz C: Rhabdomyosarcoma of the head and neck in
children, Oral Oncol 38:450-459, 2002.
Kaste SC, Hopkins KP, Bowman LC: Dental abnormalities in
long-term survivors of head and neck rhabdomyosarcoma,
Med Pediatr Oncol 25:96-101, 1995.
Nakhleh RE, Swanson PE, Dehner LP: Juvenile (embryonal and
alveolar) rhabdomyosarcoma of the head and neck in adults:
a clinical, pathologic, and immunohistochemical study of 12
cases, Cancer 67:1019-1024, 1991.
Parham DM, Ellison DA: Rhabdomyosarcomas in adults and
children. An update, Arch Pathol Lab Med 130:1454-1465,
2006.
Walterhouse DO, Pappo AS, Baker KS et al: Rhabdomyosarcoma
of the parotid region occurring in childhood and adolescence.
A report from the Intergroup Rhabdomyosarcoma Study
Group, Cancer 92:3135-3146, 2001.
Synovial Sarcoma
Bukachevsky RP, Pincus RL, Shechtman FG et al: Synovial
sarcoma of the head and neck, Head Neck 14:44-48, 1992.
Ferrari A, Gronchi A, Casanova M et al: Synovial sarcoma: a ret-
rospective analysis of 271 patients of all ages treated at a
single institution, Cancer 101:627-634, 2004.
Fisher C: Synovial sarcoma, Ann Diagn Pathol 2:401-421, 1988.
Meer S, Coleman H, Altini M: Oral synovial sarcoma: a report of
2 cases and a review of the literature, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 96:306-315, 2003.
Shmookler BM, Enzinger FM, Brannon RB: Orofacial synovial
sarcoma: a clinicopathologic study of 11 new cases and
review of the literature, Cancer 50:269-276, 1982.
Alveolar Soft-Part Sarcoma
do Nascimento Souza KC, Faria PR, Costa IM et al: Oral alveolar
soft-part sarcoma: review of literature and case report with
immunohistochemistry study for prognostic markers, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 99:64-70, 2005.
Fanburg-Smith JC, Miettinen M, Folpe AL et al: Lingual alveolar
soft part sarcoma; 14 cases: novel clinical and morphological
observations, Histopathology 45:526-537, 2004.
Folpe AL, Deyrup AT: Alveolar soft-part sarcoma: a review and
update, J Clin Pathol 59:1127-1132, 2006.
Lieberman PH, Brennan MF, Kimmel M et al: Alveolar soft-part
sarcoma: a clinico-pathologic study of half a century, Cancer
63:1-13, 1989.
Ordóñez NG: Alveolar soft part sarcoma: a review and update,
Adv Anat Pathol 6:125-139, 1999.
Metastases to the Oral Soft Tissues
Allen CM, Neville B, Damm DD et al: Leiomyosarcoma meta-
static to the oral region: report of three cases, Oral Surg Oral
Med Oral Pathol 76:752-756, 1993.
Hirshberg A, Buchner A: Metastatic tumours to the oral region.
An overview, Eur J Cancer B Oral Oncol 31B:355-360, 1995.
Hirshberg A, Leibovich P, Buchner A: Metastases to the oral
mucosa: analysis of 157 cases, J Oral Pathol Med 22:385-390,
1993.
Lim S-Y, Kim S-A, Ahn S-G et al: Metastatic tumours to the jaws
and oral soft tissues: a retrospective analysis of 41 Korean
patients, Int J Oral Maxillofac Surg 35:412-415, 2006.
van der Waal RIF, Buter J, van der Wall I: Oral metastases: report
of 24 cases, Br J Oral Maxillofac Surg 41:3-6, 2003.
Zachariades N: Neoplasms metastatic to the mouth, jaws and
surrounding tissues, J Craniomaxillofac Surg 17:283-290,
1989. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

571
13
Hematologic Disorders
CHAPTER OUTLINE
Lymphoid Hyperplasia
Hemophilia
Plasminogen Deﬁciency
Anemia
Sickle Cell Anemia
Thalassemia
Aplastic Anemia
Neutropenia
Agranulocytosis
Cyclic Neutropenia
Thrombocytopenia
involved, although any lymph node in the area may be
affected.
With acute infections, the lymphadenopathy appears
as enlarged, tender, relatively soft, freely movable
nodules. Chronic inﬂammatory conditions produce
enlarged, rubbery ﬁrm, nontender, freely movable
nodes. Sometimes these chronic hyperplastic lymph
nodes may be difﬁcult to distinguish clinically from
lymphoma, and a history of a preceding inﬂammatory
process and lack of progressive enlargement are helpful
clues that are consistent with a reactive process.
Another condition, however, that should be considered
in the differential diagnosis of multiple, persistently
enlarged, nontender lymph nodes is human immuno-
deﬁciency virus (HIV) infection (see page 271).
Tonsillar size is variable from one person to the next,
but lymphoid tissue is normally more prominent in
younger individuals, usually reaching its peak early
during the second decade of life and gradually dimin-
ishing thereafter. Some patients have such large tonsils
that it seems as if they would occlude the airway (so-
called kissing tonsils). Often, however, these patients
have no symptoms and are unaware of a problem.
As long as the large tonsils are symmetrical and
LYMPHOID HYPERPLASIA
The lymphoid tissue of the body plays an important
role in the recognition and processing of foreign anti-
gens, such as viruses, fungi, and bacteria. In addition,
the lymphoid tissue has a protective function through
a variety of direct and indirect mechanisms. In respond-
ing to antigenic challenges, lymphoid cells proliferate,
thus increasing their numbers, to combat the offending
agent more effectively. This proliferation results in
enlargement of the lymphoid tissue, which is seen
clinically as lymphoid hyperplasia.
CLINICAL FEATURES
Lymphoid hyperplasia may affect the lymph nodes, the
lymphoid tissue of Waldeyer’s ring, or the aggregates
of lymphoid tissue that are normally scattered through-
out the oral cavity, particularly in the oropharynx,
the soft palate, the lateral tongue, and the ﬂoor of
the mouth. When lymphoid hyperplasia affects the
lymph nodes, usually the site that the lymph node
drains can be identiﬁed as a source of active or recent
infection. In the head and neck region, the anterior
cervical chain of lymph nodes is most commonly
Polycythemia Vera
Leukemia
Langerhans Cell Histiocytosis
Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma
Mycosis Fungoides
Burkitt’s Lymphoma
Extranodal NK/T-Cell Lymphoma, Nasal-type
Multiple Myeloma
Plasmacytoma `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

572 ORAL AND MAXILLOFACIAL PATHOLOGY
asymptomatic (Fig. 13-1), it is likely that they are
normal for that particular patient. Tonsillar asymmetry
is a potentially serious sign that should be evaluated
further to rule out the presence of a metastatic tumor
or lymphoma.
Hyperplastic intraoral lymphoid aggregates appear
as discrete, nontender, submucosal swellings, usually
less than 1 cm in diameter, which may appear normal
or dark pink in color if the aggregate is deeper; they
may have a creamy yellow-orange hue if the collection
of lymphocytes is closer to the surface (Figs. 13-2 and
13-3). Lymphoid hyperplasia commonly involves the
posterior lateral tongue, where it may appear some-
what ominous. The enlargement is usually bilaterally
symmetrical, however, which helps to distinguish the
condition from a malignancy. The buccal lymph node
may also become hyperplastic and appear as a non-
tender, solitary, freely movable nodule, usually less
than 1 cm in diameter, within the substance of the
cheek. Infrequently, a more diffuse lymphoid hyper-
plasia involves the posterior hard palate, producing a
slowly growing, nontender, boggy swelling with an
intact mucosal surface and little color change. These
palatal lesions may be clinically impossible to distin-
guish from extranodal lymphoma and would, there-
fore, necessitate biopsy.
HISTOPATHOLOGIC FEATURES
The microscopic features of lymphoid hyperplasia
include sheets of small, well-differentiated lympho-
cytes with numerous interspersed, sharply demarcated
collections of reactive lymphoblasts called germinal
centers. The cells that comprise the germinal centers
are primarily transformed B lymphocytes that may
demonstrate numerous mitoses. Macrophages can also
be identiﬁed by the presence of phagocytized material
(tingible bodies) in their cytoplasm as they engulf
nuclear debris from the proliferating lymphocytes. In
some instances, immunohistochemical studies and
clonality assays must be performed to rule out the pos-
sibility of follicular lymphoma.
TREATMENT AND PROGNOSIS
Once the diagnosis of lymphoid hyperplasia is con-
ﬁrmed, no treatment is usually required because it is a
completely benign process. For those patients with
palatal lymphoid hyperplasia that may interfere with a
dental prosthesis, complete excision of the lesion is
recommended.
Fig. 13-1 Lymphoid hyperplasia. The large tonsil observed
in this patient represents a benign hyperplasia of the
lymphoid cells. If signiﬁcant asymmetry is observed, further
investigation may be warranted to rule out the possibility of
lymphoma.
Fig. 13-2 Lymphoid hyperplasia. The smooth-surfaced
papule of the posterior lateral tongue represents an enlarged
lymphoid aggregate. The lesion exhibits a lighter color as a
result of the accumulation of lymphocytes, which are white
blood cells. (Courtesy of Dr. Dean White.)
Fig. 13-3 Lymphoid hyperplasia. Multiple prominent
lymphoid aggregates in the ﬂoor of the mouth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 13 HEMATOLOGIC DISORDERS 573
HEMOPHILIA
Hemophilia (hemo = blood; philia = loving) represents
a variety of bleeding disorders associated with a genetic
deﬁciency of any one of the clotting factors of the blood
(Table 13-1). This condition was common in certain
European royal families, many of whom carried an
X-linked hereditary deﬁciency of either factor VIII or
factor IX. Consequently, as a result of inbreeding, a
signiﬁcant proportion of the male members of these
families had hemophilia. In the days before blood
transfusions and clotting factor replacement therapy,
many of these patients died as a direct result of, or from
the complications of, uncontrolled hemorrhage. It is
not known whether these people had factor VIII or
factor IX deﬁciency, because all of the affected indi-
viduals died before the deﬁnitive diagnostic studies
were developed to determine precisely which deﬁ-
ciency was present. Because hemophilia A (factor VIII
deﬁciency) is the most signiﬁcant and widely recog-
nized form of hemophilia and accounts for 80% to 85%
of the bleeding diatheses associated with a speciﬁc
clotting factor deﬁciency, most of this discussion
centers on that entity. Its estimated prevalence in the
United States is 1 in 10,000 persons (or 1 in 5000
males).
As previously mentioned, a deﬁciency of factor IX
or hemophilia B (Christmas disease) also may be
encountered. Hemophilia B is similar to hemophilia A
in its presentation, being transmitted in an X-linked
fashion. Hemophilia B is much less common than
hemophilia A, occurring with a prevalence of 1 in
60,000 (or 1 in 30,000 males). The term Christmas
disease was obtained from the surname of the ﬁrst
person, a Canadian boy, who was identiﬁed as having
hemophilia B in 1952.
Another clotting disorder that is sometimes seen,
von Willebrand’s disease, is the result of a genetic
deﬁciency of a plasma glycoprotein called von Wille-
brand’s factor. This glycoprotein aids in the adhesion
of platelets at a site of bleeding, and it also binds to
factor VIII, acting as a transport molecule. Von Wille-
brand’s disease is a genetically heterogeneous condi-
tion, with several subtypes currently identiﬁed, and it
may be transmitted in an autosomal dominant or reces-
sive pattern. It is the most common of the inherited
bleeding disorders, affecting an estimated 1 in 800
to 1000 persons. However, many cases of von
Willebrand’s disease are mild and may be clinically
insigniﬁcant.
CLINICAL FEATURES
Hemophilia A is an X-linked disorder. Females typi-
cally carry the trait, but it is expressed primarily in
males. Approximately 1 in 5000 males is born with
this genetic disease, with about 30% of the cases repre-
senting new mutations. Failure of normal hemostasis
after circumcision is typically one of the ﬁrst signs that
a bleeding disorder is present.
The severity of the bleeding disorder depends on the
extent of the clotting factor deﬁciency. Hemophilia A
is a heterogeneous disorder that is caused by any one
of a variety of mutations associated with the gene for
factor VIII. Because the mutations occur at different
sites in the factor VIII gene (more than 900 different
mutations have been identiﬁed), a clinical spectrum of
deﬁciency of factor VIII is seen. This results in varying
degrees of disease expression, with those mutations
affecting more signiﬁcant or larger portions of the
factor VIII gene causing more severe clinical disease.
Not all patients have an absolute lack of the particular
clotting factor; rather, the deﬁciency may be a percent-
age of the normal value in a given patient. For example,
a patient with only 25% of normal factor VIII levels
may be able to function normally under most circum-
stances; one with less than 5% commonly manifests a
marked tendency to bruise with only minor trauma.
In infants, oral lacerations and ecchymoses that
involve the lips and tongue are a frequent occurrence
as a result of the common falls and bumps experienced
by this age group. If not treated appropriately, then
such lacerations may result in signiﬁcant blood loss in
more severely affected patients. Sometimes deep hem-
orrhage occurs during normal activity and may involve
Table 13-1 Comparison of the Most Commonly Encountered Inherited Bleeding Disorders
Type Defect Inheritance Findings
Hemophilia A (classic hemophilia)Factor VIII deﬁciency X-linked recessive Abnormal PTT
Hemophilia B (Christmas disease)Factor IX deﬁciency X-linked recessive Abnormal PTT
von Willebrand’s disease Abnormal von Willebrand’s
factor, abnormal platelets
Autosomal dominant Abnormal BT, abnormal PTT
PTT, Partial thromboplastin time; BT, bleeding time. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

574 ORAL AND MAXILLOFACIAL PATHOLOGY
the muscles, soft tissues, and weight-bearing joints
(hemarthrosis), especially the knees (Fig. 13-4). The
result of such uncontrolled bleeding is the formation
of scar tissue as the body removes the extravasated
blood. This often causes a crippling deformity of the
knee joints secondary to arthritis and ankylosis. Some-
times the tissue hemorrhage results in the formation of
a tumorlike mass, which has been called pseudotu-
mor of hemophilia. Such lesions have been reported
in the oral regions.
An increased coagulation time (delay in blood clot-
ting), of course, is the hallmark feature of this group of
conditions. Uncontrollable or delayed hemorrhage
may result from any laceration; this includes surgical
incisions, dental extractions, and periodontal curettage
(Fig. 13-5). Measurements of the platelet count, bleed-
ing time, prothrombin time (PT), and partial thrombo-
plastin time (PTT) should be ordered as screening tests
for any patient with a possible bleeding disorder.
TREATMENT AND PROGNOSIS
The treatment of clotting factor deﬁciencies essentially
consists of replacement therapy with the appropriate
clotting factor. Whether treatment is instituted depends
on the severity of the clotting factor deﬁciency.
Patients who have greater than 25% of normal values
of factor VIII may function normally. For patients
with mild hemophilia (5% to 40% of normal levels of
factor VIII), no special treatment is typically required
for normal activities. If surgery is to be performed,
then clotting factor replacement therapy may be
indicated.
For patients with severe deﬁciencies (<1% of normal
levels of factor VIII), injections with the clotting factor
must be performed as soon as a hemorrhagic episode
occurs to prevent such complications as the crippling
joint deformities of the knees.
The use of aspirin is strictly contraindicated because
of its adverse effect on blood platelet function. Severe
hemorrhage may result if these patients use aspirin-
containing medications.
Genetic counseling should be provided to these
patients and their families to help them understand
the mechanism of inheritance. Using molecular tech-
niques, women who are carriers can be conﬁrmed. In
addition, affected male fetuses can now be identiﬁed,
and the severity of the factor VIII mutation can be
assessed.
Optimal dental care is strongly encouraged for these
patients to prevent oral problems that might require
surgery. If oral or periodontal surgery is necessary,
then consultation with the patient’s physician is man-
datory. The patient is usually prepared for the proce-
dure by the administration of clotting factor just before
the surgery. With an extensive surgical procedure,
additional doses of clotting factor may be needed sub-
sequently. In addition, epsilon-aminocaproic acid
(EACA), an antiﬁbrinolytic agent that inhibits clot deg-
radation, should be given 1 day before the surgery and
continued for 7 to 10 days afterward. Alternative
therapy for patients who have levels of factor VIII
greater than 5% of normal is desmopressin, which can
be given just before surgery. This drug causes the
release of bound factor VIII, producing a temporary
increase in the plasma levels of the clotting factor. Des-
mopressin may also be used to manage most patients
affected by type 1 von Willebrand’s disease, which rep-
resents approximately 70% to 80% of the cases of that
disorder.
Although it saved many lives, clotting factor replace-
ment therapy has also resulted in a tragic complication
Fig. 13-4 Hemophilia. The enlargement of the knees of
this patient with factor VIII deﬁciency is due to repeated
episodes of bleeding into the joints (hemarthrosis).
Inﬂammation and scarring have resulted.
Fig. 13-5 Hemophilia. Hemorrhage in a patient with factor
IX deﬁciency occurred after routine periodontal curettage. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 575
for many of these patients. Cryoprecipitation, the tradi-
tional method of concentrating clotting factors from the
serum, also resulted in the concentration of several
viruses, including the hepatitis viruses and human
immunodeﬁciency virus (HIV). Currently more than
40% of hemophilia A and B patients in the United States
are estimated to be infected with hepatitis C virus. In
addition, as many as 80% to 90% of hemophiliac patients
treated with multiple doses of factor VIII cryoprecipi-
tate were infected with HIV. The methods of preparing
the clotting factors have been modiﬁed to eliminate the
risk of acquiring HIV from the preparation; however,
many hemophiliac patients who were infected devel-
oped acquired immunodeﬁciency syndrome (AIDS).
Recombinant DNA technology now provides a source
of factor VIII that is manufactured by inserting the
human factor VIII gene into bacteria that then synthe-
size the protein. Therefore, this product can now be
manufactured without contamination by any viral
organisms, and young people affected by hemophilia
have minimal risk of contracting these infections.
Other problems must occasionally be confronted,
however. Approximately 6% of patients with hemo-
philia A may develop antibodies directed against factor
VIII, and this is a very serious complication. Because
the antibodies react with the factor VIII molecule, the
result is an inhibition of the activity of the clotting
factor, and these patients are once more faced with the
prospect of uncontrolled bleeding. Patients with factor
IX deﬁciency can develop similar inhibitory antibodies
to factor IX, but this appears to occur much less fre-
quently. Attempts to induce immune tolerance may
help some individuals, although more immediate care
has generally centered on bypassing the factor VIII–
related portion of the clotting cascade by administra-
tion of recombinant factor VIIa. Research has shown
this approach to be effective, although costly.
PLASMINOGEN DEFICIENCY
(LIGNEOUS CONJUNCTIVITIS;
HYPOPLASMINOGENEMIA)
Plasminogen deﬁciency is a rare autosomal recessive
condition that is caused by any one of several muta-
tions of the gene responsible for the production of plas-
minogen, the precursor to plasmin. In the clotting
cascade, factors are activated that lead to the develop-
ment of a clot; however, simultaneously serum proteins
such as plasminogen are converted to plasmin, which
is responsible for degrading the clot. Without the for-
mation of plasmin, the clot tends to grow and persist
despite having performed its original hemostatic func-
tion. The result of plasminogen deﬁciency is a buildup
of ﬁbrin, deposited as irregular plaques and nodules
that primarily affect mucosal surfaces. Involvement of
the conjunctival mucosa is characterized by the forma-
tion of thick, ﬁrm plaques, for which the term ligneous
conjunctivitis has been used (ligneous means “woodlike”).
Even though this condition was initially described in
the nineteenth century, it was during the late 1990s
that an explanation for the majority of these cases was
provided. Similar lesions have been produced in mice
that have been genetically manipulated to create
knock-out mutations of the plasminogen gene.
CLINICAL FEATURES
The most striking aspect of plasminogen deﬁciency is
the development of thick, creamy yellow to erythema-
tous, ﬁrm plaques and nodules involving primarily the
conjunctival mucosa of the upper eyelid. Typically the
condition is detected during the ﬁrst decade of life, but
lesions can develop later as well. Even though this is an
autosomal recessive condition, there is a tendency for
the disease to present more often in women, although
the reason for this is unknown.
In addition to the conjunctival lesions, other mucosal
surfaces can be affected, including the oral mucosa,
laryngeal mucosa, and vaginal mucosa. In a recent
series of 50 patients with this condition, ocular lesions
were documented in 80%, gingival lesions in 34%,
respiratory tract lesions in 16%, and vaginal lesions in
8%. Laryngeal mucosal involvement often includes the
vocal cords, which will typically cause a raspy, hoarse
voice.
Oral lesions of plasminogen deﬁciency primarily
involve the gingivae, presenting as patchy ulcerated
papules and nodules with a very irregular surface (Fig.
13-6). These lesions may be few in number or distrib-
uted diffusely in all quadrants, and they tend to wax
and wane in severity.
Fig. 13-6 Plasminogen deﬁciency. The ulcerated plaques
and papules seen on the gingiva of this patient with
plasminogen deﬁciency represent accumulations of ﬁbrin.
(Courtesy of Dr. Kenneth Rasenberger.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

576 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
The microscopic features of the lesions associated with
this condition can be very confusing for the pathologist
who is not familiar with the disease. The accumulation
of ﬁbrin appears as diffuse sheets of acellular eosino-
philic material that bears a close resemblance to
amyloid (Fig. 13-7). Special stains for amyloid (such
as Congo red) are negative, however, because this
material represents ﬁbrin. Conﬁrmation that the
eosinophilic material is ﬁbrin can be done using the
Fraser-Lendrum histochemical staining method. Vari-
able numbers of inﬂammatory cells are seen, and
granulation tissue is usually seen adjacent to the ﬁbrin
deposits.
TREATMENT AND PROGNOSIS
Treatment of plasminogen deﬁciency remains a
problem. Damage to the mucosal tissues, including
surgical trauma, should be minimized to reduce the
likelihood of ﬁbrin accumulation. Careful, thorough
oral hygiene practices should be encouraged to dimin-
ish the effect of local inﬂammation. Sporadic reports
describe resolution of the conjunctival lesions with
either topical or systemic plasminogen; however, this
agent is not available commercially. Some patients
have experienced spontaneous regression of their
lesions over time. Currently topical heparin combined
with prednisone may be the most reasonable approach
until replacement plasminogen is marketed or gene
therapy is feasible. Interestingly, these patients do not
have any unusual problems with intravascular throm-
bus formation, and their lifespan does not appear to be
shortened.
ANEMIA
Anemia is a general term for either a decrease in the
volume of red blood cells (hematocrit) or in the con-
centration of hemoglobin. This problem can result
from a number of factors, including a decreased pro-
duction of erythrocytes or an increased destruction or
loss of erythrocytes. Laboratory studies, such as the red
blood cell (RBC) count, hematocrit, hemoglobin con-
centration, mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH), and mean corpuscu-
lar hemoglobin concentration (MCHC), can help indi-
cate the probable cause of the anemia.
Rather than being a disease itself, anemia is often a
sign of an underlying disease, such as renal failure,
liver disease, chronic inﬂammatory conditions, malig-
nancies, or vitamin or mineral deﬁciencies. The diverse
causes and complexity of the problem of anemia are
presented in Box 13-1.
CLINICAL FEATURES
The symptoms of anemia are typically related to the
reduced oxygen-carrying capacity of the blood, which
is a result of the reduced numbers of erythrocytes.
Symptoms such as tiredness, headache, or lightheaded-
ness are often present.
Pallor of the mucous membranes may be observed
in severe cases of anemia. The palpebral conjunctiva is
often the site where this paleness is most easily appre-
ciated, but the oral mucosa may show similar signs.
TREATMENT AND PROGNOSIS
The treatment of anemia depends on determining the
underlying cause of the anemia and correcting that
problem, if possible.
SICKLE CELL ANEMIA
Sickle cell anemia is one of the more severe genetic
disorders of hemoglobin synthesis (hemoglobinopa-
thies). Because of the mutational substitution of a
thymine molecule for an adenine in DNA, the codon
is altered to code for the amino acid valine rather than
glutamic acid in the β-globin chain of hemoglobin. This
results in a hemoglobin molecule that, in the deoxygen-
ated state, is prone to molecular aggregation and
Fig. 13-7 Plasminogen deﬁciency. This high-power
photomicrograph shows attenuated surface epithelium and a
collection of relatively acellular eosinophilic material that
superﬁcially resembles amyloid. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 577
polymerization. Consequently, the red blood cells of
patients with sickle cell anemia have a marked ten-
dency to undergo deformation from the normal bicon-
cave disk shape to a rigid-and-curved (sickle) shape.
Because the genes for hemoglobin synthesis are codom-
inant, if only one allele is affected, then only 40% to 50%
of that patient’s hemoglobin will be abnormal. Such a
patient is simply a carrier and is said to have sickle cell
trait, a condition that has no signiﬁcant clinical mani-
festations in most everyday circumstances. Some sick-
ling may be precipitated under certain conditions,
however, particularly with low-oxygen tensions associ-
ated with exercise or high altitudes.
This abnormal gene has persisted in the human race
perhaps because it confers a degree of resistance to the
malarial organism. As a result, the gene is seen most
frequently in populations, such as African, Mediterra-
nean, and Asian, who reside in areas where malaria
is endemic. In the United States, nearly 2.5 million
people (approximately 8% of the black population)
carry this trait.
Unfortunately, in patients who inherit two alleles
that code for sickle hemoglobin, the red blood cells
contain primarily sickle hemoglobin, which results in
the condition called sickle cell disease. In the United
States, about 1 of every 350 to 400 blacks is born with
this disease. Such patients are often susceptible to the
problems associated with abnormal red blood cell mor-
phology. The sickled erythrocytes are more fragile than
normal and they tend to block the capillaries because
of their shape and adherence properties. As a result,
these patients have a chronic hemolytic anemia and
many difﬁculties related to reduced blood ﬂow to
organs and tissues, which produces ischemia, infarc-
tion, and tissue death.
CLINICAL AND RADIOGRAPHIC
FEATURES
Virtually any tissue or organ may be affected in sickle
cell disease. The clinical spectrum of involvement can
vary tremendously, with approximately one third of
patients exhibiting severe manifestations. Perhaps the
most dramatic sign of this disease is the sickle cell
crisis, a situation in which the sickling of the erythro-
cytes becomes severe. Hypoxia, infection, hypother-
mia, or dehydration may precipitate a crisis; however,
for most crises there is no identiﬁable predisposing
factor. Patients who experience a crisis suffer extreme
pain from ischemia and infarction of the affected tissue.
The long bones, lungs, and abdomen are among the
most commonly affected sites, and each episode lasts
3 to 10 days. Pulmonary involvement, known as acute
chest syndrome, is particularly serious, and one large
study indicated that this is frequently precipitated by
fat embolism or community-acquired pneumonia.
Some patients may experience such crises monthly;
others may go for 1 year or longer without problems.
Often fever accompanies the crisis; therefore, infection
must be considered in the differential diagnosis.
Patients with sickle cell disease are susceptible to
infections, especially those caused by Streptococcus
pneumoniae, probably because of the destruction of the
spleen at an early age by repeated infarctions. Such
infections are the most common cause of death among
Box 13-1
Causes of Anemia
ANEMIAS WITH DISTURBED IRON METABOLISM
● Iron deﬁciency anemia
● Sideroblastic anemias
MEGALOBLASTIC ANEMIAS
● Cobalamin (B12) deﬁciency (pernicious anemia)
●Folic acid deﬁciency
ANEMIA ASSOCIATED WITH CHRONIC DISORDERS
●Anemia of chronic infection (infective endocarditis,
tuberculosis, osteomyelitis, lung abscess,
pyelonephritis)
●Anemia of inﬂammatory connective tissue disorders
(rheumatoid arthritis, lupus erythematosus, sarcoid-
osis, temporal arteritis, regional enteritis)
●Anemia associated with malignancy
●Secondary to chronic bleeding
● Myelophthisic anemia
●Anemia of uremia
●Anemia of endocrine failure
●Anemia of liver disease
HEMOLYTIC ANEMIAS
● Extrinsic causes
● Splenomegaly
●Red cell antibodies
●Trauma in the circulation
●Direct toxic effects (various microorganisms,
copper salts, venom of certain snakes)
● Membrane abnormalities
●Spur cell anemia
●Paroxysmal nocturnal hemoglobinuria
● Hereditary spherocytosis
● Hereditary elliptocytosis
●Disorders of the interior of the red cell
●Defects in the Embden-Meyerhof pathway
●Defects in the hexose monophosphate shunt
DISORDERS OF HEMOGLOBIN
●Sickle cell anemia
● Thalassemias `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

578 ORAL AND MAXILLOFACIAL PATHOLOGY
children affected by sickle cell disease in the United
States.
Other problems include delayed growth and devel-
opment in most patients. Impaired kidney function
and ocular abnormalities develop secondary to the
damage caused by vaso-occlusive episodes in the capil-
lary networks of those organs. If the patient lives long
enough, then renal failure may eventually develop. In
addition, approximately 5% to 8% of these patients will
experience central nervous system (CNS) damage in
the form of a stroke, which occurs at an average age of
about 8 years.
The oral radiographic features of sickle cell disease
are relatively nonspeciﬁc. They consist of a reduced
trabecular pattern of the mandible because of increased
hematopoiesis occurring in the marrow spaces. Occa-
sionally, a “hair-on-end” appearance is seen on the
skull radiograph, although this is less prominent than
that seen in thalassemia (Fig. 13-8). Other oral prob-
lems that have been reported include an increased
prevalence of osteomyelitis of the mandible, prolonged
paresthesia of the mandibular nerve, and asymptom-
atic pulpal necrosis.
HISTOPATHOLOGIC FEATURES
In homozygous sickle cell disease, a peripheral blood
smear shows a peculiar curved distortion of the eryth-
rocytes, resembling a sickle or boomerang shape.
TREATMENT AND PROGNOSIS
The patient experiencing a sickle cell crisis should be
managed with supportive care, including ﬂuids, rest,
and appropriate analgesic therapy (usually narcotic
preparations). It is important, but often difﬁcult, to rule
out the possibility of infection.
All 50 states now screen for this hemoglobin disor-
der as part of their newborn infant health care system
to identify affected individuals as soon as possible so
that appropriate therapy can be instituted. For children
with a diagnosis of sickle cell disease, continuous pro-
phylactic penicillin therapy is indicated until at least 5
years of age. In addition, the child should be given
polyvalent pneumococcal vaccinations. Situations that
might precipitate a crisis, such as strenuous exercise,
dehydration, or exposure to cold, should be avoided.
For adults with relatively severe disease, hydroxyurea
has been approved for treatment. This drug increases
the fetal form of hemoglobin (hemoglobin F), which
may inhibit polymerization of hemoglobin S and may
also reduce the adherence of erythrocytes to the vessel
walls. Unfortunately, hydroxyurea has a number of
potential side effects and should be used judiciously.
Bone marrow transplantation is curative, but this is a
procedure with multiple potential complications and
is used primarily for severely affected patients having
a histocompatibility antigen (HLA)-matched donor
sibling. Only about 1% of sickle cell anemia patients
currently meet these criteria.
When surgery is necessary, local anesthesia, if pos-
sible, is usually preferred. If general anesthesia is indi-
cated, then precautions should be taken to avoid
conditions that might induce a crisis, such as hypoxia,
vascular stasis, acidosis, infection, reduced body tem-
perature, or dehydration.
For patients who have either the sickle cell trait or
the disease, genetic counseling is appropriate. DNA
diagnostic techniques have been used for several years
to assess whether a fetus is affected by sickle cell
disease, permitting consideration of termination of the
pregnancy. Molecular evaluation of the DNA from a
single cell obtained from an embryo that was fertilized
in vitro has allowed selection of a nonaffected embryo
for uterine implantation. For parents who are carriers
of the sickle cell trait, this is one method to ensure that
their offspring do not have sickle cell disease.
Although the mortality rate for sickle cell disease in
developed countries has improved dramatically over
the past few years, the prognosis is variable because of
the wide spectrum of disease activity. Those who are
severely affected, however, often are quite disabled
because of the many complications of the disease and
have a decreased life span.
THALASSEMIA
Thalassemia represents a group of disorders of hemo-
globin synthesis that are characterized by reduced syn-
thesis of either the α-globin or β-globin chains of the
Fig. 13-8 Sickle cell anemia. Lateral skull radiograph
reveals an altered trabecular pattern, including a slight
degree of “hair-on-end” appearance of the cranial bones.
(Courtesy of Dr. Reg Munden.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 579
hemoglobin molecule. As in those with sickle cell trait,
people who carry the trait for one of the forms of thalas-
semia seem to be more resistant to infection by the
malarial organism; an increased frequency of these
genes is seen in Mediterranean, African, Indian, and
Southeast Asian populations. Because the original cases
were reported from the region of the Mediterranean
Sea, the name thalassemia was given, derived from the
Greek word thalassa, meaning “sea.” The thalassemias
are considered to be among the most common inher-
ited conditions that affect humans.
An understanding of the structure and synthesis of
hemoglobin is helpful in explaining the pathophysiol-
ogy of these conditions. The hemoglobin molecule is a
tetramer that is composed of two α chains and two β
chains; if one of the chains is not being made in ade-
quate quantities, then the normal amount of hemoglo-
bin cannot be made. Furthermore, the excess globin
chains accumulate within the erythrocyte, further
compromising the structure and function of the cell.
These abnormal erythrocytes are recognized by the
spleen and selected for destruction (hemolysis). In
addition, there is evidence of ineffective erythropoiesis
caused by premature cell death of erythrocyte precur-
sors in the bone marrow because of activation of
apoptotic mechanisms. The net result is that the patient
has hypochromic, microcytic anemia.
Because two genes code for the β chain and four
genes code for the α chain, the degree of clinical sever-
ity in these conditions can vary considerably. The
severity depends on which speciﬁc genetic alteration
is present and whether it is heterozygous or homozy-
gous. In the heterozygous state, an adequate amount of
normal hemoglobin can be made and the affected
patient experiences few signs or symptoms. In the
homozygous state, however, the problems are often
severe or even fatal. In addition, variations in the sever-
ity of the clinical presentation may be a reﬂection of
the speciﬁc alteration in the genetic code, because
more than 200 different mutations have been docu-
mented for β-thalassemia alone.
CLINICAL AND RADIOGRAPHIC
FEATURES
b-THALASSEMIA
If only one defective gene for the β-globin molecule is
inherited (thalassemia minor), no signiﬁcant clinical
manifestations are usually present.
When two defective genes for the β-globin molecule
are inherited, the patient is affected with thalassemia
major, also called Cooley’s anemia or Mediterra-
nean anemia. The disease is usually detected during
the ﬁrst year of life because a severe microcytic, hypo-
chromic anemia develops when fetal hemoglobin syn-
thesis ceases after 3 to 4 months of age. The red blood
cells that are produced are extremely fragile and
survive for only a few days in the peripheral
circulation.
In an attempt to maintain adequate oxygenation, the
rate of hematopoiesis (despite being ineffective) is
greatly increased (up to 30 times normal), resulting in
massive bone marrow hyperplasia, as well as hepato-
splenomegaly and lymphadenopathy because of extra-
medullary hematopoiesis. The bone marrow hyperplasia
may affect the jaws especially, producing an altered
trabecular pattern and marked, painless enlargement
of the mandible and maxilla (Fig. 13-9). This results in
a characteristic “chipmunk” facies and causes reduced
size or obliteration of the paranasal sinuses. Frontal
bossing is also present, and a skull radiograph may
show a prominent “hair-on-end” appearance of the cal-
varia (Fig. 13-10). Generalized maturational delay of
the patient is typically seen. Delayed development of
the dentition also has been described, with the teeth
showing a mean delay of approximately 1 year com-
pared with a matched population.
Fig. 13-9 Thalassemia. Periapical radiographs of the
anterior mandible showing reduced trabeculation because of
increased hematopoiesis. (Courtesy of Dr. José Luis Tapia.)
Fig. 13-10 Thalassemia. Lateral skull radiograph depicting
the characteristic “hair-on-end” appearance in a patient with
thalassemia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

580 ORAL AND MAXILLOFACIAL PATHOLOGY
Without therapy, tissue hypoxia worsens and serious
bacterial infections with pneumococcal organisms
often develop. Eventually, high-output cardiac failure
occurs; many patients die by 1 year of age as a result
of infection or heart problems.
a-THALASSEMIA
Because four α-globin genes may be affected, a-thalas-
semia has a broader spectrum of involvement than
does β-thalassemia.
With the alteration of only one gene, no disease can
be detected. With the inheritance of two altered genes,
the condition is known as a-thalassemia trait. These
patients have a mild degree of anemia and microcyto-
sis that is usually not clinically signiﬁcant. With three
altered genes, the term hemoglobin H (HbH) disease
is applied. Patients have problems with hemolytic
anemia and splenomegaly. For patients with severe
hemolysis, splenectomy may be indicated.
The homozygous state, in which all four genes are
abnormal, causes severe generalized fetal edema, a
condition that has been termed hydrops fetalis.
Hydrops fetalis is not speciﬁc for α-thalassemia and
can be seen as a manifestation of other diseases, such
as severe Rh incompatibility. Infants with α-thalasse-
mia who are affected by this problem typically die
within a few hours of birth.
TREATMENT AND PROGNOSIS
Thalassemia major is treated today primarily by means
of blood transfusions. These should be administered
every 2 to 3 weeks to simulate the normal hematologic
state. Unfortunately, with repeated blood transfusions,
iron overload inevitably develops because of the con-
stant infusion of exogenous red blood cells. This is a
serious problem, and often death is due to hemochro-
matosis, an abnormal deposition of iron throughout
the tissues of the body. The heart, liver, and endocrine
glands are particularly affected by the toxic accumula-
tion of iron. To combat this problem, an iron-chelating
agent, deferoxamine (also known as desferrioxamine),
must be given. If such therapy is used steadfastly,
patients with β-thalassemia may have a relatively
normal life span; however, problems may arise with
patient compliance because this medication must be
infused parenterally over several hours for at least 250
nights each year. Hematopoietic stem cell transplanta-
tion has also been used with considerable success for
individuals who are relatively young, have little organ
damage, and have an HLA-matched donor.
Clinicians can now identify α-thalassemia, with its
attendant hydrops fetalis (historically considered a
fatal condition), in utero by molecular testing, and the
fetus can be given intrauterine umbilical vein transfu-
sions. An 80% survival rate has been reported for these
infants, although they will require either lifelong
transfusion therapy or hematopoietic stem cell
transplantation.
For patients who have developed an abnormal facial
appearance caused by thalassemia, surgical correction
can be performed in many cases. Prevention of thalas-
semia also is desirable, either by screening for carriers
of the genetic trait or by prenatal diagnosis.
APLASTIC ANEMIA
Aplastic anemia is a rare, life-threatening hemato-
logic disorder that is characterized by failure of the
hematopoietic precursor cells in the bone marrow to
produce adequate numbers of all types of blood cells.
A signiﬁcant amount of evidence supports the concept
that most cases of aplastic anemia represent an
immune-mediated disease caused by cytotoxic T lym-
phocytes that target differentiating hematopoietic cells
in the marrow. As a result, the hematopoietic stem cells
do not seem to undergo normal maturation despite
normal or increased levels of cytokines, such as granu-
locyte-macrophage colony-stimulating factor (GM-
CSF), which normally induce the production and
maturation of several types of white blood cells.
Although the underlying trigger for the immune-
mediated destruction of the hematopoietic cells is
unknown, some cases of aplastic anemia are associated
with exposure to certain environmental toxins (e.g.,
benzene), treatment with certain drugs (especially the
antibiotic chloramphenicol), or infection with certain
viruses (particularly non-A, non-B, non-C, non-G
hepatitis). It is possible that the abnormal immune
response is perhaps initiated by such exogenous stimuli
in certain instances. A few genetic disorders, such as
Fanconi’s anemia and dyskeratosis congenita (see
page 746), also are associated with an increased fre-
quency of aplastic anemia.
CLINICAL FEATURES
Because all of the formed elements of the blood are
decreased in patients with aplastic anemia, the initial
symptoms may be related to any one or several of the
deﬁciencies. The erythrocyte deﬁciency produces signs
and symptoms related to a decreased oxygen-carrying
capacity of the blood; therefore, patients may experi-
ence fatigue, lightheadedness, tachycardia, or weak-
ness. The platelet deﬁciency (thrombocytopenia) is
seen as a marked tendency for bruising and bleeding,
which affects a variety of sites. Retinal and cerebral
hemorrhages are some of the more devastating mani-
festations of this bleeding tendency. Deﬁciency of
white blood cells (neutropenia, leukopenia, or granulo- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 581
cytopenia) is the most signiﬁcant complication of this
disease, predisposing the patient to bacterial and fungal
infections that often are the cause of death.
The oral ﬁndings related to thrombocytopenia
include gingival hemorrhage (Fig. 13-11), oral mucosal
petechiae, purpura, and ecchymoses. The oral mucosa
may appear pale because of the decreased numbers of
red blood cells. Oral ulcerations associated with infec-
tion, particularly those that involve the gingival tissues,
may be present. Minimal erythema is usually associ-
ated with the periphery of the ulcers. Gingival hyper-
plasia has also been reported in association with aplastic
anemia.
HISTOPATHOLOGIC FEATURES
A bone marrow biopsy specimen usually demonstrates
a relatively acellular marrow with extensive fatty inﬁl-
tration. The histopathologic features of an oral ulcer-
ation in a patient with aplastic anemia show numerous
microorganisms in addition to a remarkable lack of
inﬂammatory cells in the ulcer bed.
DIAGNOSIS
The diagnosis of aplastic anemia is usually established
by laboratory studies. A pancytopenia is characterized
by at least two of the following ﬁndings:
●Fewer than 500 granulocytes/μL
●Fewer than 20,000 platelets/μL
●Fewer than 20,000 reticulocytes/μL
TREATMENT AND PROGNOSIS
The course for patients with aplastic anemia is unpre-
dictable. For the milder forms of the disease, spontane-
ous recovery of the marrow may occur in some
instances; progression to severe aplastic anemia may
be seen in others. Generally, in severe cases, the
chances of spontaneous recovery are slim. If a particu-
lar environmental toxin or drug is associated with the
process, then withdrawal of the offending agent may
sometimes result in recovery.
The treatment is initially supportive. Appropriate
antibiotics are given for the infections that develop,
and transfusions of packed red blood cells or platelets
are administered for symptomatic treatment of anemia
and bleeding problems, respectively.
Deﬁnitive therapy for aplastic anemia is to replace
the defective marrow with normal marrow, either by
bone marrow transplantation or peripheral blood stem
cell transplantation from a matched donor. Patients
must be carefully selected; patients younger than 40
years of age and those with an HLA-matched donor
(usually a sibling) have the best prognosis, but unfortu-
nately only about 30% of patients meet these criteria.
For those patients who would not be a good prospect
for bone marrow transplantation because of their
advanced age or no matched donor, immunosuppres-
sive therapy is recommended. Antithymocyte globulin
(in the United States) or antilymphocyte globulin (in
Europe) combined with cyclosporine produces a
response in the majority of these patients. Compared
with treatment results from only 25 years ago, the
prognosis for this condition has markedly improved. In
the past, for patients with severe aplastic anemia treated
with only antibiotics and transfusions, the mortality
rate was greater than 80% in the ﬁrst year after the
diagnosis. Currently, an overall long-term survival of
75% of these patients can be achieved with either bone
marrow transplant or immunosuppressive therapy.
However, even if the disease is controlled, then these
patients remain at risk for recurrent marrow aplasia
and are at increased risk for acute leukemia.
NEUTROPENIA
Neutropenia refers to a decrease in the number of the
circulating neutrophils below 1500/mm
3
in an adult.
It is often associated with an increased susceptibility of
the patient to bacterial infections. Clinicians must be
aware of this disorder because infection of the oral
mucosa may be the initial sign of the disease. Interest-
ingly, several ethnic groups, including patients of
African and Middle Eastern background, will consis-
tently have neutrophil counts that would qualify as
neutropenia (as low as 1200/mm
3
), yet these individu-
als are otherwise healthy. This ﬁnding has been termed
benign ethnic neutropenia, and it appears to have no
effect on the health of the patient because neutrophil
counts respond to bacterial challenge.
A decrease in neutrophils may be precipitated by
several mechanisms, most of which involve decreased
Fig. 13-11 Aplastic anemia. Diffuse gingival hyperplasia
with sulcular hemorrhage. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

582 ORAL AND MAXILLOFACIAL PATHOLOGY
production or increased destruction of these important
inﬂammatory cells. When infections are noted in
infancy and neutropenia is detected, the problem is
usually the result of a congenital or genetic abnormal-
ity, such as Schwachman-Diamond syndrome, dys-
keratosis congenita (see page 746), cartilage-hair
syndrome, or severe congenital neutropenia. If the
neutropenia is detected later in life, it usually repre-
sents one of the acquired forms. Many acquired neutro-
penias have an unknown cause; however, others are
clearly associated with various causes. A decreased pro-
duction of neutrophils and the other formed elements
of the blood may result from the destruction of the bone
marrow by malignancies, such as leukemia (see page
587), or by metabolic diseases, such as Gaucher disease
(see page 818), and osteopetrosis (see page 615).
Many drugs may affect neutrophil production, either
through direct toxic effects on the bone marrow pro-
genitor cells or by unknown idiosyncratic mechanisms.
These drugs include the following:
●Anticancer chemotherapeutic agents (e.g.,
nitrogen mustard, busulfan, chlorambucil,
cyclophosphamide)
●Antibiotics (e.g., penicillins and sulfonamides)
● Phenothiazines
● Tranquilizers
● Diuretics
Nutritional deﬁciencies of vitamin B
12 or folate,
which may be a consequence of malabsorption syn-
dromes, can inhibit neutrophil production.
A variety of viral and bacterial infections not only
may reduce production of neutrophils but also seem to
increase their destruction, typically at the sites of infec-
tion. Viral infections that have been implicated include
the following:
●Hepatitis A and B
● Rubella
● Measles
●Respiratory syncytial virus
● Varicella
● Human immunodeﬁciency virus (HIV)
Numerous bacterial infections, such as typhoid,
tuberculosis, brucellosis, and tularemia, may also cause
neutropenia. The increased destruction of neutrophils
by an autoimmune mechanism also occurs in such dis-
orders as systemic lupus erythematosus (SLE), in which
autoantibodies directed against the neutrophil are
produced.
CLINICAL FEATURES
Most patients with neutropenia have some form of bac-
terial infection rather than a viral or fungal infection,
particularly if the other elements of the immune system
(lymphocytes, plasma cells, and monocytes) are still
intact. Staphylococcus aureus and gram-negative organ-
isms seem to cause the most problems for patients
with neutropenia. The suppuration and abscess forma-
tion normally associated with such infections may be
markedly reduced because of the lack of neutrophils.
The most common sites of infection include the middle
ear, the oral cavity, and the perirectal area. When
neutrophil counts drop below 500/mm
3
, however, pul-
monary infections often develop.
The oral lesions of neutropenia consist of ulcerations
that usually involve the gingival mucosa, probably
because of the heavy bacterial colonization of this
area and the chronic trauma that it receives. These
ulcers characteristically lack an erythematous periph-
ery, although this ﬁnding has been variable. Premature
periodontal bone loss with exfoliation of the deciduous
dentition has been described.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of a neutropenic ulceration usually
shows a reduced number or the absence of neutro-
phils. Bacterial invasion of the host tissue may be
apparent in some instances.
TREATMENT AND PROGNOSIS
Infections related to neutropenia are managed with
appropriate antibiotic therapy. The patient should be
encouraged to maintain optimal oral hygiene to
decrease the bacterial load in the oral cavity. Studies
using recombinant human granulocyte colony-stimu-
lating factor (G-CSF), a cytokine that promotes the
growth and differentiation of neutrophils, have shown
remarkable results. Patients with severe neutropenia
have a signiﬁcant increase in neutrophil counts and
resolution of infections after treatment with this agent.
Patients who do not respond to G-CSF may have to be
considered for hematopoietic stem cell transplanta-
tion, depending on the severity of the neutropenia and
subsequent infections.
AGRANULOCYTOSIS
Agranulocytosis is a condition in which the cells of
the granulocytic series, particularly neutrophils, are
absent. As in other disorders of the formed elements of
the blood, agranulocytosis may occur as a result of
decreased production or increased destruction or use
of these cells. Although some cases are idiopathic, most
are induced by exposure to one of several drugs. Some
drugs, such as the anticancer chemotherapeutic agents,
induce agranulocytosis by inhibiting the normal mitotic
division and maturation of the hematopoietic stem
cells. In other instances, the drugs trigger an immuno- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 583
logic reaction that results in the destruction of granu-
locytes. Rarely, agranulocytosis may be a congenital
syndrome (congenital agranulocytosis, Kostmann
syndrome) that results from a decreased level of
the cytokine granulocyte colony-stimulating factor
(G-CSF).
CLINICAL FEATURES
Agranulocytosis typically develops within a few days
after a person ingests the offending drug. Because of
the lack of granulocytes (especially neutrophils), bacte-
rial infections often develop and patients may show
signs and symptoms of malaise, sore throat, swelling,
fever, chills, bone pain, pneumonia, and shock. The
erythrocyte and platelet counts are usually normal or
only slightly depressed.
Oral lesions are common and include necrotizing,
deep, punched-out ulcerations of the buccal mucosa,
tongue, and palate. The gingivae are especially suscep-
tible to infection, often resembling the pattern of nec-
rotizing ulcerative gingivitis (NUG) (see page 157).
HISTOPATHOLOGIC FEATURES
Microscopic examination of a biopsy specimen from
one of the oral ulcerations in agranulocytosis charac-
teristically shows abundant bacterial organisms, both
on the surface and within the tissue. The host inﬂam-
matory response is relatively sparse, with few granulo-
cytes, particularly neutrophils, seen in the ulcer bed.
TREATMENT AND PROGNOSIS
If the clinician believes that a particular drug has
caused the agranulocytosis, the medication should be
discontinued as soon as is reasonably possible. In many
instances, the granulocyte count returns to normal
within 10 to 14 days after cessation of the offending
agent. For patients who have agranulocytosis second-
ary to cancer chemotherapy, oral hygiene should be
meticulous to foster an immaculate oral environment.
In addition, the use of chlorhexidine-containing mouth
rinses seems to reduce the severity of the oral lesions.
Active infections are treated with appropriate antibi-
otic medications.
If the agranulocytosis is related to cancer treatment,
the white blood cell count usually returns to normal
after a period of weeks. For patients whose granulocyte
counts do not recover, administration of G-CSF or
granulocyte-macrophage colony-stimulating factor
(GM-CSF) may be beneﬁcial. The overall mortality rate
for this condition in the past was 20% to 30%, although
cytokine therapy and the newer broad-spectrum anti-
biotics have improved the outlook for these patients.
CYCLIC NEUTROPENIA (CYCLIC
HEMATOPOIESIS)
Cyclic neutropenia is a rare idiopathic hematologic
disorder that is characterized by regular periodic
reductions in the neutrophil population of the affected
patient. The underlying cause seems to be a mutation
of the neutrophil elastase (ELA2) gene, resulting in
arrested development of neutrophils at the promyelo-
cyte stage within the marrow. This mutation is also
associated with premature apoptosis of these myeloid
precursor cells. The best estimated frequency of this
disease in the population is about 1 in 1 million.
Although an autosomal dominant pattern of inheri-
tance has been described in a few cases, most examples
of cyclic neutropenia are isolated.
Symptoms usually begin in childhood and tend to
correlate with the neutrophil counts. When the neutro-
phil count is at its nadir (i.e., lowest point), the patient
experiences problems with infection. As the neutrophil
count rises toward normal, the signs and symptoms
abate. Very low neutrophil counts usually are present
for 3 to 6 days, and blood monocyte and eosinophil
levels are typically increased when the neutrophil
count is depressed. Even when the neutrophil count is
at its peak, the levels are often less than normal.
CLINICAL AND RADIOGRAPHIC
FEATURES
The signs and symptoms of cyclic neutropenia occur in
rather uniformly spaced episodes, which usually have
a 21-day cycle. Patients typically complain of recurrent
episodes of fever, anorexia, cervical lymphadenopathy,
malaise, pharyngitis, and oral mucosal ulcerations.
Other gastrointestinal mucosal areas, including the
colon, rectum, and anus, may be affected by recurrent
ulcerations.
The oral ulcerations develop on any oral mucosal
surface that is exposed to even minor trauma, particu-
larly the lips, tongue, buccal mucosa, and oropharynx
(Fig. 13-12). An erythematous halo is variably present
at the periphery of the ulcers. The gingiva is the most
severely affected region of the oral cavity. Severe peri-
odontal bone loss with marked gingival recession and
tooth mobility are also characteristic (Fig. 13-13).
DIAGNOSIS
The diagnosis of cyclic neutropenia should be estab-
lished by sequential complete blood counts (typically
two to three times per week for 8 weeks) to determine
whether cycling of the neutrophil levels occurs. The
neutrophil count should be less than 500/mm
3
for 3 to
5 days during each of at least three successive cycles to
make this diagnosis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

584 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
The histopathologic features of cyclic neutropenia are
similar to those of the other neutropenic and granulo-
cytopenic ulcerations if the biopsy is performed during
the nadir of the neutrophil count.
TREATMENT AND PROGNOSIS
Supportive care for the patient with cyclic neutropenia
includes antibiotic therapy for signiﬁcant infections
that might occur while the neutrophil count is at its
lowest. Unfortunately, this approach cannot be consid-
ered a permanent treatment. Other methods that have
been used with marginal success include splenectomy,
corticosteroid therapy, and nutritional supplementa-
tion. Studies have shown that administration of the
cytokine granulocyte colony-stimulating factor (G-CSF)
several times weekly seems to correct the lack of pro-
duction of neutrophils. This treatment results in a
decrease in the time of neutropenia from 5 days to 1
day, which improves the clinical course of the disease.
The cycles are reduced from 18 to 21 days to 11 to 13
days, and the severity of mucositis and infection are
reduced.
Supportive care in the form of optimal oral hygiene
should be maintained to reduce the number and sever-
ity of oral infections and improve the prognosis of the
periodontal structures. Fortunately, for many of these
patients, the severity of symptoms related to cyclic neu-
tropenia seems to diminish after the second decade of
life, despite the fact that the cycling of the neutrophils
continues.
THROMBOCYTOPENIA
Thrombocytopenia is a hematologic disorder that is
characterized by a markedly decreased number of cir-
culating blood platelets (formed elements derived from
megakaryocyte precursors in the bone marrow). Plate-
lets are necessary for hemostasis and clot formation. A
platelet count of 200,000 to 400,000/mm
3
is consid-
ered normal. The decrease in platelets may be the
result of the following:
● Reduced production
● Increased destruction
●Sequestration in the spleen
REDUCED PLATELET PRODUCTION
Reduced production of platelets may be the result of
various causes, such as inﬁltration of the bone marrow
by malignant cells or the toxic effects of cancer chemo-
therapeutic drugs. In such instances, decreases in the
other formed elements of the blood are also seen.
INCREASED PLATELET DESTRUCTION
Increased destruction of platelets may be caused by an
immunologic reaction, which is often precipitated by
any one of more than 100 different drugs; heparin is
one of the most common offending agents. This type of
reaction is typically idiosyncratic and, therefore, not
related to the dose of the drug. Similarly, autoantibod-
ies directed against platelets, speciﬁcally certain surface
glycoproteins, may on rare occasions be induced by
viral infection or vaccination. In addition, certain sys-
temic diseases may have thrombocytopenia as a com-
ponent, such as systemic lupus erythematosus and HIV
infection. Increased destruction may also occur by non-
immunologic means because of increased consump-
tion of platelets associated with abnormal blood clot
formation. This occurs in patients with conditions such
as thrombotic thrombocytopenic purpura (TTP).
Fig. 13-12 Cyclic neutropenia. Ulceration of the lateral
tongue is typical of the lesions associated with cyclic
neutropenia. (From Allen CM, Camisa C: Diseases of the mouth and lips.
In Sams WM, Lynch P, editors: Principles and practice of dermatology, ed
2, New York, 1996, Churchill Livingstone.)
Fig. 13-13 Cyclic neutropenia. Cyclic neutropenia is one
of several conditions that may produce premature bone loss,
as shown in the interradicular regions of the mandibular
deciduous molar teeth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 585
SEQUESTRATION IN THE SPLEEN
Under normal conditions, one third of the platelet
population is sequestered in the spleen. Consequently,
conditions that cause splenomegaly (e.g., portal hyper-
tension secondary to liver disease, splenic enlargement
secondary to tumor inﬁltration, splenomegaly associ-
ated with Gaucher disease) also cause larger numbers
of platelets to be taken out of circulation. Regardless of
the cause, the result for the patient is a bleeding
problem because normal numbers of platelets are not
available for proper hemostasis.
CLINICAL FEATURES
Clinical evidence of thrombocytopenia is not usually
seen until the platelet levels drop below 100,000/mm
3
.
The severity of involvement is directly related to the
extent of platelet reduction. The condition often is ini-
tially detected because of the presence of oral lesions.
Minor traumatic events are continuously inﬂicted on
the oral mucosa during chewing and swallowing of
food. The small capillaries that are damaged during
this process are normally sealed off with microscopic
thrombi. In a patient with thrombocytopenia, however,
the thrombi do not form properly. This results in a
leakage of blood from the small vessels. Clinically, this
usually produces pinpoint hemorrhagic lesions known
as petechiae. If a larger quantity of blood is extrava-
sated, then an ecchymosis or bruise results (Fig.
13-14). With even larger amounts of extravasated
blood, a hematoma (hemat = blood; oma = tumor) will
develop (Fig. 13-15). Spontaneous gingival hemor-
rhage often occurs in these patients, as does bleeding
from sites of minor trauma.
Similar hemorrhagic events occur throughout the
body. With severe thrombocytopenia (<10,000 plate-
lets/mm
3
), massive bleeding from the gastrointestinal
or urinary tract may be fatal. Epistaxis is often present
in these patients, and hemoptosis indicates signiﬁ-
cant pulmonary hemorrhage. Intracranial hemorrhage
is also a potentially fatal complication of severe
thrombocytopenia.
Special types of thrombocytopenia include idio-
pathic (immune) thrombocytopenic purpura (ITP)
and TTP. ITP usually occurs during childhood, classi-
cally after a nonspeciﬁc viral infection. The symptoms
of thrombocytopenia appear quickly and may be
severe. Most cases, however, resolve spontaneously
within 4 to 6 weeks, and 90% of patients recover by 3
to 6 months.
TTP is a serious disorder of coagulation and is
thought to be caused by some form of endothelial
damage that appears to trigger the formation of numer-
ous thrombi within the small blood vessels of the
body.
HISTOPATHOLOGIC FEATURES
Gingival biopsy may be performed for diagnostic pur-
poses in patients with suspected TTP. Approximately
30% to 40% of such biopsy specimens show the pres-
ence of ﬁbrin deposits in the small vessels. These
deposits are more readily appreciated after staining the
tissue section using the periodic acid-Schiff (PAS)
method.
TREATMENT AND PROGNOSIS
If the clinician believes the thrombocytopenia to be
drug-related, the drug should be discontinued imme-
diately. In most instances, the platelet count returns to
normal after several days. Platelet transfusions and
Fig. 13-14 Thrombocytopenia. The bruising (purpura)
seen on this patient’s forearm is a result of reduced platelet
count secondary to myelodysplasia, a preleukemic bone
marrow disorder.
Fig. 13-15 Thrombocytopenia. This dark palatal lesion
represents a hematoma caused by a lack of normal
coagulation, characteristic of thrombocytopenia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

586 ORAL AND MAXILLOFACIAL PATHOLOGY
corticosteroid therapy may be necessary if life-threat-
ening hemorrhage occurs. As mentioned earlier, ITP
often resolves spontaneously, but those cases that are
more severe may require corticosteroid therapy or
intravenous immunoglobulin (IVIG) therapy. For some
forms of thrombocytopenia, such as TTP, the patient’s
prognosis is relatively guarded. In the past, the condi-
tion was almost uniformly fatal, although the outlook
has improved since therapy with plasmapheresis or
plasma exchange transfusions became available. More
than 70% of these patients now survive with proper
treatment.
POLYCYTHEMIA VERA (PRIMARY
POLYCYTHEMIA; POLYCYTHEMIA
RUBRA VERA; PRIMARY
ACQUIRED ERYTHROCYTOSIS)
Polycythemia vera is a rare idiopathic hematologic
disorder that is best thought of as an increase in the
mass of the red blood cells. Uncontrolled production of
platelets and granulocytes, however, is often seen con-
currently, and most authorities feel that this condition
represents a relatively nonaggressive myelopro lifera-
tive disorder. Researchers believe the overproduction
is related to the abnormal behavior of a single progeni-
tor marrow stem cell, which begins multiplying without
regard to the normal regulatory hormones, such as
erythropoietin. This gives rise to a group or clone of
unregulated cells that then produce the excess numbers
of these formed elements of the blood at two to three
times the normal rate. These cells generally function in
a normal fashion.
CLINICAL FEATURES
Polycythemia vera typically affects older adults. The
median age at diagnosis is 60 years. Only 5% of cases
are diagnosed before the age of 40 years. No sex pre-
dilection is seen, and the annual incidence estimates
of the condition have ranged widely, from 0.2 to 28.0
cases per million population. Recent evidence suggests
that an acquired mutation of one of the tyrosine kinase
genes, Janus kinase 2 (JAK2), may play a signiﬁcant
role in the development of this disorder, because more
than 95% of patients with polycythemia vera have
been shown to have this mutation.
The initial symptoms of the disease are nonspeciﬁc
and include the following:
● Headache
● Weakness
● Dizziness
● Drowsiness
● Visual disturbances
● Sweating
● Weight loss
● Dyspnea
● Epigastric pain
A ruddy complexion may be evident on physical
examination. One relatively characteristic complaint,
described in about 40% of affected patients, is that of
generalized pruritus (itching), particularly after bathing,
without evidence of a rash.
The problems caused by thrombus formation, which
would be expected with the increased viscosity of the
blood and the increased platelet numbers, include
transient ischemic attacks, cerebrovascular accidents,
and myocardial infarctions. Hypertension and spleno-
megaly are also common.
A peculiar peripheral vascular event called eryth-
romelalgia affects the hands and feet. Patients experi-
ence a painful burning sensation accompanied by
erythema and warmth. This may eventually lead to
thrombotic occlusion of the vessels that supply the
digits. Digital gangrene and necrosis may result. Eryth-
romelalgia is probably caused by excessive platelets,
and its onset seems to be precipitated by exercise,
standing, or warm temperatures.
Strangely enough, these patients may also have
problems with excess hemorrhage. Epistaxis and ecchy-
moses are often a problem, and gingival hemorrhage
has been described.
TREATMENT AND PROGNOSIS
With the initial diagnosis of polycythemia vera, an
immediate attempt is made to reduce the red blood
cell mass. The ﬁrst treatment is usually phlebotomy,
with as much as 500 mL of blood removed daily. If
thrombotic events are an immediate problem, then
treatment with low-dose aspirin should be started. To
control the platelet levels, anagrelide hydrochloride, a
selective inhibitor of megakaryocyte maturation and
platelet production, may be prescribed. Antihistamines
are used to help control the symptoms of pruritus.
Long-term management may include intermittent
phlebotomy, although myelosuppressive therapy has
also been advocated. Each has disadvantages. An
increased risk of thrombosis is associated with phle-
botomy, and an increased risk of leukemia is associated
with some chemotherapeutic drugs. Hydroxyurea is
one chemotherapeutic agent that may not pose an
increased risk of leukemia, however, because it acts as
an antimetabolite and does not appear to have any
mutagenic properties. Nevertheless, in 2% to 10% of
patients with polycythemia vera, acute leukemia ulti-
mately develops.
Overall, the prognosis is fair; patients with polycy-
themia vera survive an average of 10 to 12 years after `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 587
the diagnosis, if treated. Given the fact that the median
age at diagnosis is 60 years, the majority of affected
patients do not seem to have a markedly higher death
rate compared with their unaffected peers.
LEUKEMIA
Leukemia represents several types of malignancies of
hematopoietic stem cell derivation. The disease begins
with the malignant transformation of one of the stem
cells, which initially proliferates in the bone marrow
and eventually overﬂows into the peripheral blood of
the affected patient. Problems arise when the leukemic
cells crowd out the normal defense cell and erythro-
cyte precursors. In the United States, approximately
2.5% of all cancers are leukemia, and 3.9% of deaths
from cancer can be attributed to this disease.
Leukemias are usually classiﬁed according to their
histogenesis and clinical behavior. Therefore, the broad
categories would be acute or chronic (referring to the
clinical course) and myeloid or lymphocytic/lym-
phoblastic (referring to the histogenetic origin).
Myeloid leukemias can differentiate along several dif-
ferent pathways; thus they produce malignant cells that
usually show features of granulocytes or monocytes,
and less frequently, erythrocytes or megakaryocytes.
Acute leukemias, if untreated, run an aggressive
course and often result in the death of the patient
within a few months. Chronic leukemias tend to follow
a more indolent course, although the end result is the
same. One of the greatest successes in cancer treat-
ment has been achieved in acute lymphoblastic leuke-
mia of childhood, a condition that used to be uniformly
fatal but now is often capable of being controlled.
Leukemias are probably the result of a combination
of environmental and genetic factors. Certain syn-
dromes are associated with an increased risk. These
genetic disorders include the following:
● Down syndrome
● Bloom syndrome
● Neuroﬁbromatosis type I
● Schwachman syndrome
● Ataxia-telangiectasia syndrome
● Klinefelter syndrome
● Fanconi’s anemia
● Wiskott-Aldrich syndrome
In addition, certain types of leukemia show speciﬁc
chromosomal abnormalities. The ﬁrst chromosomal
abnormality to be detected was found in patients with
chronic myeloid leukemia, and this malignancy was
characterized by a genetic alteration called the Phila-
delphia chromosome. This abnormality represents a
translocation of the chromosomal material between
the long arms of chromosomes 22 and 9. This rear-
rangement of the genetic material occurs in such a
fashion as to fuse the breakpoint cluster region (bcr)
gene with the Abelson (c-abl) oncogene, producing an
entirely new gene: bcr-abl. This gene is continuously
transcribed, and the resulting protein product, a tyro-
sine kinase, causes the uncontrolled proliferation of
the leukemic cells. Identifying such pathogenetic
mechanisms has opened up an entirely new ﬁeld of
chemotherapy that targets speciﬁc molecular mecha-
nisms of carcinogenesis. A variety of other genetic
alterations in the bone marrow stem cells has been
associated with the myelodysplasia syndromes, a
group of disorders that appear to represent early stages
in the evolution of acute myeloid leukemia. As the
genetic alterations accumulate in the stem cells, the
chances of the patient developing leukemia increase.
Some environmental agents are associated with an
increased risk of leukemia, but their overall contribu-
tion to the leukemia problem is thought to be less than
5%. Exposure to pesticides, benzene, and benzene-like
chemicals has been associated with an increased risk
of developing leukemia. Ionizing radiation has also
been implicated; this was documented by the increased
frequency of chronic myeloid leukemia in the survi-
vors of the atomic bomb blasts at Hiroshima and Naga-
saki during World War II. Viruses have also been
shown to produce leukemia, although this is not a
common ﬁnding. The most thoroughly studied is the
retrovirus known as human T-cell leukemia/lymphoma
virus type 1 (HTLV-1), which is transmitted by contami-
nated blood from infected to uninfected individuals.
This virus can cause a relatively rare form of malig-
nancy of T lymphocytes, which may present as a
leukemia or non-Hodgkin’s lymphoma (see page
595). Most cases have been identiﬁed in parts of the
Caribbean, central Africa, and southwestern Japan.
As knowledge about this group of diseases increases,
the fact that the leukemias are diverse and complex
cannot be overlooked. For example, eight distinct sub-
types of acute myeloid leukemia have now been identi-
ﬁed, and each subtype has a different treatment
approach and prognosis. Because of the complexity of
this area, the discussion is limited to those aspects of
leukemia that are more directly related to the oral or
head and neck region.
CLINICAL FEATURES
If all types of leukemia are considered, this condition
occurs at a rate of 13 cases per 100,000 population
annually. Slightly more males than females are affected.
The myeloid leukemias generally affect an adult popu-
lation; acute myeloid leukemia affects a broader
age range, which includes children. Chronic myeloid
leukemia shows a peak incidence during the third
and fourth decades of life. Acute lymphoblastic `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

588 ORAL AND MAXILLOFACIAL PATHOLOGY
leukemia, in contrast, occurs predominantly in chil-
dren and represents one of the more common child-
hood malignancies. Chronic lymphocytic leukemia,
the most common type of leukemia, primarily affects
older adults.
Many of the clinical signs and symptoms of leukemia
are related to the marked reduction in the numbers of
normal white and red blood cells, a phenomenon that
results from the crowding out of the normal hematopoi-
etic stem cells by the malignant proliferation (myelo-
phthisic anemia). Because of the reduced red blood
cell count and subsequent reduction in oxygen-carrying
capacity of the blood, patients complain of fatigue, easy
tiring, and dyspnea on mild exertion. The malignant
cells may also inﬁltrate other organs and often cause
splenomegaly, hepatomegaly, and lymphadenopathy.
Leukemic patients may also complain of easy bruis-
ing and bleeding, problems that are caused by a lack
of blood platelets (thrombocytopenia), the result of
megakaryocytes being crowded out of the marrow.
Petechial hemorrhages of the posterior hard palate and
the soft palate may be observed, and these may be
accompanied by spontaneous gingival hemorrhage,
especially with platelet counts less than 10,000 to
20,000/mm
3
. Because disturbances in stem cell dif-
ferentiation accompany the myelodysplasia syndromes,
thrombocytopenia is often present in these patients,
and gingival hemorrhage has been reported in this
setting. Serious hemorrhagic complications may result
from bleeding into the central nervous system or the
lungs.
A fever associated with infection may be the initial
sign of the leukemic process. Perirectal infections,
pneumonia, urinary tract infections, and septicemia
are common infectious complications. The micro-
organisms that are typically involved include gram-
negative bacteria, gram-positive cocci, and certain
Candida species.
Ulceration of the oral mucosa is often present as a
result of the impaired ability of the host to combat the
normal microbial ﬂora. Usually, the gingival mucosa is
the most severely affected because of the abundant
bacteria normally present around the teeth. The neu-
tropenic ulcers that are produced are typically deep,
punched-out lesions with a gray-white necrotic base.
Oral candidiasis is often a complication of leukemia,
involving the oral mucosa diffusely. Herpetic infections
are the most common viral lesions, and these may
involve any area of the oral mucosa rather than being
conﬁned to the keratinized mucosa, as in immunocom-
petent patients.
Occasionally, the leukemic cells inﬁltrate the oral
soft tissues and produce a diffuse, boggy, nontender
swelling that may or may not be ulcerated. This occurs
most frequently with the myelomonocytic types of leu-
kemia, and it may result in diffuse gingival enlarge-
ment (Figs. 13-16 and 13-17) or a prominent tumorlike
growth (Fig. 13-18). The tumorlike collection of leuke-
mic cells is known as granulocytic sarcoma or extra-
medullary myeloid tumor, and historically the term
chloroma has been used because it is often greenish
(chlor = green; oma = tumor) on fresh-cut sections.
Other oral manifestations include inﬁltration of the
periapical tissues, simulating periapical inﬂammatory
disease both clinically and radiographically.
HISTOPATHOLOGIC FEATURES
Microscopic examination of leukemia-affected tissue
shows diffuse inﬁltration and destruction of the normal
host tissue by sheets of poorly differentiated cells with
either myelomonocytic characteristics or lymphoid
features.
Fig. 13-16 Leukemia. Diffuse gingival enlargement, as
depicted in this photograph, may occur in leukemic patients,
particularly in those with monocytic leukemia. This older
man had a history of myelodysplasia for several years before
the development of leukemia.
Fig. 13-17 Leukemia. Extensive hemorrhagic enlargement
of the maxillary and mandibular gingivae. (Courtesy of Dr. Michael
Tabor.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 589
DIAGNOSIS
The diagnosis is usually established by conﬁrming the
presence of poorly differentiated leukemic cells in the
peripheral blood and bone marrow. Bone marrow
biopsy is normally performed in conjunction with the
peripheral blood studies because some patients may go
through an aleukemic phase in which the atypical cells
are absent from the circulation. Classifying the type of
leukemia requires establishing the immunophenotype
by using immunohistochemical markers to identify cell
surface antigens expressed by the tumor cells. Immu-
nohistochemical conﬁrmation of certain characteristic
enzymes (e.g., myeloperoxidase, lysozyme) is necessary
to identify and classify the myeloid leukemias. In addi-
tion, cytogenetic and molecular characterization of the
lesional cells is typically necessary. In many cases, the
results of these various studies will be signiﬁcant
because the patient’s prognosis is directly affected.
TREATMENT AND PROGNOSIS
The treatment of a patient with leukemia consists of
various forms of chemotherapy; the type of leukemia
dictates the chemotherapeutic regimen. In most cases
the purpose of chemotherapy is to destroy as many of
the atypical cells as possible in a short time, thus induc-
ing a remission. For this reason, this technique has
been termed induction chemotherapy. Usually, this
phase of chemotherapy requires high doses of toxic
chemotherapeutic agents; often, the patient experi-
ences a number of unpleasant side effects during treat-
ment. Once remission has been induced, this state
must be maintained. This is the purpose of mainte-
nance chemotherapy, which typically requires lower
doses of chemotherapeutic drugs given over a longer
period.
If the bcr-abl fusion is identiﬁed in the leukemic
cells of a patient with chronic myeloid leukemia, then
treatment with a tyrosine kinase inhibitor is appropri-
ate. The ﬁrst tyrosine kinase inhibitor to be developed
and marketed was imatinib mesylate, and a signiﬁcant
proportion of patients will respond dramatically to this
therapy. Imatinib must be taken continuously, because
relapses develop quickly if the drug is stopped. Other
tyrosine kinase inhibitors are currently being investi-
gated as well.
Newer treatments for chronic lymphocytic leuke-
mia include monoclonal antibodies directed against
cell surface antigens, such as CD20, a B-lymphocyte
antigen. Rituximab is one such agent that is now being
investigated in the treatment of hematologic malignan-
cies of B-cell differentiation.
Drug therapy may be combined with radiation
therapy to the CNS because the chemotherapeutic
drugs often do not cross the blood-brain barrier effec-
tively. Therefore, the leukemic cells may survive in this
site and cause a relapse of the leukemia. Direct intra-
thecal infusion of the chemotherapeutic agent may be
performed to circumvent the problem of the blood-
brain barrier. If this strategy succeeds in inducing a
remission, then a bone marrow transplant may be con-
sidered as a therapeutic option, particularly for the
types of leukemia that tend to relapse. This option often
is reserved for patients younger than 45 years of age
because the success rate is less favorable in older
patients.
Supportive care is often necessary if these patients
are to survive their leukemia. For patients with
bleeding problems, transfusions with platelets may
be necessary. If severe anemia is present, packed
red blood cells may be required. Infections, of
course, should be evaluated with respect to the caus-
ative organism, and appropriate antibiotics must
be prescribed. Support must be maintained from an
oral perspective because many of these patients expe-
rience infections of the oral mucosa during the course
of their disease. Optimal oral hygiene should be
encouraged, and aggressive investigation of any
oral complaint should be performed as soon as possi-
ble to prevent potentially serious oral infectious
complications.
The prognosis of a particular patient depends on a
number of variables, including the type of leukemia,
the age of the patient, and the cytogenetic alterations
associated with the disease. In children with acute
lymphoblastic leukemia, more than 80% of these
patients are now considered to be cured after appropri-
ate treatment. In an adult with the same diagnosis,
even though the rate of initial remission induction is
80%, the 5-year survival rate is generally much lower
in most reported series.
Fig. 13-18 Leukemia. The ulcerated soft tissue nodule of
the hard palate represents leukemic cells that have
proliferated in this area. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

590 ORAL AND MAXILLOFACIAL PATHOLOGY
Patients younger than 60 years of age with acute
myeloid leukemia have a 5-year survival rate of
approximately 40% today. This form of leukemia in a
patient older than 60 years, however, has a much
poorer prognosis, with less than a 10% chance of sur-
vival seen in that population. Similarly, patients with a
previous history of myelodysplasia have an unfavor-
able prognosis.
Even though an indolent period is experienced with
chronic myeloid leukemia, eventually the neoplastic
cells undergo a process known as blast transforma-
tion, in which they become less differentiated, prolifer-
ate wildly, and cause the patient’s death within 3 to 6
months. In the past, the 5-year survival rate for chronic
myeloid leukemia was in the 20% range. Today, most
centers are reporting 5-year survival rates of approxi-
mately 80%, a dramatic improvement presumably
because of the effect of tyrosine kinase inhibitor
therapy. Additional factors that may play a role in
improved survival include diagnosis of the disease at
an earlier stage and the availability of better supportive
care. Attempts to control chronic myeloid leukemia by
bone marrow transplantation from an HLA-matched
donor have resulted in 5-year survival rates of 60% to
70% in younger patients with this disease. This may be
an option for those patients who do not respond to
tyrosine kinase inhibitor therapy.
Chronic lymphocytic leukemia is considered to
be incurable, but its course is highly variable and
depends on the stage of the disease. Patients with
limited disease have an average survival time of more
than 10 years. Those with more advanced disease
survive an average of only 2 years.
LANGERHANS CELL HISTIOCYTOSIS
(HISTIOCYTOSIS X; LANGERHANS
CELL DISEASE; IDIOPATHIC
HISTIOCYTOSIS; EOSINOPHILIC
GRANULOMA; LANGERHANS CELL
GRANULOMA; LANGERHANS CELL
GRANULOMATOSIS)
The term histiocytosis X was introduced as a collective
designation for a spectrum of clinicopathologic disor-
ders characterized by proliferation of histiocyte-like
cells that are accompanied by varying numbers of
eosinophils, lymphocytes, plasma cells, and multinucle-
ated giant cells. The distinctive histiocytic cells present
in this lesion have been identiﬁed as Langerhans cells,
and the condition is now designated as Langerhans
cell histiocytosis. Langerhans cells are dendritic
mononuclear cells normally found in the epidermis,
mucosa, lymph nodes, and bone marrow. These cells
process and present antigens to T lymphocytes. For
many years, researchers have debated whether Langer-
hans cell histiocytosis represents a nonneoplastic
condition or a true neoplasm. Studies examining the
clonality of the lesional cells of this condition have
shown this to be a monoclonal proliferation, a ﬁnding
that is more consistent with a neoplastic process.
CLINICAL AND RADIOGRAPHIC
FEATURES
The clinicopathologic spectrum traditionally consid-
ered under the designation of Langerhans cell histio-
cytosis includes the following:
●Monostotic or polyostotic eosinophilic granuloma
of bone—solitary or multiple bone lesions without
visceral involvement
●Chronic disseminated histiocytosis—a disease
involving bone, skin, and viscera (Hand-Schül-
ler-Christian disease)
●Acute disseminated histiocytosis—a disease with
prominent cutaneous, visceral, and bone marrow
involvement occurring mainly in infants (Let-
terer-Siwe disease)
It is difﬁcult to categorize many patients into one of
these classic designations because of overlapping clini-
cal features. The often-cited Hand-Schüller-Christian
triad—bone lesions, exophthalmos, and diabetes insipi-
dus—is present in only a few patients with chronic dis-
seminated disease. It is widely believed that the
traditional designations of Hand-Schüller-Christian
and Letterer-Siwe disease serve no useful purpose and
should be discontinued. Many cases reported as
Letterer-Siwe disease in the older literature probably
included obscure infections, immunodeﬁciency syn-
dromes, and malignant histiocytic lesions. Pulmonary
Langerhans cell histiocytosis has also been described,
but this probably is unrelated to the condition that
affects the jaws. Patients who develop pulmonary Lang-
erhans cell histiocytosis are usually adults with a history
of smoking, and clonality studies suggest that this is
probably a reactive process.
Although Langerhans cell histiocytosis may be
encountered in patients over a wide age range, more
than 50% of all cases are seen in patients younger than
age 15. Although some series have reported a male
predilection, overall the sexes appear to be equally
affected. Bone lesions, either solitary or multiple, are
the most common clinical presentation. Lesions may
be found in almost any bone, but the skull, ribs, verte-
brae, and mandible are among the most frequent sites.
Children younger than age 10 most often have skull
and femoral lesions; patients older than age 20 more
often have lesions in the ribs, shoulder girdle, and man-
dible. Adult patients with solitary or multiple bone
lesions may have lymphadenopathy but usually do not
have signiﬁcant visceral involvement. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 591
The jaws are affected in 10% to 20% of all cases. Dull
pain and tenderness often accompany bone lesions.
Radiographically, the lesions often appear as sharply
punched-out radiolucencies without a corticated rim,
but occasionally an ill-deﬁned radiolucency is seen.
Bone involvement in the mandible usually occurs in
the posterior areas, and a characteristic “scooped out”
appearance may be evident when the superﬁcial alveo-
lar bone is destroyed. The resulting bone destruction
and loosening of the teeth clinically may resemble
severe periodontitis (Fig. 13-19). Extensive alveolar
involvement causes the teeth to appear as if they are
“ﬂoating in air” (Fig. 13-20).
Ulcerative or proliferative mucosal lesions or a pro-
liferative gingival mass may develop if the disease
breaks out of bone (Fig. 13-21). Occasionally, this
process may involve only the oral soft tissues. Lesions
also can occur within the body of the mandible or
maxilla, where they may simulate a periapical inﬂam-
matory condition.
HISTOPATHOLOGIC FEATURES
The bone lesions of patients with Langerhans cell his-
tiocytosis show a diffuse inﬁltration of large, pale-stain-
ing mononuclear cells that resemble histiocytes. These
cells have indistinct cytoplasmic borders and rounded
or indented vesicular nuclei. Varying numbers of
eosinophils are typically interspersed among the histio-
cyte-like cells (Fig. 13-22). Plasma cells, lymphocytes,
and multinucleated giant cells are often seen, and areas
of necrosis and hemorrhage may be present.
The identiﬁcation of lesional Langerhans cells is
necessary to conﬁrm the diagnosis. Because Langer-
hans cells cannot be differentiated from other histio-
cytes by routine histologic staining, additional diagnostic
methods are required. Electron microscopic evalua-
tion of lesional tissue has been the gold standard for
many years because, ultrastructurally, Langerhans cells
contain rod-shaped cytoplasmic structures known as
Birbeck granules, which differentiate them from
other mononuclear phagocytes (Fig. 13-23). Most labo-
ratories now rely on immunohistochemical procedures
to identify the lesional Langerhans cells because of
their immunoreactivity with antibodies directed against
Fig. 13-19 Langerhans cell histiocytosis. Severe bone loss
in the mandibular molar regions that resembles advanced
periodontitis. (Courtesy of Dr. James White.)
Fig. 13-20 Langerhans cell histiocytosis. Periapical
radiograph showing marked bone loss involving the
mandibular teeth in a young girl, resulting in a “ﬂoating-in-
air” appearance of the teeth.
Fig. 13-21 Langerhans cell histiocytosis. Clinical
photograph of the same patient shown in Fig. 13-20. The
lesion has broken out of bone and produced this soft tissue
mass. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

592 ORAL AND MAXILLOFACIAL PATHOLOGY
either CD-1a or CD-207, the latter marker being even
more speciﬁc for Langerhans cells. To a lesser extent,
the lesional cells have S-100 protein immunoreactivity,
and they also may show afﬁnity for peanut agglutinin
(PNA).
TREATMENT AND PROGNOSIS
Accessible bone lesions, such as those in the maxilla
and mandible, are usually treated by curettage. Low
doses of radiation may be used for less accessible bone
lesions, although the potential for induction of malig-
nancy secondary to this treatment is a concern in
younger patients. Intralesional injection with cortico-
steroid agents has also been reported to be effective in
some patients with localized bone lesions. Infrequently,
the apparent spontaneous regression of localized Lang-
erhans cell histiocytosis has been reported. The prog-
nosis for bone lesions in the absence of signiﬁcant
visceral involvement is generally good; however, pro-
gression or dissemination of the disease may occur,
particularly for patients who have three or more bones
affected.
Chronic disseminated disease is often associated
with considerable morbidity, but few patients die as a
result of the disease. Because of the relative rarity of
disseminated cases, the ideal treatment has yet to be
identiﬁed. Single-agent chemotherapy using predniso-
lone, etoposide, vincristine, or cyclosporine has pro-
duced a good response in a signiﬁcant percentage of
such patients, although recurrence is typically seen in
over half of the cases. A combination of vincristine and
prednisone seems to reduce this risk of recurrence.
The acute disseminated form of the disease seen in
infants and young children may not respond to these
more conservative approaches, and multiple chemo-
therapeutic agents are given in that situation. Diffuse
involvement with compromise of multiple organs is
associated with a poor prognosis and is often fatal. In
general, the prognosis is poorer for patients in whom
the ﬁrst sign of the disease develops at a very young age
and somewhat better for patients who are older at the
time of onset.
HODGKIN’S LYMPHOMA
(HODGKIN’S DISEASE)
Hodgkin’s lymphoma represents a malignant lym-
phoproliferative disorder, although for many years the
exact nature of the process was poorly understood. The
difﬁculty in comprehending the character of the condi-
tion is reﬂected in the relatively noncommittal term
Hodgkin’s disease, which was used for decades and still
may be heard today. Perhaps one reason why Hodg-
kin’s lymphoma was not easily understood is that,
unlike most malignancies, the neoplastic cells (Reed-
Sternberg cells) make up only about 1% to 3% of the
cells in the enlarged lymph nodes that characterize this
condition. Current evidence regarding the histogenesis
of the Reed-Sternberg cell points to a B-lymphocyte
origin. Certainly, the disease can cause death if appro-
priate therapy is not instituted, although the treatment
of this malignancy is one of the few major success
stories in cancer therapy during the past 20 years. In
the United States, Hodgkin’s lymphoma is about one
sixth as common as non-Hodgkin’s lymphoma; approx-
imately 8000 cases are diagnosed annually. Although
the cause of this disease is unknown, epidemiologic
and molecular studies have linked Epstein-Barr virus
(EBV) infection to a signiﬁcant percentage of these
lesions.
Fig. 13-22 Langerhans cell histiocytosis. There is a diffuse
inﬁltrate of pale-staining Langerhans cells intermixed with
numerous red granular eosinophils.
Fig. 13-23 Langerhans cell histiocytosis. Electron
micrograph showing rod-shaped Birbeck bodies (black arrows)
in the cytoplasm of a Langerhans cell. (Courtesy of Richard
Geissler.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 593
CLINICAL FEATURES
Hodgkin’s lymphoma almost always begins in the
lymph nodes, and any lymph node group is susceptible.
The most common sites of initial presentation are the
cervical and supraclavicular nodes (70% to 75%) or the
axillary and mediastinal nodes (5% to 10% each).
The disease initially appears less than 5% of the time in
the abdominal and inguinal lymph nodes.
Overall, a male predilection is observed, and a
bimodal pattern is noted with respect to the patient’s
age at diagnosis. One peak is observed between 15 and
35 years of age; another peak is seen after the age of
50.
The usual presenting sign is the identiﬁcation by the
patient of a persistently enlarging, nontender, discrete
mass or masses in one lymph node region (Fig. 13-24).
In the early stages, the involved lymph nodes are often
rather movable; as the condition progresses, the nodes
become more matted and ﬁxed to the surrounding
tissues. If it is untreated, then the condition spreads to
other lymph node groups and eventually involves the
spleen and other extralymphatic tissues, such as bone,
liver, and lung. Oral involvement has been reported,
but it is rare. In about 30% of patients with Hodgkin’s
disease, other systemic signs and symptoms may be
present, such as weight loss, fever, night sweats, and
generalized pruritus (itching). The absence of these
systemic signs and symptoms is considered to be better
in terms of the patient’s prognosis, and this information
is used in staging the disease. Patients who have no
systemic signs are assigned to category A and those
with systemic signs to category B.
The staging of Hodgkin’s lymphoma is important for
planning treatment and estimating the prognosis for a
given patient. The staging procedure typically includes
conﬁrmation of the pathologic diagnosis, careful history
and physical examination, abdominal and thoracic
computed tomography (CT) scans or magnetic reso-
nance imaging (MRI) studies, chest radiographs, and
routine hematologic studies (e.g., complete blood
count, serum chemistries, erythrocyte sedimentation
rate). Evaluation of the extent of disease involvement
using positron emission tomography (PET) scans is
becoming part of the standard protocol, particularly at
large institutions. Lymphangiography, gallium scan,
bone marrow biopsy, exploratory laparotomy, and
splenectomy may be necessary if the information that
they would provide might have an effect on staging
or treatment. A summary of the staging system for
Hodgkin’s lymphoma is presented in Table 13-2.
HISTOPATHOLOGIC FEATURES
Hodgkin’s lymphoma is recognized to comprise two
main forms, (1) nodular lymphocyte–predominant
Hodgkin’s lymphoma and (2) classical Hodgkin’s lym-
phoma, the latter of which is divided into ﬁve subtypes.
Although this group of diseases has certain features in
common, current immunohistochemical and molecu-
lar biologic techniques have allowed distinctions to be
made among the various types. The common features
include effacement of the normal nodal architecture
by a diffuse, often mixed, inﬁltrate of inﬂammatory
cells that is interspersed with large, atypical neoplastic
lymphoid cells. In the case of classical Hodgkin’s
lymphoma, this atypical cell is known as a Reed-
Sternberg cell (Fig. 13-25). The Reed-Sternberg cell
is typically binucleated (“owl-eye” nuclei), although it
may be multinucleated (“pennies on a plate”), with
prominent nucleoli. The malignant cell in nodular lym-
phocyte–predominant Hodgkin’s lymphoma is the
“popcorn cell,” which is so-named because of the
resemblance of the nucleus to a kernel of popped corn.
The pathologist must see one of these types of distinc-
tive atypical cells to make a diagnosis of Hodgkin’s
lymphoma, although their presence does not automati-
cally imply that diagnosis, because similar cells may be
seen in certain viral infections, especially infectious
mononucleosis. To summarize, Hodgkin’s lymphoma
is currently classiﬁed in the following manner:
Fig. 13-24 Hodgkin’s lymphoma. The prominent
supraclavicular and cervical masses represent Hodgkin’s
lymphoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

594 ORAL AND MAXILLOFACIAL PATHOLOGY
● Nodular lymphocyte–predominant Hodgkin’s lym-
phoma, or
●Classical Hodgkin’s lymphoma (comprising ﬁve his-
topathologic subtypes):
1. Lymphocyte rich
2. Nodular sclerosis
3. Mixed cellularity
4. Lymphocyte depletion
5. Unclassiﬁable
These names describe the most prominent histopatho-
logic feature of each type, and speciﬁc epidemiologic
and prognostic characteristics are associated with each
type.
Nodular lymphocyte–predominant Hodgkin’s
lymphoma constitutes 4% to 5% of all cases of Hodg-
kin’s lymphoma in the United States. In the past, this
form was probably combined with the lymphocyte-rich
subtype, but the presence of the characteristic popcorn
cells is a signiﬁcant clue to the diagnosis.
Lymphocyte-rich classical Hodgkin’s lymphoma
represents about 6% of all cases. Sheets of small lym-
phocytes with few Reed-Sternberg cells characterize
this form.
The nodular sclerosis subtype makes up 60% to
80% of cases and occurs more frequently in females
during the second decade of life. This type gets its
name from the broad ﬁbrotic bands that extend
from the lymph node capsule into the lesional tissue.
Reed-Sternberg cells in the nodular sclerosis form
appear to reside in clear spaces and, therefore, are
referred to as lacunar cells.
The mixed cellularity form accounts for about 15%
to 30% of the cases and is characterized by a mixture
of small lymphocytes, plasma cells, eosinophils, and
histiocytes with abundant Reed-Sternberg cells.
The lymphocyte depletion subtype, the most
aggressive type, makes up less than 1% of the cases in
recent reports. Before modern immunohistochemical
techniques, many examples of large cell lymphoma or
anaplastic T-cell lymphoma were undoubtedly included
in this category. In this form of Hodgkin’s lymphoma,
numerous bizarre giant Reed-Sternberg cells are
present, with few lymphocytes.
Occasionally, examples of Hodgkin’s lymphoma are
encountered that really do not ﬁt the criteria for any of
the known subtypes, and these are designated as
unclassiﬁable.
TREATMENT AND PROGNOSIS
The treatment of Hodgkin’s lymphoma depends on the
stage of involvement. Patients who had limited disease
(stages I and II) often were managed by local radiation
therapy alone. Recent treatment trends, however,
combine less extensive radiotherapy ﬁelds with milder
multiagent chemotherapy regimens to maximize
disease control and minimize long-term complications
Table 13-2 Ann Arbor System for Classiﬁcation of Hodgkin’s Lymphoma
Stage Deﬁning Features
I Involvement of a single lymph node region (I) or a single extralymphatic organ or site (I
E)
II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or one or more lymph
node regions with an extralymphatic site (II
E)
III Involvement of lymph node regions on both sides of the diaphragm (III), possibly with an extralymphatic organ
or site (III
E), the spleen (III
S), or both (III
SE)
IV Diffuse or disseminated involvement of one or more extralymphatic organs (identiﬁed by symbols), with or
without associated lymph node involvement
A: Absence of systemic signs
B: Presence of fever, night sweats, and/or unexplained loss of 10% or more of body weight during the 6-
month period before diagnosis
Adapted from DeVita VT, Hubbard SM: Hodgkin’s disease, N Engl J Med 328:560-565, 1993.
Fig. 13-25 Hodgkin’s lymphoma. This high-power
photomicrograph shows the characteristic Reed-Sternberg
cell (arrow) of Hodgkin’s lymphoma, identiﬁed by its “owl-
eye” nucleus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 595
of therapy. Patients with stage III or IV disease require
chemotherapy; radiation therapy is used conjointly if
signiﬁcant mediastinal involvement or residual disease
is detected. For many years a regimen known as MOPP
(mechlorethamine, Oncovin, procarbazine, predni-
sone) was widely used to treat Hodgkin’s lymphoma.
Because signiﬁcant long-term side effects can be asso-
ciated with this chemotherapy, another regimen known
as ABVD (Adriamycin, bleomycin, vinblastine, dacar-
bazine [DTIC]) is now used most often, particularly for
early and intermediate stage disease, because it has
fewer complications.
Before modern cancer therapy was developed for
Hodgkin’s lymphoma, the 5-year survival rate was only
5%. The prognosis for this disease is fairly good today;
the best treatment results occur in those who present
in the early stages. Patients with stage I and II disease
often have an 80% to 90% relapse-free 10-year survival
rate; those with stage III and IV disease have a 55% to
75% 10-year survival rate.
The histopathologic subtype also inﬂuences the
response to therapy. Patients with the lymphocyte-pre-
dominant and nodular sclerosis forms have the best
prognosis, whereas those with the mixed cellularity
form have a less favorable prognosis. In the past,
researchers believed that the lymphocyte depletion
form had a poor prognosis. However, with newer
immunohistochemical studies, clinicians now realize
that many of these cases were misdiagnosed; therefore,
the available data are probably not reliable. In most
instances, however, the stage of disease now plays a
more important role in determining the patient’s prog-
nosis than does the histopathologic subtype.
After 15 years posttreatment, patient mortality is
due more often to the complications of therapy: either
secondary malignancy or cardiovascular disease. Cur-
rently, research is focused on the development of treat-
ment regimens that continue to have a superior cure
rate, while simultaneously decreasing the risk of treat-
ment-related complications.
NON-HODGKIN’S LYMPHOMA
The non-Hodgkin’s lymphomas include a diverse
and complex group of malignancies of lymphoreticular
histogenesis and differentiation. In most instances,
they initially arise within lymph nodes and tend to
grow as solid masses. This is in contrast to lymphocytic
leukemias (see page 587), which begin in the bone
marrow and are characterized by a large proportion of
malignant cells that circulate in the peripheral blood.
The non-Hodgkin’s lymphomas most commonly origi-
nate from cells of the B-lymphocyte series, with an
estimated 85% of European and American lymphoid
neoplasms having this derivation. Tumors with a T-
lymphocyte derivation are less common, whereas true
histiocyte-derived lymphomas are even rarer.
The microscopic appearance of the lesional cells
was used in the past to classify the tumors as either
lymphocytic or histiocytic. With the development of
modern immunologic techniques, however, it is now
known that many of the lesions that had been classiﬁed
as histiocytic were in fact neoplasms composed of trans-
formed B lymphocytes. In the early 1980s, a group of
American pathologists devised a classiﬁcation scheme,
known as the Working Formulation for Clinical Use, which
may still be referred to in the United States. Based on
this classiﬁcation, lymphomas were broadly grouped
into three categories:
1. Low grade
2. Intermediate grade
3. High grade
Unfortunately, the Working Formulation has been
shown to be somewhat limited in its utility and accu-
racy. Many lesions that have been recently deﬁned are
not included in this classiﬁcation. For these reasons, an
international study group in the early 1990s devised a
new method of categorizing the lymphomas, known as
the REAL (revised European-American lymphoma) classiﬁ-
cation. With this system, a combination of histopatho-
logic features, immunologic cell surface markers, and
gene rearrangement studies are used to organize this
group of neoplasms. Recently the World Health Orga-
nization (WHO) revised its lymphoma classiﬁcation
system to conform to a slightly modiﬁed version of the
REAL classiﬁcation (Box 13-2). The latter two classiﬁ-
cations appear to be more precise than the Working
Formulation, and currently most pathologists in the
United States categorize lymphomas according to the
modiﬁed REAL system, although some of the more
sophisticated molecular studies may not be available at
smaller laboratories.
More than 58,000 cases of non-Hodgkin’s lym-
phoma are diagnosed in the United States annually;
approximately one third of this number will die of the
disease each year. For reasons that are currently
unclear, the incidence of this malignancy seems to be
rising in the United States. The prevalence of lym-
phoma is increased in patients who have immunologic
problems, such as congenital immunodeﬁciencies (e.g.,
Bloom syndrome, Wiskott-Aldrich syndrome, common
variable immunodeﬁciency), AIDS, organ transplanta-
tion, and autoimmune disease (e.g., Sjögren syndrome,
systemic lupus erythematosus, rheumatoid arthritis).
Viruses may play a role in the pathogenesis of at least
some of these lesions. For example, Epstein-Barr virus
(EBV) has been implicated, but not proven, to be an
etiopathogenic agent in Burkitt’s lymphoma (see page
600), a type of high-grade, small, noncleaved B-cell
lymphoma. In addition, EBV may be related to lympho- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

596 ORAL AND MAXILLOFACIAL PATHOLOGY
mas developing in the setting of immunosuppression
after solid organ or bone marrow transplant (resulting
in the condition known as posttransplant lympho-
proliferative disorder) or in association with AIDS
(see page 272). Human herpesvirus 8 (HHV-8) has not
only been associated with Kaposi’s sarcoma but also
with primary body cavity lymphoma and some cases of
plasmablastic lymphoma. A blood-borne human retro-
virus called human T-cell leukemia/lymphoma virus type I
(HTLV-1) has been shown to cause an aggressive form
of peripheral T-cell lymphoma among certain popula-
tions in the Caribbean, central Africa, and southwest
Japan.
Even bacteria have been shown to induce the forma-
tion of so-called mucosa-associated lymphoid tissue
(MALT) lymphoma of the stomach. Antibiotic treat-
ment of Helicobacter pylori infection of the stomach
lining often results in complete regression of this low-
grade lymphoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Non-Hodgkin’s lymphoma occurs primarily in adults,
although children may be affected, particularly by the
more aggressive intermediate- and high-grade lympho-
mas. The condition most commonly develops in the
lymph nodes, but so-called extranodal lymphomas are
also found. In the United States, approximately 20% to
40% of lymphomas develop in an extranodal site, but
in Asian countries such as Korea and Japan, nearly half
of all lymphomas are extranodal.
With a nodal presentation, the patient usually is
aware of a nontender mass that has been slowly enlarg-
ing for months. The lesion typically involves a local
lymph node collection, such as the cervical, axillary,
or inguinal nodes; one or two freely movable nodules
are noticed initially. As the malignancy progresses,
the nodes become more numerous and are ﬁxed to
adjacent structures or matted together (Fig. 13-26).
Gradually, the process involves other lymph node
groups, and invasion of adjoining normal tissues
occurs.
In the oral cavity, lymphoma usually appears as
extranodal disease. Although the oral lesions of lym-
phoma are often a component of more widely dissemi-
nated disease, at times the lymphoma begins in the oral
tissues and has not spread to other sites. The malig-
nancy may develop in the oral soft tissues or centrally
within the jaws. Soft tissue lesions appear as nontender,
diffuse swellings; they most commonly affect the buccal
vestibule, posterior hard palate, or gingiva (Figs. 13-27
Box 13-2
Classiﬁcation of Hematopoietic and Lymphoid Neoplasms, Modiﬁed from the REAL/WHO
Classiﬁcation
B-CELL NEOPLASMS
I.Precursor B-cell neoplasm: precursor B-acute
lymphoblastic leukemia/lymphoblastic lymphoma (LBL)
II.Peripheral (mature) B-cell neoplasms
A. B-cell chronic lymphocytic leukemia/small
lymphocytic lymphoma
B.B-cell prolymphocytic leukemia
C.Lymphoplasmacytic lymphoma/immunocytoma
D.Mantle cell lymphoma
E.Follicular lymphoma
F. Extranodal marginal zone B-cell lymphoma of
mucosa-associated lymphatic tissue (MALT) type
G. Nodal marginal zone B-cell lymphoma (±
monocytoid B-cells)
H. Splenic marginal zone lymphoma (± villous
lymphocytes)
I.Hairy cell leukemia
J.Plasmacytoma/plasma cell myeloma
K.Diffuse large B-cell lymphoma
L.Burkitt lymphoma
T-CELL AND PUTATIVE NK-CELL NEOPLASMS
I.Precursor T-cell neoplasm: precursor T-acute
lymphoblastic leukemia/LBL
II.Peripheral (mature) T-cell and NK-cell neoplasms
A. T-cell chronic lymphocytic leukemia/prolymphocytic
leukemia
B.T-cell granular lymphocytic leukemia
C.Mycosis fungoides/Sézary syndrome
D. Peripheral T-cell lymphoma, not otherwise
characterized
E.Hepatosplenic gamma/delta T-cell lymphoma
F.Subcutaneous panniculitis-like T-cell lymphoma
G.Angioimmunoblastic T-cell lymphoma
H.Extranodal T-/NK-cell lymphoma, nasal type
I.Enteropathy-type intestinal T-cell lymphoma
J. Adult T-cell lymphoma/leukemia (human
T-lymphotrophic virus [HTLV] 1+)
K. Anaplastic large cell lymphoma, primary systemic
type
L. Anaplastic large cell lymphoma, primary cutaneous
type
M.Aggressive NK-cell leukemia
REAL, Revised European-American Lymphoma; WHO, World Health Organization; NK, natural killer. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 597
and 13-28). Such swellings characteristically have a
boggy consistency. The lesion may appear erythema-
tous or purplish, and it may or may not be ulcerated.
Patients who wear a denture that contacts the lesional
site often complain that their denture does not ﬁt
because it feels too tight.
Lymphoma of bone may cause vague pain or dis-
comfort, which might be mistaken for a toothache. The
patient may complain of paresthesia, particularly with
a mandibular lesion (so-called numb chin syndrome).
Radiographs usually show an ill-deﬁned or ragged
radiolucency, although in the early stages, the radio-
graphic changes may be subtle or nonexistent. If
untreated, then the process typically causes expansion
of the bone, eventually perforating the cortical plate
and producing a soft tissue swelling. Such lesions have
been mistaken for a dental abscess, although a signiﬁ-
cant amount of pain is not present in most cases.
Clinical staging to determine the extent to which the
disease has spread is an important factor in assessing
the prognosis for a particular patient. The staging eval-
uation should include a history, physical examination,
complete blood count, liver function studies, routine
chest radiographs, CT scans of the pelvic and abdomi-
nal regions, lymphangiography, and bone marrow
biopsy. The staging system for Hodgkin’s lymphoma
(see Table 13-2) has been widely adopted for use with
the non-Hodgkin’s lymphomas.
HISTOPATHOLOGIC FEATURES
Non-Hodgkin’s lymphomas are histopathologically
characterized by a proliferation of lymphocytic-appear-
ing cells that may show varying degrees of differentia-
tion, depending on the type of lymphoma. Low-grade
lesions consist of well-differentiated small lympho-
cytes. High-grade lesions tend to be composed of less
differentiated cells. All lymphomas grow as inﬁltrative,
broad sheets of relatively uniform neoplastic cells that
usually show little or no evidence of lesional tissue
necrosis (Figs. 13-29 and 13-30). In some lesions, par-
ticularly those of B-lymphocyte origin, a vague sem-
blance of germinal center formation may be seen (i.e.,
a nodular or follicular pattern). Other lymphomas show
Fig. 13-26 Non-Hodgkin’s lymphoma. The matted,
nontender lymph node enlargement in the lateral cervical
region represents a common presentation of lymphoma.
Fig. 13-27 Non-Hodgkin’s lymphoma. One of the
frequent locations of extranodal lymphoma in the head and
neck area is the palate, where the tumor appears as a
nontender, boggy swelling. Note the overlying telangiectatic
blood vessels, a feature often seen with malignancy.
Fig. 13-28 Non-Hodgkin’s lymphoma. Ulcerated mass of
the left posterior maxilla. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

598 ORAL AND MAXILLOFACIAL PATHOLOGY
no evidence of such differentiation, and this pattern is
termed diffuse. If the lymphoma arises in a lymph node,
then the tumor destroys the normal architecture of the
node. An extranodal lymphoma destroys the normal
adjacent host tissue by inﬁltrating throughout the area.
In the oral cavity, diffuse large B-cell lymphoma, which
is considered to be a high-grade lymphoma, is the most
common diagnosis, comprising approximately 60% of
the cases.
Standard of care demands that appropriate immu-
nohistochemical and cytogenetic studies be performed
for a tumor diagnosed as lymphoma. In general, these
studies can become quite involved and, therefore, are
beyond the scope of this text.
TREATMENT AND PROGNOSIS
The treatment of a patient with non-Hodgkin’s lym-
phoma is based on several factors, including the stage
and grade of the lymphoma, the overall health of the
patient, and the patient’s pertinent past medical history.
The patient’s health must be considered because many
of the chemotherapeutic regimens are quite debilitat-
ing. Surgical management is not usually indicated.
Low-grade lymphomas are perhaps the most con-
troversial in terms of treatment. Some authorities rec-
ommend no particular treatment because these tumors
are slow growing and tend to recur despite chemo-
therapy. Given the fact that low-grade lymphomas
arise in older adults and the median survival without
treatment is 8 to 10 years, many clinicians opt for a
“watch and wait” strategy, treating the patient only if
symptoms develop. Unfortunately, approximately 40%
of low-grade lymphomas eventually transform to a
high-grade lymphoma, leading to the patient’s demise.
Because these low-grade lymphomas have been con-
sidered “incurable,” new treatments are being investi-
gated. Most of these lesions are of B-cell differentiation,
so treatment strategies using monoclonal antibodies
directed against CD20, a B-cell surface antigen, are
now being evaluated. Rituximab is one of the agents
being examined in clinical trials.
For the intermediate-grade and high-grade lym-
phomas, the treatment of localized disease consists of
radiation plus chemotherapy. With more advanced
and disseminated disease, chemotherapy alone usually
is implemented. Multiagent chemotherapy is used rou-
tinely, and new combinations are being evaluated con-
tinuously. Unfortunately, although the response rate of
many lesions is good and much progress has been
made in this area, the cure rate is not high. For inter-
mediate-grade lesions, a failure rate of 30% to 50% can
be expected. High-grade lymphomas are associated
with a 60% mortality rate at 5 years after diagnosis and
treatment.
MYCOSIS FUNGOIDES (CUTANEOUS
T-CELL LYMPHOMA)
From its name, one might think that mycosis fungoi-
des is a fungal infection. The early dermatologists who
ﬁrst recognized mycosis fungoides knew that this was
not the case; however, they still thought the disease
resembled a fungal condition. Thus this term has per-
sisted. This condition, in fact, represents a lymphoma
that is derived from T lymphocytes, speciﬁcally the
T-helper (CD4+) lymphocyte. With modern diagnostic
techniques, clinicians now know that there are several
types of cutaneous lymphomas, each having speciﬁc T-
lymphocyte or B-lymphocyte differentiation patterns.
Even though mycosis fungoides is the most common of
these cutaneous lymphomas, it is still a relatively rare
Fig. 13-29 Non-Hodgkin’s lymphoma. This low-power
photomicrograph shows a diffuse inﬁltration of the
subepithelial connective tissue by lymphoma.
Fig. 13-30 Non-Hodgkin’s lymphoma. This high-power
photomicrograph shows lesional cells of lymphoma,
consisting of a population of poorly differentiated cells of the
lymphocytic series with minimal cytoplasm. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 599
malignancy; only about 400 new cases are diagnosed in
the United States annually. This condition exhibits a
peculiar property called epidermotropism (i.e., a pro-
pensity to invade the epidermis of the skin). Oral involve-
ment, although infrequent, may also be present.
CLINICAL FEATURES
Mycosis fungoides is a condition that usually affects
middle-aged adult men; there is a 2:1 male-to-female
ratio and a mean age at diagnosis of 55 to 60 years. The
disease progresses through three stages, usually over
the course of several years.
The ﬁrst stage, known as the eczematous (ery-
thematous) stage, is often mistaken for psoriasis of the
skin because of the well-demarcated, scaly, erythema-
tous patches that characterize these lesions. Patients
may complain of pruritus. With time, the erythematous
patches evolve into slightly elevated, red lesions
(plaque stage). These plaques tend to grow and
become distinct papules and nodules. At this time, the
disease has entered the tumor stage (Fig. 13-31). Vis-
ceral involvement is also seen at this point.
Approximately 35 cases of mycosis fungoides with
oral involvement have been reported. The most com-
monly affected sites are the tongue, hard and soft
palates, and gingiva (Fig. 13-32). The buccal mucosa,
tonsils, lips, sinuses, and nasopharynx may also be
affected. The oral lesions present as erythematous,
indurated plaques or nodules that are typically ulcer-
ated. Generally, these lesions appear late in the course
of the disease and develop after the cutaneous lesions.
Sézary syndrome is an aggressive expression of
mycosis fungoides that essentially represents a derma-
topathic T-cell leukemia. The patient has a generalized
exfoliative erythroderma, as well as lymphadenopathy,
hepatomegaly, and splenomegaly. The lung, kidneys,
and CNS can also be involved. This condition follows
a fulminant course and typically results in the patient’s
death within a short period of time; the median sur-
vival for this form of the disease is 2 to 3 years.
HISTOPATHOLOGIC FEATURES
ECZEMATOUS STAGE
The early stages of mycosis fungoides may be difﬁcult
to diagnose histopathologically because of the subtle
changes that characterize the initial lesions. A psoria-
siform pattern of epithelial alteration is seen, with
parakeratin production and elongation of the epithelial
rete ridges. Scattered, slightly atypical lymphocytic
cells may be seen in the connective tissue papillae, but
such features are often mistaken for an inﬂammatory
process.
PLAQUE STAGE
With the development of the plaque stage, a more
readily identiﬁable microscopic pattern emerges.
Examination of the surface epithelium reveals inﬁltra-
tion by atypical lymphocytic cells, which are some-
times referred to as mycosis cells or Sézary cells. These
atypical lymphocytes classically form small intraepi-
thelial aggregates termed Pautrier’s microabscesses (Fig.
13-33). The lesional cells have an extremely unusual
nucleus because of the marked infolding of the nuclear
membrane, which results in what is termed a cerebri-
form nucleus. This feature can best be appreciated when
viewed in special semithin, plastic-embedded micro-
scopic sections (Fig. 13-34). The diagnosis of mycosis
Fig. 13-31 Mycosis fungoides. In the tumor stage of the
disease, patients with mycosis fungoides have ulcerated
nodules of the skin. (From Damm DD, White DK, Cibull ML et al:
Mycosis fungoides: initial diagnosis via palatal biopsy with discussion of
diagnostic advantages of plastic embedding, Oral Surg Oral Med Oral
Pathol 58:413-419, 1984.)
Fig. 13-32 Mycosis fungoides. The ulcerated palatal
lesions represent a rare example of oral mucosal involvement
by mycosis fungoides. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

600 ORAL AND MAXILLOFACIAL PATHOLOGY
fungoides can be conﬁrmed by demonstrating positiv-
ity for CD4 (a cell surface marker for T-helper cells) in
the lesional cell population. In addition, T-cell receptor
gene rearrangement analysis should identify a mono-
clonal population of T lymphocytes. A mixed inﬁltrate
of eosinophils, histiocytes, and plasma cells may be
observed in the subepithelial connective tissue.
TUMOR STAGE
As the condition progresses to the tumor stage, the
diffuse inﬁltration of the dermis and epidermis by
atypical lymphocytic cells makes it easier to identify as
a malignant process. Other types of lymphoma would
enter into the histopathologic differential diagnosis.
Immunohistochemical studies demonstrating a
T-helper phenotype, combined with the T-cell receptor
gene rearrangement studies, would help to distinguish
the malignant inﬁltrate from other lymphomas and
establish the diagnosis of mycosis fungoides. Examina-
tion of the peripheral blood of a patient with Sézary
syndrome shows circulating atypical lymphoid cells.
TREATMENT AND PROGNOSIS
Topical nitrogen mustard, topical carmustine, superpo-
tent topical corticosteroids, electron beam therapy, or
photochemotherapy (PUVA [8-methoxy-psoralen +
ultraviolet A]) are effective in controlling mycosis
fungoides during the early stages. Ultimately, the
topical forms of therapy fail, and aggressive chemo-
therapy is necessary, particularly if there is visceral
involvement. Newer agents that may be added to the
chemotherapy regimen include monoclonal antibod-
ies directed against the cell surface marker CD52,
certain retinoid compounds, and speciﬁc interferon
compounds. Another new agent that may be used for
advanced disease is known as denileukin diftitox, which
is derived from diphtheria toxin and targets the inter-
leukin-2 receptor on the neoplastic lymphocytes. If
Sézary syndrome develops, then extracorporeal photo-
pheresis or chemotherapy is used as a treatment modal-
ity. Extracorporeal photopheresis involves the ingestion
of the photoactive drug 8-methoxypsoralen, followed
by the removal of a portion of the patient’s blood and
a separation of red and white blood cells. The red blood
cells are returned to the patient immediately. The
white blood cells are irradiated outside the body (extra-
corporeal) with ultraviolet A. These altered white cells
are then infused back into the patient. Their altered
state may help generate an immunologic response to
the patient’s own abnormal lymphocytes.
Although mycosis fungoides is not considered to be
curable, the disease is usually slowly progressive. As a
result, there is a median survival time of 8 to 10 years,
and patients may die of causes unrelated to their lym-
phoma. Once the disease progresses beyond the cuta-
neous involvement, the course becomes much worse.
The patient usually dies of organ failure or sepsis within
1 year.
BURKITT’S LYMPHOMA
Burkitt’s lymphoma is a malignancy of B-lymphocyte
origin that represents an undifferentiated lymphoma.
It was named after the missionary doctor, Denis Burkitt,
who ﬁrst documented the process. In the original
report, this type of lymphoma was described in young
African children, and it seemed to have a predilection
for the jaws. Because it was seen frequently in sub-
Saharan Africa, the term African Burkitt’s lymphoma
has been applied to the disease. In addition, there is
increased prevalence in other areas of the world, such
Fig. 13-33 Mycosis fungoides. This medium-power
photomicrograph of a cutaneous lesion of mycosis fungoides
shows inﬁltration of the epithelium by the malignant
inﬁltrate that forms Pautrier’s microabscesses.
Fig. 13-34 Mycosis fungoides. This high-power
photomicrograph of an oral biopsy specimen reveals the
atypical, malignant lymphoid cells of mycosis fungoides that
exhibit a cerebriform morphology (inset). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 601
as northeastern Brazil, and some investigators now
refer to such tumors arising in these areas of increased
prevalence as endemic Burkitt’s lymphoma. Re-
searchers believe this malignancy is related pathoge-
netically to Epstein-Barr virus (EBV), because more
than 90% of the tumor cells, particularly in the African
type, show expression of EBV nuclear antigen, and
affected patients have elevated antibody titers to EBV.
Characteristic cytogenetic chromosomal transloca-
tions, which may also be responsible for neoplastic
transformation, have also been described. Tumors with
a similar histomorphology, commonly referred to as
sporadic or American Burkitt’s lymphoma, have
been observed in other countries where the neoplasm
is usually ﬁrst detected as an abdominal mass. Some
HIV-related lymphomas may also have the microscopic
features of Burkitt’s lymphoma, and these lesions
have been designated immunodeﬁciency-associated
Burkitt’s lymphoma. Similar tumors have been
reported in other immunodeﬁciency settings, such as
in patients who have received allografts or have a con-
genital immunodeﬁciency syndrome.
CLINICAL AND RADIOGRAPHIC
FEATURES
As many as 50% to 70% of the cases of endemic Burkitt’s
lymphoma present in the jaws. The malignancy usually
affects children (peak prevalence, about 7 years of age)
who live in Central Africa, and a male predilection is
usually reported. The posterior segments of the jaws
are more commonly affected, and the maxilla is
involved more commonly than the mandible (a 2:1
ratio). Sometimes all four quadrants of the jaws show
tumor involvement.
The tendency for jaw involvement seems to be age
related; nearly 90% of 3-year-old patients have jaw
lesions, in contrast to only 25% of patients older than
age 15. Sporadic Burkitt’s lymphoma tends to affect
patients over a greater age range than is noted for the
African tumor. Although the abdominal region is typi-
cally affected, jaw lesions have been reported in spo-
radic Burkitt’s lymphoma (Fig. 13-35).
The growth of the tumor mass may produce facial
swelling and proptosis. Pain, tenderness, and paresthe-
sia are usually minimal, although marked tooth mobil-
ity may be present because of the aggressive destruction
of the alveolar bone. Premature exfoliation of decidu-
ous teeth and enlargement of the gingiva or alveolar
process may also be seen.
The radiographic features are consistent with a
malignant process and include a radiolucent destruc-
tion of the bone with ragged, ill-deﬁned margins (Fig.
13-36). This process may begin as several smaller sites,
which eventually enlarge and coalesce. Patchy loss of
the lamina dura has been mentioned as an early sign
of Burkitt’s lymphoma.
HISTOPATHOLOGIC FEATURES
Burkitt’s lymphoma histopathologically represents an
undifferentiated, small, noncleaved B-cell lymphoma.
The lesion invades as broad sheets of tumor cells that
exhibit round nuclei with minimal cytoplasm. Each
tumor nucleus often has several prominent nucleoli,
and numerous mitoses are seen. Immunohistochemi-
cal studies using markers that identify proliferating
cells (e.g., Ki-67) typically indicate that almost 100% of
the tumor cells are in the process of replicating. On
viewing the lesion on low-power magniﬁcation, a
classic “starry-sky” pattern is often appreciated—a
phenomenon that is caused by the presence of
Fig. 13-35 Burkitt’s lymphoma. This patient had
documented American Burkitt’s lymphoma involving the
abdominal region. The retromolar swelling represents oral
involvement with the malignancy.
Fig. 13-36 Burkitt’s lymphoma. This 4-year-old child had
evidence of bone destruction with tooth mobility in all four
quadrants of his jaws. Note the patchy, ill-deﬁned loss of
bone. (Courtesy of Dr. Gregory Anderson.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

602 ORAL AND MAXILLOFACIAL PATHOLOGY
macrophages within the tumor tissue (Fig. 13-37).
These macrophages have abundant cytoplasm, which
microscopically appears less intensely stained in com-
parison with the surrounding process. Thus these cells
tend to stand out as “stars” set against the “night sky”
of deeply hyperchromatic neoplastic lymphoid cells
(Fig. 13-38).
Because the histopathologic features of Burkitt’s
lymphoma can appear similar to some cases of diffuse
large B-cell lymphoma, standard of care now dictates
that, in addition to immunohistochemical studies,
molecular genetic analysis of the tumor tissue should
be performed. This distinction is important because
these two malignancies are treated differently. Burkitt’s
lymphoma is characterized by one of several speciﬁc
translocations, the most common being t(8;14), that
results in overexpression of the oncogene c-myc, an
event that presumably drives the neoplastic
proliferation.
TREATMENT AND PROGNOSIS
Burkitt’s lymphoma is an aggressive malignancy that
usually results in the death of the patient within 4 to 6
months after diagnosis if it is not treated. Treatment
generally consists of an intensive chemotherapeutic
regimen, which emphasizes the use of high doses of
cyclophosphamide. More than 90% of the patients
respond to this treatment.
The prognosis for Burkitt’s lymphoma in the past
was poor, with a median survival time of only 10
1
/
2
months. More recent trials with more intensive, multi-
agent chemotherapeutic protocols have shown an 85%
to 95% event-free (no evidence of recurrence) survival
rate 3 to 5 years after treatment for patients with stage
I or II disease. Even for advanced stage (III and IV)
Burkitt’s lymphoma, the event-free survival has
improved to 75% to 85%.
EXTRANODAL NK/T-CELL
LYMPHOMA, NASAL-TYPE
(ANGIOCENTRIC T-CELL LYMPHOMA;
MIDLINE LETHAL GRANULOMA;
IDIOPATHIC MIDLINE DESTRUCTIVE
DISEASE; POLYMORPHIC
RETICULOSIS; MIDLINE MALIGNANT
RETICULOSIS; ANGIOCENTRIC
IMMUNOPROLIFERATIVE LESION)
Also known as angiocentric T-cell lymphoma, extra-
nodal NK/T-cell lymphoma, nasal-type is a rare
process that is characterized clinically by aggressive,
nonrelenting destruction of the midline structures of
the palate and nasal fossa. For many decades, the
nature of this process has been controversial, a fact that
can readily be appreciated by the wide variety of terms
by which it has been called. In actuality, many of the
cases reported as “midline lethal granuloma” in the
past represented a wide variety of immunologic (e.g.,
Wegener’s granulomatosis) and infectious (e.g., tertiary
syphilis) diseases. The term midline lethal granu-
loma should be used only as a descriptive designation
of a destructive midline condition, and thorough diag-
nostic evaluation, including biopsy and culture, is nec-
essary to make a deﬁnitive diagnosis. Once the other
causes of midline destruction have been eliminated,
the consensus among most investigators is that this
disorder should be classiﬁed as a natural killer (NK)
T-cell lymphoma, based on modern cytogenetic, immu-
nologic, and molecular studies. The difﬁculty in distin-
guishing among these destructive disorders can be
appreciated by the fact that lymphomatoid granulo-
Fig. 13-37 Burkitt’s lymphoma. This low-power
photomicrograph shows the classic “starry-sky” appearance, a
pattern caused by interspersed histiocytic cells with
abundant cytoplasm (“stars”) set against a background of
malignant, darkly staining lymphoma cells (“night sky”).
Fig. 13-38 Burkitt’s lymphoma. This high-power
photomicrograph demonstrates the undifferentiated, small,
dark lesional cells with numerous histiocytes. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 603
matosis, which until recently was considered part
of this T-cell lymphoma spectrum, has now been
determined to be an Epstein-Barr virus (EBV)-driven
proliferation of B lymphocytes.
Even though extranodal NK/T-cell lymphoma often
does not have the classic histopathologic features of
lymphoma microscopically, it behaves in a malignant
fashion and responds to the same treatments to which
lymphomas respond. For reasons that are unclear, this
condition is seen with greater frequency in Asian, Gua-
temalan, and Peruvian populations.
CLINICAL FEATURES
Extranodal NK/T-cell lymphoma is typically observed
in adults. The initial signs and symptoms are often
localized to the nasal region and include nasal stufﬁ-
ness or epistaxis. Pain may accompany the nasal symp-
toms. Swelling of the soft palate or posterior hard palate
may precede the formation of a deep, necrotic ulcer-
ation, which usually occupies a midline position. This
ulceration enlarges and destroys the palatal tissues,
which typically creates an oronasal ﬁstula (Fig. 13-39).
Secondary infection may complicate the course of the
disease, and life-threatening hemorrhage is a potential
problem in some instances.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of one of these lesions
shows a mixed inﬁltrate of a variety of inﬂammatory
cells, often arranged around blood vessels (angiocen-
tric) (Fig. 13-40). The lesional process appears to invade
and destroy the normal tissue in the area. Necrosis is
often present in some areas of the lesion, presumably
secondary to inﬁltration of the blood vessels by the
tumor cells. Large, angular, lymphocytic cells with an
atypical appearance are usually identiﬁed as a compo-
nent of the cellular inﬁltrate. Immunohistochemical
evaluation of this inﬁltrate often shows that the large
atypical cells mark with antibodies directed against
T-lymphocyte antigens. Molecular genetic studies typi-
cally show monoclonal gene rearrangements of the
T-lymphocyte receptor, consistent with a lymphoretic-
ular malignancy.
TREATMENT AND PROGNOSIS
Without treatment, extranodal NK/T-cell lymphoma
is a relentlessly progressive, highly destructive process
that ultimately leads to the patient’s death by secondary
A B
Fig. 13-39 Extranodal NK/T-cell lymphoma, nasal-type. A, This 62-year-old man had a
destructive palatal lesion that proved to be a T-cell lymphoma, and evaluation showed cervical
lymph node involvement as well. B, Resolution of the lesion 1 month later, after multiagent
chemotherapy.
Fig. 13-40 Extranodal NK/T-cell lymphoma, nasal-type.
This medium-power photomicrograph shows atypical
lymphoid cells inﬁltrating the wall and ﬁlling the lumen of a
blood vessel. Such a pattern is termed angiocentric (i.e.,
around blood vessels). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

604 ORAL AND MAXILLOFACIAL PATHOLOGY
infection, massive hemorrhage, or inﬁltration of vital
structures in the area. Lesions that are localized usually
respond to radiation therapy, a feature that is similar
to that of T-cell lymphomas of other sites. Approxi-
mately 4500 cGy is required to control the disease,
and many of these patients show no evidence of recur-
rence or dissemination of the lesion. Five-year sur-
vival rates in some series have been reported to be as
high as 85%. For patients with more disseminated
disease, combination chemotherapy is indicated, and a
less favorable prognosis can be expected, with 30% to
50% 5-year survival generally reported.
MULTIPLE MYELOMA
Multiple myeloma is a relatively uncommon malig-
nancy of plasma cell origin that often appears to have
a multicentric origin within bone. The cause of the
condition is unknown, although sometimes a plasma-
cytoma (see page 606) may evolve into multiple
myeloma. This disease makes up about 1% of all malig-
nancies and 10% to 15% of hematologic malignancies.
If metastatic disease is excluded, then multiple
myeloma accounts for nearly 50% of all malignancies
that involve the bone. Nearly 20,000 cases are diag-
nosed annually in the United States.
The abnormal plasma cells that compose this tumor
are typically monoclonal. The abnormal cells probably
arise from a single malignant precursor that has under-
gone uncontrolled mitotic division and has spread
throughout the body. Because the neoplasm develops
from a single cell, all the daughter cells that comprise
the lesional tissue have the same genetic makeup and
produce the same proteins. These proteins are the
immunoglobulin components that the plasma cell
would normally produce, although in the case of this
malignant tumor the immunoglobulins are not normal
or functional. The signs and symptoms of this disease
result from the uncontrolled proliferation of the tumor
cells and the uncontrolled manufacture of their protein
products.
CLINICAL AND RADIOGRAPHIC
FEATURES
Multiple myeloma is typically a disease of adults, with
men being affected slightly more often than women.
The median age at diagnosis is between 60 and 70
years, and it is rarely diagnosed before age 40. For
reasons that are not understood, the disease occurs
twice as frequently in blacks as whites, making this the
most common hematologic malignancy among black
persons in the United States.
Bone pain, particularly in the lumbar spine, is the
most characteristic presenting symptom. Some patients
experience pathologic fractures caused by tumor
destruction of bone. They may also complain of fatigue
as a consequence of myelophthisic anemia. Petechial
hemorrhages of the skin and oral mucosa may be seen
if platelet production has been affected. Fever may be
present as a result of neutropenia with increased sus-
ceptibility to infection. Metastatic calciﬁcations may
involve the soft tissues and are thought to be caused by
hypercalcemia secondary to tumor-related osteolysis.
Radiographically, multiple well-deﬁned, punched-
out radiolucencies or ragged radiolucent lesions may
be seen in multiple myeloma (Fig. 13-41). These may
be especially evident on a skull ﬁlm. Although any
bone may be affected, the jaws have been reported to
be involved in as many as 30% of cases. The radiolucent
areas of the bone contain the abnormal plasma cell
proliferations that characterize multiple myeloma.
Renal failure may be a presenting sign in these
patients because the kidneys become overburdened
with the excess circulating light chain proteins of the
tumor cells. These light chain products, which are
found in the urine of 30% to 50% of patients with mul-
tiple myeloma, are called Bence Jones proteins, after
the British physician who ﬁrst described them in
detail.
Approximately 15% of patients with multiple
myeloma show deposition of amyloid (see page 822)
in various soft tissues of the body, and this may be the
initial manifestation of the disease. Amyloid deposits
are due to the accumulation of the abnormal light
chain proteins. Sites that are classically affected include
the oral mucosa, particularly the tongue. The tongue
may show diffuse enlargement and ﬁrmness or may
have more of a nodular appearance. Sometimes the
nodules are ulcerated. Another area that is commonly
affected is the periorbital skin, with the amyloid
Fig. 13-41 Multiple myeloma. Multiple myeloma affecting
the mandible. The disease produced several radiolucencies
with ragged, ill-deﬁned margins. (Courtesy of Dr. Joseph Finelli.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 605
deposits appearing as waxy, ﬁrm, plaquelike lesions
(see Fig. 17-7 on page 823).
HISTOPATHOLOGIC FEATURES
Histopathologic examination of the lesional tissue in
multiple myeloma shows diffuse, monotonous sheets of
neoplastic, variably differentiated, plasmacytoid cells
that invade and replace the normal host tissue (Fig.
13-42). Mitotic activity may be seen with some fre-
quency. The monoclonality of the plasma cell popula-
tion can be demonstrated using antibodies directed
against the lambda and kappa light chain components
of the immunoglobulin molecule. In a neoplastic pro-
liferation of plasma cells, virtually all of the lesional
cells will mark with only one of these antibodies. In
contrast, a reactive plasma cell inﬁltrate will show a
mixture of lambda- and kappa-producing plasma cells.
Occasionally, deposition of amyloid may be observed
in association with the neoplastic cells. Like other types
of amyloid, this material appears homogeneous, eosin-
ophilic, and relatively acellular. It stains metachromati-
cally with crystal violet and shows an afﬁnity for Congo
red, demonstrating apple-green birefringence on
viewing with polarized light. A biopsy specimen of
bone marrow from a patient with multiple myeloma
should show at least 10% atypical plasma cells making
up the marrow cell population.
DIAGNOSIS
Although the histopathologic and radiographic ﬁnd-
ings strongly suggest a diagnosis of multiple myeloma,
screening of the serum or urine by protein electro-
phoresis should be performed. If an abnormality is
detected, then this should be conﬁrmed by protein
immunoelectrophoresis, which is a more sensitive test,
as an additional parameter to establish the diagnosis.
The serum and urine protein immunoelectrophore-
sis should show the presence of myeloma protein
(M-protein). This represents the massive overproduc-
tion of one abnormal immunoglobulin by the neoplas-
tic clone of plasma cells, thus this feature is termed
monoclonal gammopathy. This monoclonal protein
consists of two heavy chain polypeptides of the same
immunoglobulin (Ig) class (IgA, IgG, IgM, IgD, or IgE)
and one of two light chain polypeptides of the same
class (kappa or lambda). Occasionally, the neoplastic
cells produce only the light chain component.
TREATMENT AND PROGNOSIS
The goals of treatment related to multiple myeloma
include not only controlling the malignancy but also
making the patient comfortable and prolonging the
patient’s survival. Initial attempts to control multiple
myeloma generally consist of chemotherapy. An alkyl-
ating agent, such as melphalan or cyclophosphamide,
is often used in conjunction with prednisone, and
approximately 60% of patients will respond initially to
this regimen. However, virtually all patients eventually
experience relapse of their disease. More aggressive
chemotherapeutic regimens and bone marrow trans-
plantation, either autologous or allogeneic, may be con-
sidered in otherwise healthy patients under the age of
55 to 65 years, but these individuals comprise a minor-
ity of multiple myeloma patients. Addition of thalido-
mide to the treatment protocol may improve survival;
however, ongoing studies are evaluating the effect of
this drug. Radiation therapy is useful only as palliative
treatment for painful bone lesions. Any one of several
bisphosphonate medications (clodronate, pamidro-
nate, or zoledronic acid) can be prescribed to reduce
the possibility of myeloma-related fracture with its
attendant pain, but these medications do not appear to
increase survival. A small percentage of these patients
may experience the complication of bisphosphonate-
related osteonecrosis of the jaws (see page 299).
The prognosis is considered poor, but younger
patients tend to fare better than older ones. Pretreat-
ment serologic studies examining the levels of β
2-
microglobulin and albumin should be performed. With
lower levels of β
2-microglobulin (<3.5 mg/L) and higher
levels of albumin (>35 g/L), the median survival is
approximately 5 years. In contrast, when serum β
2-
microglobulin levels are >5.5 mg/L, the 5-year survival
rate falls to about 2
1
/
2 years. A median survival time of
about 3 to 4 years can be expected after the onset of
symptoms. In the past, a 10% 5-year survival rate was
typical; the prognosis today has improved only slightly.
Most hematology and oncology centers report a 5-year
Fig. 13-42 Multiple myeloma. This high-power
photomicrograph reveals sheets of malignant plasma cells
with eccentric nuclei and stippled nuclear chromatin.
Immunohistochemical studies (inset) show a uniform reaction
of the lesional cells for antibodies directed against kappa
light chains, indicating a monoclonal neoplastic proliferation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

606 ORAL AND MAXILLOFACIAL PATHOLOGY
survival rate of 25%. With aggressive chemotherapy
and bone marrow transplantation, the 5-year survival
rate may be improved to as high as 50%; however, only
a small percentage of multiple myeloma patients can
reasonably tolerate this treatment. This approach
seems to hold the most promise for control of this
aggressive disease, however, and some centers have
indicated that as many as 20% of their patients may
survive for longer than 10 years.
PLASMACYTOMA
The plasmacytoma is a unifocal, monoclonal, neoplas-
tic proliferation of plasma cells that usually arises
within bone. Infrequently, it is seen in soft tissue, in
which case, the term extramedullary plasmacytoma
is used. Some investigators believe that this lesion rep-
resents the least aggressive part of a spectrum of plasma
cell neoplasms that extends to multiple myeloma.
Therefore, the plasmacytoma is important because it
may ultimately give rise to the more serious problem
of multiple myeloma.
CLINICAL AND RADIOGRAPHIC
FEATURES
The plasmacytoma usually is detected in an adult male,
with an average age at diagnosis of 55 years. The
male-to-female ratio is 3:1. Most of the lesions present
centrally within a single bone, and the spine is the most
commonly involved site. About one third of the cases
are reported in that location. The initial symptoms
often relate to swelling or bone pain; occasionally,
however, this lesion is detected on routine radiogra-
phic examination. The extramedullary plasmacytoma
appears as a relatively nondescript, well-circumscribed,
nontender soft tissue mass. An even stronger male pre-
dilection is seen with this lesion, approaching a 6:1
male-to-female ratio. Approximately 80% to 90% of
extramedullary plasmacytomas develop in the head
and neck region, and such lesions have been reported
in the tonsils, the nasopharynx, the paranasal sinuses,
the nose, and the parotid gland.
Radiographically, the lesion may be seen as a well-
deﬁned, unilocular radiolucency with no evidence of
sclerotic borders or as a ragged radiolucency similar to
the appearance of multiple myeloma (Fig. 13-43). No
other lesions should be identiﬁable by a skeletal survey
or careful physical examination, however.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the plasmacytoma are
identical to those of multiple myeloma. Sheets of
plasma cells show varying degrees of differentiation.
Immunohistochemical studies demonstrate that these
plasma cells are monoclonal. As many as 25% to 50%
of these patients also show a monoclonal gammopathy
on evaluation by serum protein immunoelectrophore-
sis, although the amount of abnormal protein is much
less than that seen with multiple myeloma. Solitary
plasmacytoma also differs from multiple myeloma in
that no evidence of plasma cell inﬁltration should be
seen by a random bone marrow biopsy, and the patient
should not show signs of anemia, hypercalcemia, or
renal failure. Immunohistochemically, extramedullary
plasmacytoma appears to differ from its intrabony
counterparts in that it shows a marked decrease or lack
of immunoreactivity for antibodies directed against
cyclin D1 and CD56.
TREATMENT AND PROGNOSIS
Plasmacytomas are usually treated with radiation
therapy, and typically a dose of at least 4000 cGy is
delivered to the tumor site. A few lesions have been
surgically excised with good results, although this is not
the preferred treatment in most instances. Unfortu-
nately, when patients with plasmacytoma of bone are
observed on a long-term basis, most will eventually
develop multiple myeloma. About 50% show evidence
of disseminated disease within 2 to 3 years. However,
one third of these patients will not have symptoms of
multiple myeloma for as long as 10 years. Extramedul-
lary plasmacytoma seems to have a much better prog-
Fig. 13-43 Plasmacytoma. This computed tomography
(CT) scan depicts a solitary plasmacytoma involving the left
maxillary sinus and nasal cavity. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 607
nosis, with only 30% of these patients showing
progression to multiple myeloma and 70% having a
10-year disease-free period after treatment.
BIBLIOGRAPHY
Lymphoid Hyperplasia
Bradley G, Main JHP, Birt BD et al: Benign lymphoid hyperplasia
of the palate, J Oral Pathol 16:18-26, 1987.
Harsany DL, Ross J, Fee WE: Follicular lymphoid hyperplasia of
the hard palate simulating lymphoma, Otolaryngol Head Neck
Surg 88:349-356, 1980.
Kolokotronis A, Dimitrakopoulos I, Asimaki A: Follicular lym-
phoid hyperplasia of the palate: report of a case and review
of the literature, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 96:172-175, 2003.
Menasce LP, Shanks JH, Banerjee SS et al: Follicular lymphoid
hyperplasia of the hard palate and oral mucosa: report of
three cases and a review of the literature, Histopathology
39:353-358, 2001.
Napier SS, Newlands C: Benign lymphoid hyperplasia of the
palate: report of two cases and immunohistochemical proﬁle,
J Oral Pathol Med 19:221-225, 1990.
Wright J, Dunsworth A: Follicular lymphoid hyperplasia of the
hard palate: a benign lymphoproliferative process, Oral Surg
Oral Med Oral Pathol 55:162-168, 1983.
Hemophilia
Blanco-Carrion J, Liñares-Gonzalez A, Batalla-Vazquez P et al:
Morbidity and economic complications following mucogingi-
val surgery in a hemophiliac HIV-infected patient: a case
report, J Periodontol 75:1413-1416, 2004.
Cahill MR, Colvin BT: Haemophilia, Postgrad Med J 73:201-206,
1997.
Dunn AL, Abshire TC: Recent advances in the management of
the child who has hemophilia, Hematol Oncol Clin North Am
18:1249-1276, 2004.
Federici AB: Clinical diagnosis of von Willebrand disease, Hae-
mophilia 10(suppl 4):169-176, 2004.
Federici AB, Berntorp E, Lee CA: The 80th anniversary of von
Willebrand’s disease: history, management and research,
Haemophilia 12:563-572, 2006.
Heiland M, Weber M, Schmelzle R: Life-threatening bleeding
after dental extraction in a hemophilia A patient with inhibi-
tors to factor VIII: a case report, J Oral Maxillofac Surg 61:1350-
1353, 2003.
Izumi Y, Taniguchi T, Maruyama Y et al: Effective periodontal
treatment in a patient with type IIA von Willebrand’s disease:
report of a case, J Periodontol 70:548-553, 1999.
Kitchens CS: Approach to the bleeding patient, Hematol Oncol
Clin North Am 6:983-989, 1992.
Laguna P, Klukowska A: Management of oral bleedings with
recombinant factor VIIa in children with haemophilia A and
inhibitor, Haemophilia 11:2-4, 2005.
Lee CA, Lillicrap D, Astermark J: Inhibitor development in
hemophiliacs: the roles of genetic versus environmental
factors, Semin Thromb Hemost 32(suppl 2):10-14, 2006.
Lofqvist T, Nilsson IM, Berntorp E et al: Haemophilia prophylaxis
in young patients—a long-term follow-up, J Intern Med
241:395-400, 1997.
Mannucci PM: Treatment of von Willebrand’s disease, N Engl J
Med 351:683-694, 2004.
Morimoto Y, Yoshioka A, Shima M et al: Intraoral hemostasis
using a recombinant activated factor VII preparation in a
hemophilia A patient with inhibitor, J Oral Maxillofac Surg
61:1095-1097, 2003.
Pruthi RK: Hemophilia: a practical approach to genetic testing,
Mayo Clin Proc 80:1485-1499, 2005.
Sutor AH: Desmopressin (DDAVP) in bleeding disorders of
childhood, Semin Thromb Hemost 24:555-566, 1998.
Plasminogen Deﬁciency
Drew AF, Kaufman AH, Kombrinck KW et al: Ligneous conjunc-
tivitis in plasminogen-deﬁcient mice, Blood 91:1616-1624,
1998.
Gokbuget AY, Mutlu S, Scully C et al: Amyloidaceous ulcer-
ated gingival hyperplasia: a newly described entity related
to ligneous conjunctivitis, J Oral Pathol Med 26:100-104,
1997.
Schott D, Dempﬂe C-E, Beck P et al: Therapy with a puriﬁed
plasminogen concentrate in an infant with ligneous conjunc-
tivitis and homozygous plasminogen deﬁciency, N Engl J Med
339:1679-1686, 1998.
Schuster V, Seregard S: Ligneous conjunctivitis, Surv Ophthalmol
48:369-388, 2003.
Scully C, Gokbuget AY, Allen C et al: Oral lesions indicative of
plasminogen deﬁciency (hypoplasminogenemia), Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 91:334-337, 2001.
Tefs K, Gueorguieva M, Klammt J et al: Molecular and clinical
spectrum of type I plasminogen deﬁciency: a series of 50
patients, Blood 108:3021-3026, 2006.
Watts P, Suresh P, Mezer E et al: Effective treatment of ligneous
conjunctivitis with topical plasminogen, Am J Ophthalmol
133:451-455, 2002.
Anemia
Beddall A: Anaemias, Practitioner 234:713-715, 1990.
Brown RG: Determining the cause of anemia: general approach,
with emphasis on microcytic hypochromic anemias, Postgrad
Med 89:161-170, 1991.
Groopman JE, Itri LM: Chemotherapy-induced anemia in adults:
incidence and treatment, J Natl Cancer Inst 91:1616-1634,
1999.
Hoggarth K: Macrocytic anaemias, Practitioner 237:331-335,
1993.
Hoggarth K: Microcytic anaemias, Practitioner 237:338-341,
1993.
Means RT: Advances in the anemia of chronic disease, Int J
Hematol 70:7-12, 1999.
Provan D: Mechanisms and management of iron deﬁciency
anaemia, Br J Haematol 105(suppl 1):19-26, 1999.
Remuzzi G, Ingelﬁnger JR: Correction of anemia—payoffs and
problems, N Engl J Med 355:2144-2146, 2006.
Tefferi A: Anemia in adults: a contemporary approach to diagno-
sis, Mayo Clin Proc 78:1274-1280, 2003.
Sickle Cell Anemia
Ashley-Koch A, Yang Q, Olney RS: Sickle hemoglobin (HbS)
allele and sickle cell disease: a human genome epidemiology
review, Am J Epidemiol 151:839-845, 2000.
Brosco JP, Seider MI, Dunn AC: Universal newborn screening
and adverse medical outcomes: a historical note, Ment Retard
Dev Disabil Res Rev 12:262-269, 2006.
Crowley JJ, Sarnaik S: Imaging of sickle cell disease, Pediatr
Radiol 29:646-661, 1999.
Kelleher M, Bishop K, Briggs P: Oral complications associated
with sickle cell anemia. A review and case report, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 82:225-228,
1996. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

608 ORAL AND MAXILLOFACIAL PATHOLOGY
Mehta SR, Afenyi-Annan A, Byrns PJ et al: Opportunities to
improve outcomes in sickle cell disease, Am Fam Physician
74:303-310, 313-314, 2006.
Okpala IE: New therapies for sickle cell disease, Hematol Oncol
Clin North Am 19:975-987, 2005.
Steinberg MH: Management of sickle cell disease, N Engl J Med
340:1021-1030, 1999.
Stuart MJ, Nagel RL: Sickle-cell disease, Lancet 364:1343-1360,
2004.
Vichinsky EP, Neumayr LD, Earles AN et al: Causes and out-
comes of the acute chest syndrome in sickle cell disease, N
Engl J Med 342:1855-1865, 2000.
Xu K, Shi ZM, Veeck LL et al: First unaffected pregnancy using
preimplantation genetic diagnosis for sickle cell anemia,
JAMA 281:1701-1706, 1999.
Thalassemia
Cannell H: The development of oral and facial signs in beta-
thalassaemia major, Br Dent J 164:50-51, 1988.
Clarke GM, Higgins TN: Laboratory investigation of hemoglobin-
opathies and thalassemias: review and update, Clin Chem
46:1284-1290, 2000.
Drew SJ, Sachs SA: Management of the thalassemia-induced
skeletal facial deformity, J Oral Maxillofac Surg 55:1331-1339,
1997.
Hazza’a AM, Al-Jamal G: Dental development in subjects
with thalassemia major, J Contemp Dent Pract 7:63-70,
2006.
Hazza’a AM, Al-Jamal G: Radiographic features of the jaws and
teeth in thalassemia major, Dentomaxillofac Radiol 35:283-
288, 2006.
Joshi D-D, Nickerson HJ, McManus MJ: Hydrops fetalis caused
by homozygous α-thalassemia and Rh antigen alloimmuniza-
tion: report of a survivor and literature review, Clin Med Res
2:228-232, 2004.
Olivieri NF: The beta-thalassemias, N Engl J Med 341:99-109,
1999.
Richer J, Chudley AE: The hemoglobinopathies and malaria, Clin
Genet 68:332-336, 2005.
Riggs DR: The thalassemia syndromes, Q Rev Med 86:559-564,
1993.
Rund D, Rachmilewitz E: β-thalassemia, N Engl J Med 353:1135-
1146, 2005.
Schrier SL, Angelucci E: New strategies in the treatment of the
thalassemias, Annu Rev Med 56:157-171, 2005.
Tyler PA, Madani G, Chaudhuri R et al: The radiological appear-
ances of thalassaemia, Clin Radiol 61:40-52, 2006.
Aplastic Anemia
Bacigalupo A, Brand R, Oneto R et al: Treatment of acquired
severe aplastic anemia: bone marrow transplantation com-
pared with immunosuppressive therapy—the European
Group for Blood and Marrow Transplantation experience,
Semin Hematol 37:69-80, 2000.
Ball SE: The modern management of severe aplastic anaemia, Br
J Haematol 110:41-53, 2000.
Brodsky RA, Jones RJ: Aplastic anemia, Lancet 365:1647-1656,
2005.
Fonseca R, Tefferi A: Practical aspects in the diagnosis and man-
agement of aplastic anemia, Am J Med Sci 313:159-169,
1997.
Horowitz MM: Current status of allogeneic bone marrow trans-
plantation in acquired aplastic anemia, Semin Hematol 37:30-
42, 2000.
Keohane EM: Acquired aplastic anemia, Clin Lab Sci 17:165-171,
2004.
Luker J, Scully C, Oakhill A: Gingival swelling as a manifestation
of aplastic anemia, Oral Surg Oral Med Oral Pathol 71:55-56,
1991.
Marsh JCW: Hematopoietic growth factors in the pathogenesis
and for the treatment of aplastic anemia, Semin Hematol
37:81-90, 2000.
Schrezenmeier H, Raghavachar A, Heimpel H: Granulocyte-
macrophage colony-stimulating factor in the sera of patients
with aplastic anemia, Clin Investig 71:102-108, 1993.
Sepúlveda E, Brethauer U, Rojas J et al: Oral manifestations of
aplastic anemia in children, J Am Dent Assoc 137:474-478,
2006.
Socie G, Henry-Amar M, Bacigalupo A et al: Malignant tumors
occurring after treatment of aplastic anemia, N Engl J Med
329:1152-1157, 1993.
Young NS: Acquired aplastic anemia, Ann Intern Med 136:534-
546, 2002.
Young NS, Calado RT, Scheinberg P: Current concepts in the
pathophysiology and treatment of aplastic anemia, Blood
108:2509-2519, 2006.
Neutropenia
Alexander SW, Pizzo PA: Current considerations in the manage-
ment of fever and neutropenia, Curr Clin Top Infect Dis 19:160-
180, 1999.
Ancliff PJ: Congenital neutropenia, Blood Rev 17:209-216,
2003.
Boxer LA, Hutchinson R, Emerson S: Recombinant human gran-
ulocyte-colony-stimulating factor in the treatment of patients
with neutropenia, Clin Immunol Immunopathol 62:S39-S46,
1992.
Dale DC: Immune and idiopathic neutropenia, Curr Opin Hematol
5:33-36, 1998.
Haddy TB, Rana SR, Castro O: Benign ethnic neutropenia: what
is a normal absolute neutrophil count? J Lab Clin Med 133:15-
22, 1999.
Hakki SS, Aprikyan AAG, Yildirim S et al: Periodontal status in
two siblings with severe congenital neutropenia: diagnosis
and mutational analysis of the cases, J Periodontol 76:837-844,
2005.
James RM, Kinsey SE: The investigation and management of
chronic neutropenia in children, Arch Dis Child 91:852-858,
2006.
Vandendries ER, Drews RE: Drug-associated disease: hemato-
logic dysfunction, Crit Care Clin 22:347-355, 2006.
Welte K, Zeidler C, Dale DC: Severe congenital neutropenia,
Semin Hematol 43:189-195, 2006.
Zaromb A, Chamberlain D, Schoor R et al: Periodontitis as a
manifestation of chronic benign neutropenia, J Periodontol
77:1921-1926, 2006.
Agranulocytosis
Bergman OJ: Oral infections in haematological patients, Dan Med
Bull 39:15-29, 1992.
Carey PJ: Drug-induced myelosuppression: diagnosis and man-
agement, Drug Safety 26:691-706, 2003.
Deas DE, Mackey SA, McDonnell HT: Systemic disease and peri-
odontitis: manifestations of neutrophil dysfunction, Periodon-
tol 2000 32:82-104, 2003.
Glasser L, Duncan BR, Corrigan JJ: Measurement of serum gran-
ulocyte-colony-stimulating factor in a patient with congenital
agranulocytosis (Kostmann’s syndrome), Am J Dis Child
145:925-928, 1991.
Kuipers EJ, Vellenga E, de Wolf JTM et al: Sulfasalazine-induced
agranulocytosis treated with granulocyte-macrophage colony
stimulating factor, J Rheumatol 19:621-622, 1992. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 609
Pisciotta AV: Drug-induced agranulocytosis: peripheral destruc-
tion of polymorphonuclear leukocytes and their marrow pre-
cursors, Blood Rev 4:226-237, 1990.
Salama A, Mueller-Eckhardt C: Immune-mediated blood cell
dyscrasias related to drugs, Semin Hematol 29:54-63, 1992.
Cyclic Neutropenia
Aprikyan AAG, Liles WC, Boxer LA et al: Mutant elastase in
pathogenesis of cyclic and severe congenital neutropenia,
J Pediatr Hematol Oncol 24:784-786, 2002.
Baer PN, Iacono VJ: Cyclic neutropenia: report of a case with a
15-year follow-up, Periodontal Clin Investig 16:14-19, 1994.
Boxer LA, Hutchinson R, Emerson S: Recombinant human gran-
ulocyte-colony-stimulating factor in the treatment of patients
with neutropenia, Clin Immunol Immunopathol 62:S39-S46,
1992.
Dale DC, Bolyard AA, Aprikyan A: Cyclic neutropenia, Semin
Hematol 39:89-94, 2002.
Haurie C, Dale DC, Mackey MC: Cyclical neutropenia and other
periodic hematological disorders: a review of mechanisms
and mathematical models, Blood 92:2629-2640, 1998.
Kinane D: Blood and lymphoreticular disorders, Periodontol
2000 21:84-93, 1999.
Nakai Y, Ishihara C, Ogata S et al: Oral manifestations of cyclic
neutropenia in a Japanese child: case report with a 5-year
follow-up, Pediatr Dent 25:383-388, 2003.
Pernu HE, Pajari UH, Lanning M: The importance of regular
dental treatment in patients with cyclic neutropenia. Follow-
up of 2 cases, J Periodontol 67:454-459, 1996.
Thrombocytopenia
Bolton-Maggs PHB: Idiopathic thrombocytopenic purpura, Arch
Dis Child 83:220-222, 2000.
Chong BH: Clinical aspects of thrombocytopenias, Aust Fam Phy-
sician 23:1463-1464, 1468-1470, 1473, 1994.
George JN: Thrombotic thrombocytopenic purpura, N Engl J Med
354:1927-1935, 2006.
Lusher JM: Screening and diagnosis of coagulation disorders, Am
J Obstet Gynecol 175:778-783, 1996.
Medeiros D, Buchanan GR: Idiopathic thrombocytopenic
purpura: beyond consensus, Curr Opin Pediatr 12:4-9,
2000.
Murrin RJA, Murray JA: Thrombotic thrombocytopenic purpura:
aetiology, pathophysiology and treatment, Blood Rev 20:51-
60, 2006.
Rogers GM: Overview of platelet physiology and laboratory eval-
uation of platelet function, Clin Obstet Gynecol 42:349-359,
1999.
Thompson CC, Tacke RB, Woolley LH et al: Purpuric oral and
cutaneous lesions in a case of drug-induced thrombocytope-
nia, J Am Dent Assoc 105:465-467, 1982.
Wazny LD, Ariano RE: Evaluation and management of drug-
induced thrombocytopenia in the acutely ill patient, Pharma-
cotherapy 20:292-307, 2000.
Polycythemia Vera
Campbell PJ, Green AR: The myeloproliferative disorders, N Engl
J Med 355:2452-2466, 2006.
Cao M, Olsen RJ, Zu Y: Polycythemia vera: new clinicopatho-
logic perspectives, Arch Pathol Lab Med 130:1126-1132,
2006.
Johansson P: Epidemiology of the myeloproliferative disorders
polycythemia vera and essential thrombocythemia, Semin
Thromb Hemost 32:171-173, 2006.
Lengfelder E, Merx K, Hehlmann R: Diagnosis and therapy of
polycythemia vera, Semin Thromb Hemost 32:267-275, 2006.
Silver RT: Treatment of polycythemia vera, Semin Thromb Hemost
32:437-442, 2006.
Tefferi A, Spivak JL: Polycythemia vera: scientiﬁc advances and
current practice, Semin Hematol 42:206-220, 2005.
Leukemia
Abbott BL: Recent advances in chronic lymphocytic leukemia,
Cancer Invest 24:302-309, 2006.
Amin KS, Ehsan A, McGuff HS et al: Minimally differentiated
acute myelogenous leukemia (AML-M0) granulocytic sarcoma
presenting in the oral cavity, Oral Oncol 38:516-519, 2002.
Barrett AP: Gingival lesions in leukemia: a classiﬁcation, J Peri-
odontol 55:585-588, 1984.
Bhatia S, Robison LL: Epidemiology of leukemia and lymphoma,
Curr Opin Hematol 6:201-204, 1999.
Chapple ILC, Saxby MS, Murray JA: Gingival hemorrhage,
myelodysplastic syndromes, and acute myeloid leukemia. A
case report, J Periodontol 70:1247-1253, 1999.
Estey E, Döhner H: Acute myeloid leukaemia, Lancet 368:1894-
1907, 2006.
Faderl S, Talpaz M, Estrov Z et al: Chronic myelogenous leuke-
mia: biology and therapy, Ann Intern Med 131:207-219,
1999.
Farhi DC, Rosenthal NS: Acute lymphoblastic leukemia, Clin Lab
Med 20:17-28, 2000.
Heaney ML, Golde DW: Myelodysplasia, N Engl J Med 340:1649-
1660, 1999.
Hollsberg P, Hailer DA: Pathogenesis of diseases induced by
human lymphotropic virus type I infection, N Engl J Med
328:1173-1182, 1993.
Keating MJ: Chronic lymphocytic leukemia, Semin Oncol 26(suppl
14):107-114, 1999.
Krause JR: Morphology and classiﬁcation of acute myeloid
leukemias, Clin Lab Med 20:1-16, 2000.
Larson RA: Management of acute lymphoblastic leukemia in
older patients, Semin Hematol 43:126-133, 2006.
Lowenberg B, Downing JR, Burnett A: Acute myeloid leukemia,
N Engl J Med 341:1051-1062, 1999.
Menasce LP, Banerjee SS, Beckett E et al: Extra-medullary
myeloid tumour (granulocytic sarcoma) is often misdiag-
nosed: a study of 26 cases, Histopathology 34:391-398,
1999.
Peterson DE, Gerad H, Williams LT: An unusual instance of
leukemic inﬁltrate: diagnosis and management of periapical
tooth involvement, Cancer 51:1716-1719, 1983.
Pui C-H, Evans WE: Treatment of acute lymphoblastic leukemia,
N Engl J Med 354:166-178, 2006.
Quintás-Cardama A, Cortes JE: Chronic myeloid leukemia: diag-
nosis and treatment, Mayo Clin Proc 81:973-988, 2006.
Rhee D, Myssiorek D, Zahtz G et al: Recurrent attacks of facial
nerve palsy as the presenting sign of leukemic relapse, Laryn-
goscope 112:235-237, 2002.
Shanafelt TD, Byrd JC, Call TG et al: Narrative review:
initial management of newly diagnosed, early-stage chronic
lymphocytic leukemia, Ann Intern Med 145:435-447,
2006.
Sollecito TP, Draznin J, Parisi E et al: Leukemic gingival inﬁltrate
as an indicator of chemotherapeutic failure following mono-
clonal antibody therapy: a case report, Spec Care Dentist
23:108-110, 2003.
Stoopler ET, Pinto A, Alawi F et al: Granulocytic sarcoma: an
atypical presentation in the oral cavity, Spec Care Dentist
24:65-69, 2004.
Vibhute P, Carneiro E, Genden E et al: Palatal enlargement
in chronic lymphocytic leukemia, AJNR Am J Neuroradiol
27:1649-1650, 2006. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

610 ORAL AND MAXILLOFACIAL PATHOLOGY
Vural F, Ozcan MA, Ozsan GH et al: Gingival involvement in a
patient with CD56
+
chronic myelomonocytic leukemia, Leuk
Lymphoma 45:415-418, 2004.
Weirda WG, Kipps TJ: Chronic lymphocytic leukemia, Curr Opin
Hematol 6:253-261, 1999.
Yee KWL, O’Brien SM: Chronic lymphocytic leukemia: diagno-
sis and treatment, Mayo Clin Proc 81:1105-1129, 2006.
Langerhans Cell Histiocytosis
Azouz EM, Saigal G, Rodriguez MM et al: Langerhans’ cell his-
tiocytosis: pathology, imaging and treatment of skeletal
involvement, Pediatr Radiol 35:103-115, 2005.
Bartnick A, Friedrich RE, Roeser K et al: Oral Langerhans cell
histiocytosis, J Craniomaxillofac Surg 30:91-96, 2002.
Cleveland DB, Goldberg KM, Greenspan JS et al: Langerhans’
cell histiocytosis. Report of three cases with unusual oral soft
tissue involvement, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 82:541-548, 1996.
Dagenais M, Pharoah MJ, Sikorski PA: The radiographic charac-
teristics of histiocytosis X: a study of 29 cases that involve the
jaws, Oral Surg Oral Med Oral Pathol 74:230-236, 1992.
Eckardt A, Schultze A: Maxillofacial manifestations of Langer-
hans cell histiocytosis: a clinical and therapeutic analysis of
10 patients, Oral Oncol 39:687-694, 2003.
Hartman KH: A review of 114 cases of histiocytosis X, Oral Surg
Oral Med Oral Pathol 49:38-54, 1980.
Hicks J, Flaitz CM: Langerhans cell histiocytosis: current insights
in a molecular age with emphasis on clinical oral and maxil-
lofacial pathology practice, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 100:S42-S66, 2005.
Howarth DM, Gilchrist GS, Mullan BP et al: Langerhans cell
histiocytosis: diagnosis, natural history, management, and
outcome, Cancer 85:2278-2290, 1999.
Key SJ, O’Brien CJ, Silvester KC et al: Eosinophilic granuloma:
resolution of maxillofacial bony lesions following minimal
intervention. Report of three cases and a review of the litera-
ture, J Craniomaxillofac Surg 32:170-175, 2004.
Manfredi M, Corradi D, Vescovi P: Langerhans-cell histiocytosis:
a clinical case without bone involvement, J Periodontol 76:143-
147, 2005.
Mitomi T, Tomizawa, Noda T: Tooth development included in
the multifocal jaw lesions of Langerhans cell histiocytosis, Int
J Paediatr Dent 15:123-126, 2005.
Muzzi L, Prato GPP, Ficarra G: Langerhans’ cell histiocytosis
diagnosed through periodontal lesions: a case report, J Peri-
odontol 73:1528-1533, 2002.
Putters TF, de Visscher JGAM, van Veen A et al: Intralesional
inﬁltration of corticosteroids in the treatment of localized
Langerhans’ cell histiocytosis of the mandible. Report of
known cases and three new cases, Int J Oral Maxillofac Surg
34:571-575, 2005.
Scolozzi P, Lombardi T, Monnier P et al: Multisystem Langer-
hans’ cell histiocytosis (Hand-Schüller-Christian disease) in
an adult: a case report and review of the literature, Eur Arch
Otorhinolaryngol 261:326-330, 2004.
Yousem SA, Colby TV, Chen Y-Y et al: Pulmonary Langerhans’
cell histiocytosis. Molecular analysis of clonality, Am J Surg
Pathol 25:630-636, 2001.
Hodgkin’s Lymphoma
Advani RH, Horning SJ: Treatment of early-stage Hodgkin’s
disease, Semin Hematol 36:270-281, 1999.
Aisenberg AC: Problems in Hodgkin’s disease management,
Blood 93:761-779, 1999.
Ansell SM, Armitage JO: Management of Hodgkin lymphoma,
Mayo Clin Proc 81:419-426, 2006.
Connors JM: State-of-the-art therapeutics: Hodgkin’s lymphoma,
J Clin Oncol 23:6400-6408, 2005.
Diehl V, Josting A: Hodgkin’s disease, Cancer J Sci Am 6(suppl 2):
S150-S158, 2000.
Harris NL: Hodgkin’s disease: classiﬁcation and differential diag-
nosis, Mod Pathol 12:159-176, 1999.
Herrin HK: The oral implications of Hodgkin’s disease, Gen Dent
47:572-575, 1999.
Jaffe ES: Introduction: Hodgkin’s lymphoma—pathology, patho-
genesis, and treatment, Semin Hematol 36:217-219, 1999.
Küppers R, Hansmann M-L: The Hodgkin and Reed/Sternberg
cell, Int J Biochem Cell Biol 37:511-517, 2005.
Küppers R, Yahalom J, Josting A: Advances in biology, diagnos-
tics, and treatment of Hodgkin’s disease, Biol Blood Marrow
Transplant 12:66-76, 2006.
Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin’s
lymphoma, J Clin Oncol 23:6379-6386, 2005.
Yencha MW: Primary parotid gland Hodgkin’s lymphoma, Ann
Otol Rhinol Laryngol 111:338-342, 2002.
Non-Hodgkin’s Lymphoma
Ando M, Matsuzaki M, Murofushi T: Mucosa-associated lym-
phoid tissue lymphoma presented as diffuse swelling of the
parotid gland, Am J Otolaryngol 26:285-288, 2005.
Armitage JO: Staging non-Hodgkin lymphoma, CA Cancer J Clin
55:368-376, 2005.
Chan JKC, Banks PM, Cleary ML et al: A revised European-
American classiﬁcation of lymphoid neoplasms proposed by
the International Lymphoma Study Group, Am J Clin Pathol
103:543-560, 1995.
Chang C-C, Rowe JJ, Hawkins P et al: Mantle cell lymphoma of
the hard palate: a case report and review of the differential
diagnosis based on the histomorphology and immunopheno-
typing pattern, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 96:316-320, 2003.
Cheson BD: What is new in lymphoma? CA Cancer J Clin 54:260-
272, 2004.
Evans LS, Hancock BW: Non-Hodgkin lymphoma, Lancet
362:139-146, 2003.
Folk GS, Abbondanzo SL, Childers EL et al: Plasmablastic lym-
phoma: a clinicopathologic correlation, Ann Diagn Pathol
10:8-12, 2006.
Hennessy BT, Hanrahan EO, Daly PA: Non-Hodgkin lymphoma:
an update, Lancet Oncol 5:341-353, 2004.
Isaacson PG, Du M-Q: MALT lymphoma: from morphology to
molecules, Nature Rev Cancer 4:644-653, 2004.
Kolokotronis A, Konstantinou N, Christakis I et al: Localized
B-cell non-Hodgkin’s lymphoma of the oral cavity and
maxillofacial region: a clinical study, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 99:303-310, 2005.
Krause JR, Shahidi-Asl M: Molecular pathology in the diagnosis
and treatment of non-Hodgkin’s lymphomas, J Cell Mol Med
7:494-512, 2003.
Knowles DM: Immunodeﬁciency-associated lymphoprolifera-
tive disorders, Mod Pathol 12:200-217, 1999.
Lu P: Staging and classiﬁcation of lymphoma, Semin Nucl Med
35:160-165, 2005.
Mealey BL, Tunder GS, Pemble CW: Primary extranodal malig-
nant lymphoma affecting the periodontium, J Periodontol
73:937-941, 2002.
Mishima K, Matsuoka H, Yamada E et al: Application of the
polymerase chain reaction for the diagnosis of malignant lym-
phoma of the nasal and oral cavities, J Oral Pathol Med 27:43-
47, 1998.
Mounter PJ, Lennard AL: Management of non-Hodgkin’s lym-
phomas, Postgrad Med J 75:2-6, 1999. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 13 HEMATOLOGIC DISORDERS 611
Ostrowski ML, Unni KK, Banks PM et al: Malignant lymphoma
of bone, Cancer 58:2646-2655, 1986.
Rizvi MA, Evens AM, Tallman MS et al: T-cell non-Hodgkin lym-
phoma, Blood 107:1255-1264, 2006.
Sandlund JT, Downing JR, Crist WM: Non-Hodgkin’s lymphoma
in childhood, N Engl J Med 334:1238-1248, 1996.
Shine NP, Blake SP, O’Leary G: Extranodal lymphoma: clinical
presentation and diagnostic pitfalls, Hosp Med 66:341-345,
2005.
Solomides CC, Miller AS, Christman RA et al: Lymphomas of the
oral cavity: histology, immunologic type, and incidence of
Epstein-Barr virus infection, Hum Pathol 33:153-157, 2002.
Tomich CE, Shafer WG: Lymphoproliferative disease of the hard
palate: a clinicopathologic entity, Oral Surg Oral Med Oral
Pathol 39:754-768, 1975.
Van der Waal RIF, Huijgens PC, van der Valk P et al: Charac-
teristics of 40 primary extranodal non-Hodgkin lymphomas
of the oral cavity in perspective of the new WHO classiﬁca-
tion and the International Prognostic Index, Int J Oral Maxil-
lofac Surg 34:391-395, 2005.
Vega F, Lin P, Medeiros J: Extranodal lymphomas of the head
and neck, Ann Diagn Pathol 9:340-350, 2005.
Mycosis Fungoides
Abel EA, Wood GS, Hoppe RT: Mycosis fungoides: clinical and
histologic features, staging evaluation, and approach to treat-
ment, CA Cancer J Clin 43:93-115, 1993.
Berti E, Tomasini D, Vermeer MH et al: Primary cutaneous CD8-
positive epidermotropic cytotoxic T cell lymphomas: a dis-
tinct clinicopathological entity with an aggressive clinical
behavior, Am J Pathol 155:483-492, 1999.
Chua M S-T, Veness MJ: Mycosis fungoides involving the oral
cavity, Australas Radiol 46:336-339, 2002.
Damm DD, White DK, Cibull ML et al: Mycosis fungoides: initial
diagnosis via palatal biopsy with discussion of diagnostic
advantages of plastic embedding, Oral Surg Oral Med Oral
Pathol 58:413-419, 1984.
Hata T, Aikoh T, Hirokawa M et al: Mycosis fungoides with
involvement of the oral mucosa, Int J Oral Maxillofac Surg
27:127-128, 1998.
Kerl H, Cerroni L: Primary cutaneous B-cell lymphomas: then
and now, J Cutan Pathol 33(suppl 1):1-5, 2006.
Kim EJ, Hess S, Richardson SK et al: Immunopathogenesis and
therapy of cutaneous T cell lymphoma, J Clin Invest 115:798-
812, 2005.
Kim YH, Hoppe RT: Mycosis fungoides and the Sézary syn-
drome, Semin Oncol 26:276-289, 1999.
Scarisbrick JJ: Staging and management of cutaneous T-cell lym-
phoma, Clin Exp Dermatol 31:181-186, 2006.
Sirois DA, Miller AS, Harwick RD et al: Oral manifestations of
cutaneous T-cell lymphoma: a report of eight cases, Oral Surg
Oral Med Oral Pathol 75:700-705, 1993.
Wain EM, Setterﬁeld J, Judge MR et al: Mycosis fungoides involv-
ing the oral mucosa in a child, Clin Exp Dermatol 28:499-501,
2003.
Wright JM, Balciunas BA, Muus JH: Mycosis fungoides with oral
manifestations: report of a case and review of the literature,
Oral Surg Oral Med Oral Pathol 51:24-31, 1981.
Zackheim HS: Cutaneous T cell lymphoma: update of treatment,
Dermatology 199:102-105, 1999.
Zic J, Arzubiaga C, Salhaney KE et al: Extracorporeal photo-
pheresis for the treatment of cutaneous T-cell lymphoma, J
Am Acad Dermatol 27:729-736, 1992.
Burkitt’s Lymphoma
Cairo MS, Sposto R, Perkins SL et al: Burkitt’s and Burkitt-like
lymphoma in children and adolescents: review of the Chil-
dren’s Cancer Group experience, Br J Haematol 120:660-670,
2003.
Dave SS, Fu K, Wright GW et al: Molecular diagnosis of Burkitt’s
lymphoma, N Engl J Med 354:2431-2442, 2006.
Ferry JA: Burkitt’s lymphoma: clinicopathologic features and dif-
ferential diagnosis, Oncologist 11:375-383, 2006.
Hummel M, Bentink S, Berger H et al: A biologic deﬁnition of
Burkitt’s lymphoma from transcriptional and genomic proﬁl-
ing, N Engl J Med 354:2419-2430, 2006.
Sandlund JT, Downing JR, Crist WM: Non-Hodgkin’s lymphoma
in childhood, N Engl J Med 334:1238-1248, 1996.
Tsui SHC, Wong MH, Lam WY: Burkitt’s lymphoma presenting
as mandibular swelling—report of a case and review of publi-
cations, Br J Oral Maxillofac Surg 38:8-11, 2000.
Ug˘ar DA, Bozkaya S, Karaca I
.
et al: Childhood craniofacial
Burkitt’s lymphoma presenting as maxillary swelling: report
of a case and review of literature, J Dent Child 73:45-50,
2006.
Extranodal NK/T-Cell Lymphoma, Nasal Type
Al-Hakeem DA, Fedele S, Carlos R et al: Extranodal NK/T-cell
lymphoma, nasal type, Oral Oncol 43:4-14, 2007.
Batsakis JG, Luna MA: Midfacial necrotizing lesions, Semin Diagn
Pathol 4:90-116, 1987.
Koom WS, Chung EJ, Yang W-I et al: Angiocentric T-cell and
NK/T-cell lymphomas: radiotherapeutic viewpoints, Int J
Radiat Oncol Biol Phys 59:1127-1137, 2004.
Lee PY, Freeman NJ, Khorsand J et al: Angiocentric T-cell lym-
phoma presenting as lethal midline granuloma, Int J Dermatol
36:419-427, 1997.
Mosqueda-Taylor A, Meneses-Garcia A, Zarate-Osorno A et al:
Angiocentric lymphomas of the palate: clinico-pathological
considerations in 12 cases, J Oral Pathol Med 26:93-97, 1997.
Pagano L, Gallamini A, Fianchi L et al: NK/T-cell lymphomas
“nasal type”: an Italian multicentric retrospective survey, Ann
Oncol 17:794-800, 2006.
Patel V, Mahajan S, Kharkar V et al: Nasal extranodal NK/T-cell
lymphoma presenting as a perforating palatal ulcer: a diag-
nostic challenge, Indian J Dermatol Venereol Leprol 72:218-
221, 2006.
Vidal RW, Devaney K, Ferlito A et al: Sinonasal malignant lym-
phomas: a distinct clinicopathological category, Ann Otol
Rhinol Laryngol 108:411-419, 1999.
Wu SM, Min Y, Ostrzega N et al: Lymphomatoid granulomatosis:
a rare mimicker of vasculitis, J Rheumatol 32:2242-2245,
2005.
Yong W, Zheng W, Zhu J et al: Midline NK/T-cell lymphoma
nasal-type: treatment outcome, the effect of L-asparaginase
based regimen, and prognostic factors, Hematol Oncol 24:28-
32, 2006.
Multiple Myeloma
Baldini L, Radaelli F, Chiorboli O et al: No correlation between
response and survival in patients with multiple myeloma
treated with vincristine, melphalan, cyclophosphamide, and
prednisone, Cancer 68:62-67, 1991.
Denz U, Haas PS, Wäsch R et al: State of the art therapy in mul-
tiple myeloma and future perspectives, Eur J Cancer 42:1591-
1600, 2006.
Dimopoulos MA, Moulopoulos A, Smith T et al: Risk of disease
progression in asymptomatic multiple myeloma, Am J Med
94:57-61, 1993.
George ED, Sadovsky R: Multiple myeloma: recognition and
management, Am Fam Physician 59:1885-1894, 1999.
Hogan MC, Lee A, Solberg LA et al: Unusual presentation of
multiple myeloma with unilateral visual loss and numb chin
syndrome in a young adult, Am J Hematol 70:55-59, 2002. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

612 ORAL AND MAXILLOFACIAL PATHOLOGY
Kyle RA, Rajkumar SV: Treatment of multiple myeloma: an
emphasis on new developments, Ann Med 38:111-115,
2006.
Lebowitz RA, Morris L: Plasma cell dyscrasias and amyloidosis,
Otolaryngol Clin North Am 36:747-764, 2003.
Ludwig H: Advances in biology and treatment of multiple
myeloma, Ann Oncol (suppl 2):ii106-ii112, 2005.
Palumbo A, Bertola A, Musto P et al: Oral melphalan, predni-
sone, and thalidomide for newly diagnosed patients with
myeloma, Cancer 104:1428-1433, 2005.
Riedel DA, Pottern LM: The epidemiology of multiple myeloma,
Hematol Oncol Clin North Am 6:225-247, 1992.
Smith A, Wisloff F, Samson D: Guidelines on the diagnosis and
management of multiple myeloma 2005, Br J Haematol
132:410-451, 2005.
Plasmacytoma
Dimopoulos MA, Kiamouris C, Moulopoulos LA: Solitary plas-
macytoma of bone and extramedullary plasmacytoma,
Hematol Oncol Clin North Am 13:1249-1257, 1999.
González J, Elizondo J, Trull JM et al: Plasma-cell tumours of the
condyle, Br J Oral Maxillofac Surg 29:274-276, 1991.
Kremer M, Ott G, Nathrath M et al: Primary extramedullary
plasmacytoma and multiple myeloma: phenotypic differ-
ences revealed by immunohistochemical analysis, J Pathol
205:92-101, 2005.
Majumdar S, Raghavan U, Jones NS: Solitary plasmacytoma and
extramedullary plasmacytoma of the paranasal sinuses and
soft palate, J Laryngol Otol 116:962-965, 2002.
Meis JM, Butler JJ, Osborne BM et al: Solitary plasmacytomas of
bone and extramedullary plasmacytomas: a clinicopathologic
and immunohistochemical study, Cancer 59:1475-1485,
1987.
Nofsinger YC, Mirza N, Rowan PT et al: Head and neck mani-
festations of plasma cell neoplasms, Laryngoscope 107:741-
746, 1997.
Rothﬁeld RE, Johnson JT, Slavrides A: Extramedullary plasmacy-
toma of the parotid, Head Neck 12:352-354, 1990. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

613
14
Bone Pathology
*
Revised by ANGELA C. CHI
CHAPTER OUTLINE
Osteogenesis Imperfecta
Osteopetrosis
Cleidocranial Dysplasia
Focal Osteoporotic Marrow Defect
Idiopathic Osteosclerosis
Massive Osteolysis
Paget’s Disease of Bone
Central Giant Cell Granuloma
Cherubism
Simple Bone Cyst
Aneurysmal Bone Cyst
Fibrous Dysplasia
Cemento-Osseous Dysplasias
Familial Gigantiform Cementoma
the most common type of inherited bone disease.
Abnormal collagenous maturation results in bone with
a thin cortex, ﬁne trabeculation, and diffuse osteoporo-
sis. Upon fracture, healing will occur but may be associ-
ated with exuberant callus formation.
CLINICAL AND RADIOGRAPHIC
FEATURES
Osteogenesis imperfecta is a rare disorder that affects
1 in 8000 individuals, with many being stillborn or
dying shortly after birth. Both autosomal dominant and
recessive hereditary patterns occur, and many cases
are sporadic. The severity of the disease varies widely,
even in affected members of a single family. In addition
to bone fragility, some affected individuals also have
OSTEOGENESIS IMPERFECTA
Osteogenesis imperfecta comprises a heterogeneous
group of heritable disorders characterized by impair-
ment of collagen maturation. Except on rare occasions,
the disorder arises from heterozygosity for mutations
in one of two genes that guide the formation of type I
collagen: the COL1A1 gene on chromosome 17 and
the COL1A2 gene on chromosome 7. Collagen forms
a major portion of bone, dentin, sclerae, ligaments, and
skin; osteogenesis imperfecta demonstrates a variety of
changes that involve these sites. Several different forms
of osteogenesis imperfecta are seen, and they represent
Ossifying Fibroma
Juvenile Ossifying Fibroma
Osteoma
Gardner Syndrome
Osteoblastoma and Osteoid Osteoma
Cementoblastoma
Chondroma
Chondromyxoid Fibroma
Synovial Chondromatosis
Desmoplastic Fibroma
Osteosarcoma
Chondrosarcoma
Ewing Sarcoma
Metastatic Tumors to the Jaws
*Dr. Charles A. Waldron wrote the original version of this chapter in the
ﬁrst edition of this book. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

614 ORAL AND MAXILLOFACIAL PATHOLOGY
blue sclera, altered teeth, hypoacusis (hearing loss),
long bone and spine deformities, and joint hyper-
extensibility.
The radiographic hallmarks of osteogenesis imper-
fecta include osteopenia, bowing, angulation or defor-
mity of the long bones, multiple fractures, and wormian
bones in the skull. Wormian bones consist of 10 or
more sutural bones that are 6 × 4 mm in diameter or
larger and arranged in a mosaic pattern. Wormian
bones are not speciﬁc and can be seen in other pro-
cesses, such as cleidocranial dysplasia.
Several distinctive ﬁndings are noted in the oral
cavity. Dental alterations that appear clinically and
radiographically identical to dentinogenesis imper-
fecta (see page 106) are occasionally noted (Fig. 14-1,
A). In affected patients, both dentitions are involved
and demonstrate blue to brown translucence. Radio-
graphs typically reveal premature pulpal obliteration,
although shell teeth rarely may be seen (Fig. 14-1, B).
Although the altered teeth closely resemble dentino-
genesis imperfecta, the two diseases are the result of
different mutations and should be considered as sepa-
rate processes. Such dental defects in association with
the systemic bone disease should be termed opales-
cent teeth, reserving the diagnosis of dentinogenesis
imperfecta for those patients with alterations isolated
to the teeth.
In addition, patients with osteogenesis imperfecta
demonstrate an increased prevalence of Class III mal-
occlusion that is caused by maxillary hypoplasia, with
or without mandibular hyperplasia. On rare occasions,
panoramic radiographs may reveal multifocal radiolu-
cencies, mixed radiolucencies, or radiopacities that
resemble those seen in ﬂorid cemento-osseous dyspla-
sia. When predominantly radiopaque, these areas are
sensitive to inﬂammation and undergo sequestration
easily. In these patients, marked coarseness also is
noted in the remainder of the skeleton.
Four major types of osteogenesis imperfecta are rec-
ognized, each having several subtypes.
TYPE I OSTEOGENESIS IMPERFECTA
Type I is the most common and mildest form. Affected
patients have mild to moderately severe bone fragility.
Fractures are present at birth in about 10% of cases, but
there is great variability in frequency and age of onset
of fractures, with 10% of patients not demonstrating
fractures. Most fractures occur during the preschool
years and are less common after puberty. Hearing loss
commonly develops before age 30, and most older
patients have hearing deﬁcits. Hypermobile joints and
easy bruising because of capillary fragility are not rare.
Some affected patients have normal teeth, but others
show opalescent dentin. The sclerae are distinctly blue
at all ages and aid in classiﬁcation. Osteogenesis imper-
fecta type I is inherited as an autosomal dominant
trait.
TYPE II OSTEOGENESIS IMPERFECTA
Osteogenesis imperfecta type II is the most severe form
and exhibits extreme bone fragility and frequent frac-
tures, which may occur during delivery. Many patients
are stillborn, and 90% die before 4 weeks of age. Blue
sclerae are present (Fig. 14-2). Opalescent teeth may
be present. Both autosomal recessive and dominant
patterns may occur, and many cases appear to be
sporadic.
TYPE III OSTEOGENESIS IMPERFECTA
Type III is the most severe form noted in individuals
beyond the perinatal period and demonstrates moder-
ately severe to severe bone fragility. The sclerae are
A B
Fig. 14-1 Osteogenesis imperfecta. A, Opalescent dentin in a patient with osteogenesis
imperfecta. B, Bite-wing radiograph of the same patient showing shell teeth with thin dentin
and enamel of normal thickness. (Courtesy of Dr. Tom Ison.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 615
normal or pale blue or gray at birth; if discoloration is
present, then it fades as the child grows older. Liga-
mentous laxity and hearing loss are common. Fractures
may be present at birth, but there is a low mortality in
infancy. Although one third survive into adulthood, the
majority of affected individuals die during childhood,
usually from cardiopulmonary complications caused
by kyphoscoliosis. Some patients have opalescent
dentin, whereas others have normal teeth. Both auto-
somal dominant and recessive hereditary patterns are
noted.
TYPE IV OSTEOGENESIS IMPERFECTA
Type IV is associated with mild to moderately severe
bone fragility. The sclerae may be pale blue in early
childhood, but the blue color fades later in life. Frac-
tures are present at birth in about 50% of these patients.
The frequency of fractures decreases after puberty,
and some individuals never experience bone fracture
at any time. Some of these patients have opalescent
dentin; others have normal teeth. This variant appears
to be inherited as an autosomal dominant trait.
HISTOPATHOLOGIC FEATURES
On histopathologic examination, cortical bone appears
attenuated. Osteoblasts are present, but bone matrix
production is reduced markedly. The bone architec-
ture remains immature throughout life, and there is a
failure of woven bone to become transformed to lamel-
lar bone.
Histopathologically, teeth from affected patients can
exhibit abnormalities of dentin similar to those
described for patients with dentinogenesis imperfecta
(see page 108). These microscopic ﬁndings tend to be
most pronounced in teeth that clinically appear opal-
escent. However, mild dentinal abnormalities may be
found even in teeth that appear normal clinically and
radiographically.
TREATMENT AND PROGNOSIS
There is no cure for osteogenesis imperfecta; thus
symptomatic improvement is the primary goal of cur-
rently available treatment options. Management of the
fractures may be a major problem. The mainstays of
treatment are physiotherapy, rehabilitation, and ortho-
pedic surgery. Medical treatment with intravenous (IV)
or oral bisphosphonates can provide clinical beneﬁts,
including decreased pain, reduced risk of fracture, and
improved mobility. However, the long-term conse-
quences of bisphosphonate therapy—particularly when
administered to a pediatric patient population—are
currently unknown; therefore, bisphosphonates are
generally reserved for moderately to severely affected
patients. Patients with opalescent dentin usually show
severe attrition of their teeth, leading to tooth loss.
Treatment of the dentition is similar to that used for
dentinogenesis imperfecta (see page 108), but use of
implants is questionable because of the deﬁcient quality
of the supporting bone.
In patients with signiﬁcant malocclusion, orthog-
nathic surgery may be performed. Alternatively, osteo-
distraction may be a consideration to reduce the risk
of atypical fractures from conventional orthognathic
procedures (e.g., Le Fort I osteotomy). The potential for
associated medical problems makes presurgical plan-
ning paramount. Although the risks are highly variable,
occasional patients have associated bleeding disorders,
cardiac malformations, and an increased potential for
hyperthermia. Intubation may be difﬁcult because of
kyphoscoliosis and ease of fracture of the mandible
and cervical vertebrae.
The prognosis varies from relatively good to very
poor. Some patients have little to no disability, whereas
others have severe crippling as a result of the fractures.
In severe forms, death occurs in utero, during delivery,
or early in childhood.
OSTEOPETROSIS (ALBERS-
SCHÖNBERG DISEASE; MARBLE
BONE DISEASE)
Osteopetrosis is a group of rare hereditary skeletal
disorders characterized by a marked increase in bone
density resulting from a defect in remodeling caused
by failure of normal osteoclast function. The number
of osteoclasts present is often increased; however,
because of their failure to function normally, bone
is not resorbed. Defective osteoclastic bone resorp-
tion, combined with continued bone formation and
Fig. 14-2 Osteogenesis imperfecta. Blue sclera in a
patient with osteogenesis imperfecta. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

616 ORAL AND MAXILLOFACIAL PATHOLOGY
endochondral ossiﬁcation, results in thickening of cor-
tical bone and sclerosis of the cancellous bone.
Although genetic defects have yet to be identiﬁed in
a substantial percentage of patients with osteopetrosis,
mutations discovered thus far have been found to cause
defects in key elements necessary for osteoclast func-
tion, including the H
+
-ATPase proton pump, chloride
channel, and carbonic anhydrase II. These proteins are
necessary for acidiﬁcation of resorption lacunae, regu-
lation of ionic charge across the osteoclast cell mem-
brane, and subsequent resorption of the bone matrix.
Although a number of types have been identiﬁed,
these pathoses group into two major clinical patterns:
(1) infantile and (2) adult osteopetrosis. The infantile
form has an estimated incidence of 1:200,000 to
1:300,000, and the adult form has an estimated inci-
dence of 1 in 100,000 to 1:500,000. The clinical
severity of the disease varies widely, even within the
same pattern of osteopetrosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
INFANTILE OSTEOPETROSIS
Patients discovered with osteopetrosis at birth or in
early infancy usually have severe disease that is termed
malignant osteopetrosis. In most cases, infantile
osteopetrosis is inherited as an autosomal recessive
trait and leads to a diffusely sclerotic skeleton. Marrow
failure, frequent fractures, and evidence of cranial
nerve compression are common.
The initial signs of infantile osteopetrosis often are
normocytic anemia with hepatosplenomegaly result-
ing from compensatory extramedullary hematopoiesis.
Increased susceptibility to infection is common as a
result of granulocytopenia. Facial deformity develops
in many of the children, manifesting as a broad face,
hypertelorism, snub nose, and frontal bossing. Tooth
eruption almost always is delayed. Failure of resorption
and remodeling of the skull bones produces narrowing
of the skull foramina that press on the various cranial
nerves and results in optic nerve atrophy and blind-
ness, deafness, and facial paralysis. In spite of the dense
bone, pathologic fractures are common. Osteomyelitis
of the jaws is a common complication of tooth extrac-
tion (Fig. 14-3).
Radiographically, there is a widespread increase in
skeletal density with defects in metaphyseal remodel-
ing. The radiographic distinction between cortical and
cancellous bone is lost (Fig. 14-4). In dental radio-
graphs, the roots of the teeth often are difﬁcult to visu-
alize because of the density of the surrounding bone.
Less severe variants of infantile osteopetrosis exist
and have been termed intermediate osteopetrosis.
Affected patients often are asymptomatic at birth but
frequently exhibit fractures by the end of the ﬁrst
decade. Marrow failure and hepatosplenomegaly are
rare.
In some cases, patients show radiographic evidence
of diffuse sclerosis and associated marrow failure but
resolve without speciﬁc therapy. This pattern has been
termed transient osteopetrosis. and most affected
patients return to normalcy with no known sequelae.
ADULT OSTEOPETROSIS
Adult osteopetrosis is usually discovered later in life
and exhibits less severe manifestations. In most patients,
this pattern is inherited as an autosomal dominant trait
and has been termed benign osteopetrosis. The axial
skeleton usually reveals signiﬁcant sclerosis, whereas
the long bones demonstrate little or no defects. Approx-
imately 40% of affected patients are asymptomatic, and
marrow failure is rare. Occasionally, the diagnosis is
discovered initially on review of dental radiographs
that reveal a diffuse increased radiopacity of the med-
ullary portions of the bone. In symptomatic patients,
bone pain is frequent.
Two major variants of adult osteopetrosis are seen.
In one form, cranial nerve compression is common,
although fractures occur rarely. In contrast, the second
pattern demonstrates frequent fractures, but nerve
compression is uncommon. When the mandible is
involved, fracture and osteomyelitis after tooth extrac-
tion are signiﬁcant complications.
Although distinctly uncommon, other causes of
widespread osteosclerosis exist and should be consid-
ered during evaluation of patients with osteopetrosis.
Such diseases include autosomal dominant osteoscle-
rosis (endosteal hyperostosis, Worth type), scleroste-
osis, and Van Buchem disease.
Fig. 14-3 Osteopetrosis. This 24-year-old white man has
the infantile form of osteopetrosis. He has mandibular
osteomyelitis, and multiple draining ﬁstulae are present on
his face. (Courtesy of Dr. Dan Sarasin.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 617
HISTOPATHOLOGIC FEATURES
Several patterns of abnormal endosteal bone formation
have been described. These include the following:
●Tortuous lamellar trabeculae replacing the can-
cellous portion of the bone
●Globular amorphous bone deposition in the
marrow spaces (Fig. 14-5)
●Osteophytic bone formation
Numerous osteoclasts may be seen, but there is no
evidence that they function because Howship’s lacunae
are not visible.
TREATMENT AND PROGNOSIS
Because of the mild severity of the disease, adult osteo-
petrosis is usually associated with long-term survival.
In contrast, the prognosis of infantile osteopetrosis
without therapy is typically poor, with most affected
patients dying during the ﬁrst decade of life. Bone
marrow transplantation is the only hope for permanent
cure. However, an appropriately matched donor is
available for only about half of affected patients, and
successful engraftment occurs in only approximately
45% of those receiving bone marrow transplantation.
Because of the unavailability or risk of bone marrow
transplantation, search for other therapies is ongoing.
Interferon gamma-1b, often in combination with cal-
citriol, has been shown to reduce bone mass, decrease
the prevalence of infections, and lower the frequency
of nerve compression. Other therapeutic avenues
include administration of corticosteroids (to increase
circulating red blood cells and platelets), parathor-
mone, macrophage colony stimulating factor, and
erythropoietin. Limiting calcium intake also has been
suggested.
Additional therapy consists of supportive measures,
such as transfusions and antibiotics for the complica-
tions. Osteomyelitis of the jaws requires rapid interven-
tion to minimize osseous destruction. Affected patients
should receive early diagnosis, appropriate drainage
and surgical débridement, bacterial culture with sen-
sitivity, appropriate antibiotic therapy, and recon-
struction if necessary. The infection often requires
prolonged antibiotic therapy, with ﬂuoroquinolones
and lincomycin often being most effective. Hyperbaric
oxygen is useful in promoting healing of recalcitrant
cases.
Fig. 14-4 Osteopetrosis. Extensive mandibular involvement is apparent in this radiograph of
a 31-year-old woman. She received a diagnosis of osteopetrosis as a child. There is a history of
multiple fractures and osteomyelitis of the jaws. (Courtesy of Dr. Dan Sarasin.)
Fig. 14-5 Osteopetrosis. Low-power photomicrograph
showing sclerotic bone that is replacing the normal
cancellous bone. The inset shows a nodular pattern of the
dense bone obliterating the marrow spaces. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

618 ORAL AND MAXILLOFACIAL PATHOLOGY
CLEIDOCRANIAL DYSPLASIA
Best known for its dental and clavicular abnormalities,
cleidocranial dysplasia is a disorder of bone caused
by a defect in the CBFA1 gene (also known as the
RUNX2 gene) of chromosome 6p21. This gene nor-
mally guides osteoblastic differentiation and appropri-
ate bone formation. This condition initially was thought
to involve only membranous bones (e.g., clavicles, skull,
ﬂat bones), but it is now known to affect endochondral
ossiﬁcation and to represent a generalized disorder
of skeletal structures. Recent evidence suggests that
the CBFA1 gene additionally plays an important role
in odontogenesis via participation in odontoblast
differentiation, enamel organ formation, and dental
lamina proliferation. Disruption of these functions
might explain the distinct dental anomalies found in
patients with this disorder. The disease has an esti-
mated prevalence of 1:1,000,000 and shows an
autosomal dominant inheritance pattern, but as many
as 40% of cases appear to represent spontaneous
mutations. This condition formerly was known as
cleidocranial dysostosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
The bone defects in patients with cleidocranial dyspla-
sia chieﬂy involve the clavicles and skull, although a
wide variety of anomalies may be found in other bones.
The clavicles are absent, either unilaterally or bilater-
ally, in about 10% of all cases. More commonly, the
clavicles show varying degrees of hypoplasia and
malformation.
The muscles associated with the abnormal clavicles
are underdeveloped. The patient’s neck appears long;
the shoulders are narrow and show marked drooping.
The absence or hypoplasia of the clavicles leads to an
unusual mobility of the patient’s shoulders. In some
instances, the patient can approximate the shoulders
in front of the chest (Fig. 14-6). Although the clavicular
defects result in variations of the associated muscles,
function is remarkably good.
The appearance of the patient affected by cleidocra-
nial dysplasia often is diagnostic. The patients tend to
be of short stature and have large heads with pro-
nounced frontal and parietal bossing. Ocular hyper-
telorism and a broad base of the nose with a depressed
nasal bridge often are noted. On skull radiographs, the
sutures and fontanels show delayed closure or may
remain open throughout the patient’s life. Secondary
centers of ossiﬁcation appear in the suture lines, and
many wormian bones may be seen. Abnormal develop-
ment of the temporal bone and eustachian tube may
lead to conductive or sensorineural hearing loss.
The gnathic and dental manifestations are distinc-
tive and may lead to the initial diagnosis. The patients
often have a narrow, high-arched palate, and there is
an increased prevalence of cleft palate. Prolonged
retention of deciduous teeth and delay or complete
failure of eruption of permanent teeth are characteris-
tic features. There may be abnormal spacing in
the mandibular incisor area because of widening of
the alveolar bone. On review of dental radiographs, the
most dramatic ﬁnding is the presence of numerous
unerupted permanent and supernumerary teeth, many
of which frequently exhibit distorted crown and root
shapes (Fig. 14-7). The number of supernumerary teeth
can be impressive, with reports of some patients dem-
onstrating more than 60 such teeth.
In addition to the dental alterations, review of
panoramic radiographs reveals an increased preva-
lence of a number of additional osseous malformations.
The mandible often demonstrates coarse trabeculation
with areas of increased density. The mandibular rami
are often narrow with nearly parallel-sided anterior
and posterior borders, and the coronoid processes may
be slender and pointed with a distal curvature. In some
cases the mandibular symphysis remains patent. The
Fig. 14-6 Cleidocranial dysplasia. Patient can almost
approximate her shoulders in front of her chest. (Courtesy of Dr.
William Bruce.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 619
maxilla often is associated with a thin zygomatic arch
and small or absent maxillary sinuses.
Although young patients typically exhibit a relatively
normal jaw relationship, as the individuals age, a short
lower face height, acute gonial angle, anterior inclina-
tion of the mandible, and mandibular prognathism
develop. Clinicians believe that these changes may be
from inadequate vertical growth of the maxilla and
hypoplastic alveolar ridge development caused by
delay or lack of eruption of the permanent teeth.
Computed tomography (CT) studies have demon-
strated a decreased thickness of the masseter muscle
in some patients. This ﬁnding may be related to hypo-
plasia of the zygomatic arch resulting in hypofunction
of the attached masseter muscle.
HISTOPATHOLOGIC FEATURES
The reason for failure of permanent tooth eruption in
patients with cleidocranial dysplasia is not understood
well. Microscopic studies of unerupted permanent
teeth have shown that these teeth lack secondary
cementum. However, a recent histomorphometric
study demonstrated no statistically signiﬁcant differ-
ence in the percentage of root surface covered by
cementum between teeth extracted from a patient with
cleidocranial dysplasia and teeth from control patients.
Some investigators alternatively have proposed that
insufﬁcient alveolar bone resorption is the reason for
impaired tooth eruption; this theory is based on obser-
vations of decreased osteoclasts in the alveolar bone of
heterozygous CBFA1 knockout mice.
TREATMENT AND PROGNOSIS
No treatment exists for the skull, clavicular, and other
bone anomalies associated with cleidocranial dyspla-
sia. Most patients function well without any signiﬁcant
problems. It is not unusual for an affected individual to
be unaware of the disease until some professional calls
it to his or her attention.
Treatment of the dental problems associated with
the disease, however, may be a major problem. Thera-
peutic options include full-mouth extractions with
denture construction, autotransplantation of selected
impacted teeth followed by prosthetic restoration, or
removal of primary and supernumerary teeth followed
by exposure of permanent teeth that are subsequently
extruded orthodontically. The latter mode of therapy
appears to be the treatment of choice; if performed
before adulthood, then it can prevent the short lower
face height and mandibular prognathism.
FOCAL OSTEOPOROTIC
MARROW DEFECT
The focal osteoporotic marrow defect is an area of
hematopoietic marrow that is sufﬁcient in size to
produce an area of radiolucency that may be confused
with an intraosseous neoplasm. The area does not
Fig. 14-7 Cleidocranial dysplasia. Panoramic radiograph showing multiple unerupted teeth.
(Courtesy of Dr. John R. Cramer.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

620 ORAL AND MAXILLOFACIAL PATHOLOGY
represent a pathologic process, but its radiographic fea-
tures may be confused with a variety of pathoses. The
pathogenesis of this condition is unknown. Various
theories include the following:
● Aberrant bone regeneration after tooth extrac-
tion
●Persistence of fetal marrow
● Marrow hyperplasia in response to increased
demand for erythrocytes
CLINICAL AND RADIOGRAPHIC
FEATURES
The focal osteoporotic marrow defect is typically
asymptomatic and detected as an incidental ﬁnding on
a radiographic examination. The area appears as a
radiolucent lesion, varying in size from several milli-
meters to several centimeters in diameter. In many
instances, when discovered in panoramic radiographs,
the area appears radiolucent and somewhat circum-
scribed; however, on review of more highly detailed
periapical radiographs, the defect typically exhibits
ill-deﬁned borders and ﬁne central trabeculations
(Fig. 14-8). More than 75% of all cases are discovered
in adult women. About 70% occur in the posterior man-
dible, most often in edentulous areas. No expansion of
the jaw is noted clinically.
HISTOPATHOLOGIC FEATURES
Microscopically, the defects contain cellular hemato-
poietic and/or fatty marrow. Lymphoid aggregates may
be present. Bone trabeculae included in the biopsy
specimen show no evidence of abnormal osteoblastic
or osteoclastic activity (Fig. 14-9).
TREATMENT AND PROGNOSIS
The radiographic ﬁndings, although often suggestive of
the diagnosis, are not speciﬁc and may simulate those
of a variety of other diseases. Incisional biopsy, there-
fore, often is necessary to establish the diagnosis.
Once the diagnosis is established, no further treat-
ment is needed. The prognosis is excellent, and no
association between focal osteoporotic marrow defects
and anemia or other hematologic disorders has been
established.
IDIOPATHIC OSTEOSCLEROSIS
Idiopathic osteosclerosis refers to a focal area of
increased radiodensity that is of unknown cause and
cannot be attributed to any inﬂammatory, dysplastic,
neoplastic, or systemic disorder. Idiopathic osteoscle-
rosis also has been termed dense bone island, bone eburna-
tion, bone whorl, bone scar, enostosis, and focal periapical
osteopetrosis. These sclerotic areas are not restricted to
the jaws, and radiographically similar lesions may be
found in other bones.
Similar radiopaque foci may develop in the periapi-
cal areas of teeth with nonvital or signiﬁcantly inﬂamed
pulps; these lesions most likely represent a response to
a low-grade inﬂammatory stimulus. Such reactive foci
should be designated as condensing osteitis or focal
chronic sclerosing osteomyelitis (see page 147) and
should not be included under the designation of idio-
Fig. 14-8 Focal osteoporotic marrow defect.
Circumscribed radiolucency with central trabeculations in the
extraction site of a mandibular molar. (Courtesy of Dr. R. Sidney
Jones.)
Fig. 14-9 Focal osteoporotic marrow defect.
Photomicrograph showing normal hematopoietic bone
marrow. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 621
pathic osteosclerosis. Because past studies did not distin-
guish the idiopathic lesions from those of inﬂammatory
origin, confusion in terminology has resulted.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although previous studies often are difﬁcult to inter-
pret because of differences in diagnostic criteria, the
prevalence appears to be approximately 5%, with some
investigators suggesting a slightly increased frequency
in blacks and Asians. No signiﬁcant sex predilection is
seen.
On review of several studies with long-term follow-
up, a pattern has emerged. Although exceptions can be
seen, most areas of idiopathic osteosclerosis arise in
the late ﬁrst or early second decade. Once noted, the
lesions may remain static, but many reveal a slow
increase in size. In almost all cases, once the patient
reaches full maturity, all enlargement ceases and the
sclerotic area stabilizes. In a smaller percentage, the
lesion diminishes or undergoes complete regression.
The peak prevalence of osteosclerosis occurs in the
third decade, with the attainment of peak bone mass
seen in the fourth decade.
Idiopathic osteosclerosis is invariably asymptom-
atic, not associated with detectable cortical expansion,
and is typically detected during a routine radiographic
examination. About 90% of examples are seen in the
mandible, most often in the ﬁrst molar area. The second
premolar and second molar areas also are common
sites. In most cases, only one focus of sclerotic bone is
present. A small number of patients have two or even
three separate areas of involvement. For patients with
multiple areas of involvement, the possibility of multi-
ple osteomas within the setting of Gardner syndrome
(see page 651) should be excluded.
Radiographically, the lesions are characterized by a
well-deﬁned, rounded, or elliptic radiodense mass.
Although the majority is uniformly radiopaque, occa-
sional large lesions demonstrate a nonhomogeneous
mixture of increased and reduced radiopacity. This
is most likely because of variation in the three-
dimensional (3D) shape of the lesion and is unrelated
to differences in the mineral content of the mass. The
lesions vary from 3.0 mm to more than 2.0 cm in great-
est extent. A radiolucent rim does not surround the
radiodense area. Most examples of idiopathic osteo-
sclerosis are associated with a root apex. In a lesser
number of cases, the sclerotic area may extend into or
be located only in the interradicular area (Fig. 14-10).
In about 20% of cases, the sclerotic area is located in
the jaw, with no apparent relationship to a tooth. Rarely,
the sclerotic bone may surround all or portions of an
impacted tooth. Root resorption and movement of
teeth have been noted but are uncommon.
HISTOPATHOLOGIC FEATURES
In the few microscopic studies that have been reported,
the lesion consists of dense lamellar bone with scant
ﬁbrofatty marrow. Inﬂammatory cells are inconspicu-
ous or absent.
DIAGNOSIS
Usually a diagnosis of idiopathic osteosclerosis may
be made with conﬁdence, based on history, clinical
features, and radiographic ﬁndings. Biopsy is consid-
A B
Fig. 14-10 Idiopathic osteosclerosis. A, An asymptomatic area of bone sclerosis is seen
between and apical to the roots of the ﬁrst and second mandibular molars. B, No appreciable
change can be seen on this radiograph taken 10 years later. (Courtesy of Dr. Michael Quinn.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

622 ORAL AND MAXILLOFACIAL PATHOLOGY
ered only if associated symptoms or signiﬁcant cortical
expansion is present. Although idiopathic osteosclero-
sis demonstrates radiographic and histopathologic
similarities with a compact osteoma (see page 650), the
lack of cortical expansion and failure of continued
growth rule against a neoplastic process. Differentia-
tion from condensing osteitis may be difﬁcult; however,
in the absence of a deep restoration or caries, a periapi-
cal radiodense area associated with a vital tooth is
likely to represent idiopathic osteosclerosis.
TREATMENT AND PROGNOSIS
If the lesion is discovered during adolescence, periodic
radiographs appear prudent until the area stabilizes.
After that point, no treatment is indicated for idiopathic
osteosclerosis, because there is little or no tendency for
the lesions to progress or change in adulthood.
MASSIVE OSTEOLYSIS (GORHAM
DISEASE; GORHAM-STOUT
SYNDROME; VANISHING BONE
DISEASE; PHANTOM BONE DISEASE)
Massive osteolysis is a rare disease that is char-
acterized by spontaneous and usually progressive
destruction of one or more bones. The destroyed bone
initially is replaced by a vascular proliferation. The
affected area does not regenerate or repair itself; even-
tually, the site of destruction ﬁlls with dense ﬁbrous
tissue.
The cause of massive osteolysis is unknown. There
is no evidence of any underlying metabolic or endo-
crine imbalance. Hyperactivity of osteoclasts initially
was proposed to be the major pathogenetic mechanism
underlying this disease. However, many investigators
also believe that massive osteolysis is primarily related
to a proliferation of blood or lymphatic vessels that is
occasionally multicentric and has been termed angio-
matosis of bone.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although massive osteolysis has been documented in
patients up to 70 years of age, most affected patients
are children and young adults. About 50% of all patients
report an episode of trauma before the diagnosis, but
this is often trivial in nature. Lesions have occurred in
almost any bone or combination of bones. The most
commonly involved sites are the pelvis, humeral head,
humeral shaft, and axial skeleton. Generally, the results
of laboratory studies are completely within normal
limits.
In approximately 30% of affected patients, maxillo-
facial involvement is noted, with the mandible being
affected most frequently. Simultaneous involvement of
the maxilla and mandible may occur. Signs and symp-
toms include mobile teeth, pain, malocclusion, devia-
tion of the mandible, and clinically obvious deformity.
Obstructive sleep apnea syndrome has been noted
secondary to posterior mandibular displacement
after extensive osteolysis. Pathologic fracture of the
mandible may occur. Temporomandibular joint (TMJ)
involvement may be confused with other conditions
that can cause TMJ dysfunction.
Radiographically, the earliest changes consist of
intramedullary radiolucent foci of varying size with
indistinct margins (Fig. 14-11). These coalesce to
become larger and involve the cortical bone. Eventu-
ally, large portions of the involved bone disappear
(Fig. 14-12). As the process proceeds, newly involved
areas often demonstrate loss of the lamina dura and
thinning of the cortical plates before development of
obvious radiolucency. In some cases the bone destruc-
tion may mimic periodontitis or periapical inﬂamma-
tory disease.
HISTOPATHOLOGIC FEATURES
The microscopic ﬁndings in massive osteolysis contrast
sharply with the striking clinical and radiographic ﬁnd-
ings. In the early stages of disease, specimens removed
from the radiolucent defects consist of a nonspeciﬁc
vascular proliferation intermixed with ﬁbrous connec-
tive and a chronic inﬂammatory inﬁltrate of lympho-
cytes and plasma cells. The vascular proliferation varies
in intensity and is characterized by thin-walled chan-
nels that may be capillary or cavernous in nature
Fig. 14-11 Massive osteolysis. Periapical radiograph
showing an ill-deﬁned radiolucency associated with vital
mandibular teeth. Note the loss of lamina dura. (Courtesy of Dr.
John R. Cramer.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 623
(Fig. 14-13). Osteoclastic reaction in the adjacent bone
fragments is usually not conspicuous.
In the later stages, tissue from the area of bone loss
is more collagenized. Evidence of repair by new bone
formation is not seen.
TREATMENT AND PROGNOSIS
The clinical course of massive osteolysis is variable and
impossible to predict. In most cases, bone destruction
progresses over months to a few years and results in
the total loss of the affected bone or bones. Some
patients, however, experience a spontaneous arrest of
the process without complete loss of the affected bone.
The prognosis varies from slight to severe disability.
Mortality from massive osteolysis is relatively uncom-
mon and usually the result of severe chest cage involve-
ment or destruction of vertebral bodies with spinal
cord compression.
Treatment is not particularly satisfactory. Previous
reported therapies include estrogens, magnesium,
calcium, vitamin D, ﬂuoride, calcitonin, alpha-2b inter-
feron, and chemotherapeutic agents (e.g., cisplatin,
actinomycin D, etoposide). Surgical intervention has
met with limited success. When surgical removal is
combined with bone grafting, the newly placed bone
often undergoes osteolysis. Radiation therapy is the
most successful and widely accepted mode of therapy,
but failures may occur. In addition, this therapy places
the patient at risk for postirradiation sarcoma. In a
limited number of patients, stabilization of disease
after bisphosphonate therapy has been reported,
although longer-term studies on a greater number of
patients are needed to assess this proposed treatment
modality. The effectiveness of any therapeutic inter-
vention is difﬁcult to evaluate, not only because the
disease is so rare but also because the condition may
arrest spontaneously in some patients.
PAGET’S DISEASE OF BONE
(OSTEITIS DEFORMANS)
Paget’s disease of bone is a condition characterized
by abnormal and anarchic resorption and deposition
of bone, resulting in distortion and weakening of the
affected bones. The cause of Paget’s disease is unknown,
but inﬂammatory, genetic, and endocrine factors may
be contributing agents. In some studies, 15% to 40% of
affected patients have a positive family history of the
Fig. 14-12 Massive osteolysis. Panoramic radiograph of the same patient shown in
Fig. 14-11, showing extensive bone loss and a pathologic fracture of the left mandible. This
destruction occurred over an 8-month period. (Courtesy of Dr. John R. Cramer.)
Fig. 14-13 Massive osteolysis. Biopsy specimen from the
same patient shown in Figs. 14-11 and 14-12. The loose,
highly vascular connective tissue shows a diffuse chronic
inﬂammatory cell inﬁltrate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

624 ORAL AND MAXILLOFACIAL PATHOLOGY
disease. In recent years, recurrent mutations in the
sequestosome 1 gene (SQSTM1) (also known as p62),
which participates in the regulation of osteoclastic
activity via the nuclear factor-κB (NF-κB) transcription
activation pathway, have been identiﬁed in both
familial and sporadic cases of the disease. Mutations in
another gene involved in the NF-κB signaling pathway,
the valosin-containing protein (VCP) gene, have been
found in patients with a rare hereditary syndrome that
includes Paget’s disease of bone, inclusion body myop-
athy, and frontotemporal dementia. In addition, the
possibility that Paget’s disease is the result of a slow
virus infection has received considerable attention, but
a viral cause remains unproven. Inclusion bodies iden-
tiﬁed as nucleocapsids from a paramyxovirus have
been detected in osteoclasts in patients with Paget’s
disease, but a cause-and-effect relationship has not
been established.
CLINICAL AND RADIOGRAPHIC
FEATURES
Paget’s disease is relatively common, although there is
a marked geographic variance in its prevalence. It is
more common in Britain than in the United States,
whereas it is rare in Africa and Asia. The disease prin-
cipally affects older adults and is rarely encountered in
patients younger than 40 years of age. Men are affected
more often than women, and whites are affected more
frequently than blacks. Reviews have estimated that 1
in 100 to 150 individuals older than 45 years of age
have Paget’s disease. Subclinical disease is not rare,
and an increased number of cases are being seen as the
population ages. Asymptomatic disease often is discov-
ered in radiographs taken for unrelated reasons or
from an unexpected elevation in serum alkaline phos-
phatase. The frequency increases with age, and the
true prevalence (including undiscovered subclinical
disease) probably ranges from 1% in the ﬁfth decade to
10% in the tenth decade.
Although the disease may be monostotic (i.e.,
limited to one bone), most cases of Paget’s disease are
polyostotic (i.e., more than one bone is affected).
Symptoms vary, and some patients may remain rela-
tively asymptomatic. Bone pain, which may be quite
severe, is a common complaint. In addition, pagetic
bone often forms near joints and promotes osteoar-
thritic changes, with associated joint pain and limited
mobility.
The lumbar vertebrae, pelvis, skull, and femur are
the most commonly affected bones. Affected bones
become thickened, enlarged, and weakened. Involve-
ment of weight-bearing bones often leads to a bowing
deformity, resulting in what is described as a simian
(monkeylike) stance. Paget’s disease affecting the skull
generally leads to a progressive increase in the circum-
ference of the head.
Jaw involvement is present in approximately 17%
of patients diagnosed with Paget’s disease. Maxillary
disease, which is far more common than mandibular
involvement, results in enlargement of the middle
third of the face. In extreme cases, the alteration results
in a lionlike facial deformity (leontiasis ossea). Nasal
obstruction, enlarged turbinates, obliterated sinuses,
and deviated septum may develop secondary to maxil-
lary involvement. The alveolar ridges tend to remain
symmetrical but become grossly enlarged. If the patient
is dentulous, then the enlargement causes spacing of
the teeth. Edentulous patients may complain that their
dentures no longer ﬁt because of the increased alveolar
size.
Radiographically, the early stages of Paget’s disease
reveal a decreased radiodensity of the bone and altera-
tion of the trabecular pattern. Particularly in the skull,
large circumscribed areas of radiolucency may be
present (osteoporosis circumscripta). During the
osteoblastic phase of the disease, patchy areas of scle-
rotic bone are formed, which tend to become conﬂu-
ent. The patchy sclerotic areas often are described as
having a “cotton wool” appearance (Figs. 14-14 and
14-15). On radiographic examination, the teeth often
demonstrate extensive hypercementosis.
On initial discovery of Paget’s disease, bone scintig-
raphy should be performed to evaluate fully the extent
of involvement. When the mandible is affected, the
bone scan may demonstrate marked uptake through-
out the entire mandible from condyle to condyle, a
feature that has been termed black beard or Lincoln’s
sign.
Radiographic ﬁndings of Paget’s disease may resem-
ble those of cemento-osseous dysplasia (see page 640).
Fig. 14-14 Paget’s disease. Lateral skull ﬁlm shows
marked enlargement of the cranium with new bone
formation above the outer table of the skull and a patchy,
dense, “cotton wool” appearance. (Courtesy of Dr. Reg Munden.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 625
Patients with presumed cemento-osseous dysplasia
who demonstrate clinical expansion of the jaws should
be evaluated further to rule out Paget’s disease.
HISTOPATHOLOGIC FEATURES
Microscopic examination shows an apparent uncon-
trolled alternating resorption and formation of bone. In
the active resorptive stages, numerous osteoclasts sur-
round bone trabeculae and show evidence of resorp-
tive activity. Simultaneously, osteoblastic activity is
seen with formation of osteoid rims around bone tra-
beculae. A highly vascular ﬁbrous connective tissue
replaces the marrow. A characteristic microscopic
feature is the presence of basophilic reversal lines in
the bone. These lines indicate the junction between
alternating resorptive and formative phases of the bone
and result in a “jigsaw puzzle,” or “mosaic,” appearance
of the bone (Fig. 14-16). In the less active phases, large
masses of dense bone showing prominent reversal
lines are present.
DIAGNOSIS
Patients with Paget’s disease show high elevations in
serum alkaline phosphatase levels but usually have
normal blood calcium and phosphorus levels. Although
serum bone-speciﬁc alkaline phosphatase is consid-
ered the most sensitive marker of bone formation, it
is not widely available; thus total serum alkaline phos-
phatase is typically used in routine clinical practice.
However, because serum alkaline phosphatase also
may be elevated in other conditions, such as cholelithia-
sis, other laboratory studies are indicated to conﬁrm
the diagnosis. Urinary hydroxyproline levels often are
markedly elevated, although it is recognized that
hydroxyproline often breaks down before excretion,
making it a less precise method for measurement of
bone resorption. Newer and more sensitive markers of
bone resorption are N-telopeptides, C-telopeptides, and
pyridinoline cross-link assays. The clinical and radio-
graphic features, combined with supportive laboratory
ﬁndings, are typically sufﬁcient for diagnosis. Histo-
pathologic examination can be conﬁrmatory but often
is unnecessary for a strong presumptive diagnosis.
TREATMENT AND PROGNOSIS
Although Paget’s disease is chronic and slowly progres-
sive, it is seldom the cause of death. In patients with
more limited involvement and no symptoms, treat-
ment often is not required. In asymptomatic patients,
systemic therapy is usually not initiated unless the
alkaline phosphatase is more than 25% to 50%
above normal. When symptomatic, bone pain is noted
most frequently and often may be controlled by acet-
aminophen or nonsteroidal antiinﬂammatory drugs
(NSAIDs). Neurologic complications, such as deafness
or visual disturbances, may result from bony encro-
achment on cranial nerves passing through skull
foramina.
Pharmacologic antiresorptive therapy is recom-
mended for patients with the following signs or
symptoms: considerable bone pain, headache related
to skull involvement, deafness or visual disturbances
because of narrowing of the skull foramina, back pain
because of pagetic radiculopathy or arthropathy, bone
fractures, and hypercalcemia resulting from immobili-
zation. Use of parathyroid hormone (PTH) antagonists,
such as calcitonin and bisphosphonates, can reduce
bone turnover and improve the biochemical abnor-
malities. For several decades, the mainstays of therapy
were calcitonin and the bisphosphonate etidronate.
However, these agents have been largely supplanted by
Fig. 14-15 Paget’s disease. Periapical ﬁlm showing the
“cotton wool” appearance of the bone.
Fig. 14-16 Paget’s disease. Prominent osteoblastic and
osteoclastic activity surround the bone trabeculae. Note the
resting and reversal lines. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

626 ORAL AND MAXILLOFACIAL PATHOLOGY
the newer bisphosphonates, alendronate and risedro-
nate, which provide enhanced control of bone turn-
over. Bisphosphonates are typically administered orally
for a period of 2 to 6 months. Intravenous pamidronate
can be an alternative for those patients who cannot
tolerate oral bisphosphonates because of gastrointesti-
nal irritation or who require treatment before surgery
in an area of pagetic bone. A recently reported regimen
of notable efﬁcacy is single-infusion therapy with the
potent bisphosphonate, zoledronic acid. In mild cases,
a single infusion of a bisphosphonate often is associated
with yearlong remissions. Patients with more severe
disease usually require higher doses or more frequent
courses of a particular bisphosphonate. The goal of
therapy is to achieve midrange normal levels of serum
alkaline phosphatase, with retreatment occurring when
values rise 25% higher than normal. Plicamycin, a cyto-
toxic antibiotic, is known to inhibit osteoclastic activity,
but its use is restricted to patients with severe disease
that is refractory to calcitonin and bisphosphonate
medications.
Case reports of osteonecrosis of the jaw as a compli-
cation of bisphosphonate therapy for Paget’s disease of
bone have raised some safety concerns. Long-term
data are needed to fully assess the potential risks and
beneﬁts of bisphosphonate therapy; thus the merits
of aggressive preventive or prolonged maintenance
therapy remain uncertain at this time.
Edentulous patients may require new and larger
dentures periodically to compensate for progressive
enlargement of the alveolar processes. Dental com-
plications include difﬁculties in extraction of teeth
exhibiting signiﬁcant hypercementosis. During active
disease, pagetoid bone is extremely vascular with
multiple arteriovenous shunts. Oral surgical proce-
dures during this time can result in extensive hemor-
rhage. During the later sclerotic phase, the bone is
hypersensitive to inﬂammation and can develop osteo-
myelitis with minimal provocation. In one recent
report, long-term correction of maxillary deformity
was achieved by removal, reshaping, and reinsertion
of the maxillomalar complex in a patient who had
received no prior medical treatment for his disease.
Development of a malignant bone tumor, usually an
osteosarcoma, is a recognized complication of Paget’s
disease. Osteosarcoma in adults older than 40 years is
quite uncommon in individuals who do not have
Paget’s disease. The frequency of bone sarcoma com-
plicating Paget’s disease ranges from 0.9% to 13.0% in
various studies. The true frequency is probably in the
range of 1% or less. Most of the osteosarcomas develop
in the pelvis and long bones of the lower extremities.
The skull and jaws are very rare sites for sarcomas
associated with Paget’s disease. Clinical signs and
symptoms that should raise suspicion of possible under-
lying malignancy include the development of constant
and worsening bone pain, a new mass, or sudden frac-
ture. Osteosarcoma in Paget’s disease is very aggressive
and associated with a poor prognosis. Although sur-
vival rates generally have improved over the last several
decades for patients with nonpagetoid osteosarcoma,
no signiﬁcant improvement in survival has been
observed among patients with Paget’s-related osteosar-
coma. Benign and malignant giant cell tumors (see
page 629) also may develop in bones affected by
Paget’s disease. Most of these occur in the craniofacial
skeleton.
CENTRAL GIANT CELL GRANULOMA
(GIANT CELL LESION; GIANT
CELL TUMOR)
The giant cell granuloma is considered widely to be
a nonneoplastic lesion. Although formerly designated
as giant cell reparative granuloma, there is little evidence
that the lesion represents a reparative response. Some
lesions demonstrate aggressive behavior similar to that
of a neoplasm. Most oral and maxillofacial pathologists
have dropped the term reparative; today, these lesions
are designated as giant cell granuloma or by the more
noncommittal term, giant cell lesion. Whether or not
true giant cell tumors occur in the jaws is uncertain
and controversial. (This topic is discussed later in the
chapter.) Likewise, it is not certain whether some
reported cases of extragnathic giant cell granulomas
actually represent true giant cell tumors.
CLINICAL AND RADIOGRAPHIC
FEATURES
Giant cell granulomas may be encountered in patients
ranging from 2 to 80 years of age, although more than
60% of all cases occur before age 30. Although the sex
ratio varies in different reviews, a majority of giant cell
granulomas are noted in females, and approximately
70% arise in the mandible. Lesions are more common
in the anterior portions of the jaws, and mandibular
lesions frequently cross the midline.
Most giant cell granulomas of the jaws are asymp-
tomatic and ﬁrst come to attention during a routine
radiographic examination or as a result of painless
expansion of the affected bone. A minority of cases,
however, may be associated with pain, paresthesia, or
perforation of the cortical bone plate, occasionally
resulting in ulceration of the mucosal surface by the
underlying lesion (Fig. 14-17).
Based on the clinical and radiographic features,
several groups of investigators have suggested that
central giant cell lesions of the jaws may be divided
into two categories: `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 627
1.Nonaggressive lesions make up most cases,
exhibit few or no symptoms, demonstrate slow
growth, and do not show cortical perforation or
root resorption of teeth involved in the lesion.
2.Aggressive lesions are characterized by pain,
rapid growth, cortical perforation, and root
resorption. They show a marked tendency to
recur after treatment, compared with the non-
aggressive types.
Radiographically, central giant cell lesions appear
as radiolucent defects, which may be unilocular or
multilocular. The defect is usually well delineated, but
the margins are generally noncorticated. The lesion
may vary from an incidental radiographic ﬁnding of
5 × 5 mm to a destructive lesion greater than 10 cm in
size (Fig. 14-18). The radiographic ﬁndings are not spe-
ciﬁcally diagnostic. Small unilocular lesions may be
confused with periapical granulomas or cysts (Fig.
14-19). Multilocular giant cell lesions cannot be distin-
guished radiographically from ameloblastomas or
other multilocular lesions.
Areas histopathologically identical to giant cell gran-
uloma have been noted in aneurysmal bone cysts (see
page 634) and intermixed with central odontogenic
ﬁbromas (see page 727). Because giant cell granulo-
mas are also histopathologically identical to brown
tumors, hyperparathyroidism (see page 838) should
A B
Fig. 14-17 Central giant cell granuloma. A, A blue-purple mass is present on the anterior
alveolar ridge of this 4-year-old white boy. B, The occlusal radiograph shows a radiolucent
lesion with cortical expansion.
Fig. 14-18 Central giant cell granuloma. Panoramic
radiograph showing a large, expansile radiolucent lesion in
the anterior mandible. (Courtesy of Dr. Gregory R. Erena.)
Fig. 14-19 Central giant cell granuloma. The periapical
radiograph shows a radiolucent area involving the apex
of an endodontically treated tooth. This was considered
preoperatively to represent a periapical granuloma or
periapical cyst. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

628 ORAL AND MAXILLOFACIAL PATHOLOGY
be ruled out in all instances. In addition, multifocal
involvement in childhood suggests cherubism (see next
section) and warrants further investigation. Most giant
cell granulomas are single lesions; rarely, multifocal
involvement is seen in patients who demonstrate no
evidence of an associated disease, such as hyperpara-
thyroidism or cherubism.
HISTOPATHOLOGIC FEATURES
Giant cell lesions of the jaw show a variety of features.
Common to all is the presence of few to many multi-
nucleated giant cells in a background of ovoid to
spindle-shaped mesenchymal cells and round mono-
cyte-macrophages (Fig. 14-20). There is evidence that
these giant cells represent osteoclasts, although others
suggest the cells may be aligned more closely with
macrophages. The spindle-shaped cells appear to be
ﬁbroblast related. It has been proposed that the spindle
cell component is the proliferating cell population and
recruits monocyte-macrophage precursors, inducing
them to differentiate into osteoclastic giant cells by
activation of the receptor activator of the nuclear factor-
κB (RANK)/RANK ligand signaling pathway. The giant
cells may be aggregated focally in the lesional tissue or
may be present diffusely throughout the lesion. These
cells vary considerably in size and shape from case to
case. Some are small and irregular in shape and contain
only a few nuclei. In other cases, the giant cells are
large and round and contain 20 or more nuclei.
In some cases the stroma is loosely arranged and
edematous; in other cases it may be quite cellular.
Areas of erythrocyte extravasation and hemosiderin
deposition often are prominent. Older lesions may
show considerable ﬁbrosis of the stroma. Foci of osteoid
and newly formed bone are occasionally present within
the lesion. Correlation of the histopathologic features
with clinical behavior remains debatable, but lesions
showing large, uniformly distributed giant cells and a
predominantly cellular stroma appear more likely to
be clinically aggressive with a greater tendency to recur
after surgical treatment.
TREATMENT AND PROGNOSIS
Central giant cell lesions of the jaws are usually treated
by thorough curettage. In reports of large series of
cases, recurrence rates range from 11% to 50% or
greater. Most studies indicate a recurrence rate of
about 15% to 20%. Those lesions considered on clinical
and radiologic grounds to be potentially aggressive
show a higher frequency of recurrence. Many investi-
gators have noted a propensity for recurrence among
lesions in younger patients. Recurrent lesions often
respond to further curettage, although some aggressive
lesions require more radical surgery for cure.
In patients with aggressive tumors, three alterna-
tives to surgery—(1) corticosteroids, (2) calcitonin, and
(3) interferon alfa-2a—are being investigated. Several
investigators have reported small numbers of patients,
some of which exhibited remarkable response to these
interventions. Weekly injections directly into the tumor
with triamcinolone acetonide for approximately 6
weeks have been used successfully. Calcitonin typically
is administered daily for approximately 12 months as
an intradermal injection or nasal spray. Several cases
of large lesions resolving with systemic administration
of salmon calcitonin have been reported, although a
recent randomized, double-blind, controlled clinical
trial performed on a limited number of patients found
no signiﬁcant difference between the calcitonin-treated
and placebo patient groups. Interferon alfa-2a, alone or
in combination with surgery, also has been reported to
result in resolution of large lesions. The response of
central giant cell lesions to interferon alfa-2a has been
proposed to be the result of this drug’s antiangiogenic
properties, although speculation about the vascular
nature of these lesions has not been proven. Clinicians
should be aware of the potential side effects of inter-
feron alfa-2a therapy, which can include ﬂulike symp-
toms (e.g., fever, malaise, nausea, joint pain, weakness)
and in rare cases more serious complications, includ-
ing pancreatitis and drug-induced lupus erythemato-
sus. The previously discussed medical therapeutic
approaches provide possible alternatives for large
lesions that if treated surgically would result in signiﬁ-
cant deformity. Evaluation of greater numbers of
patients with appropriate controls is necessary to
compare these therapeutic approaches to surgery
adequately.
Fig. 14-20 Central giant cell granuloma. Numerous
multinucleated giant cells within a background of plump
proliferating mesenchymal cells. Note extensive red blood
cell extravasation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 629
In spite of the reported recurrence rate, the long-
term prognosis of giant cell granulomas is good and
metastases do not develop.
GIANT CELL TUMOR
The question of whether true giant cell tumors, which
most often occur in the epiphyses of long tubular bones,
occur in the jaws has been argued for many years and
still is unresolved. Although most central giant cell
lesions can be distinguished histopathologically from
the long bone tumors, a number of jaw lesions are
indistinguishable microscopically from the typical
giant cell tumor of long bone (Fig. 14-21). Despite the
histopathologic similarity, these jaw lesions appear to
have a biologically different behavior from long bone
lesions, which have higher recurrence rates after curet-
tage and show malignant change in up to 10% of cases.
One case of metastasis from a mandibular tumor,
however, has been reported. It has been suggested that
giant cell granulomas of the jaws and giant cell tumors
of the extragnathic skeleton are not distinct and sepa-
rate entities; rather, they represent a continuum of a
single disease process modiﬁed by the age of the
patients, the locations of the lesions, and possibly other
factors that are not yet understood.
CHERUBISM
Cherubism is a rare developmental jaw condition that
is generally inherited as an autosomal dominant trait
with high penetrance but variable expressivity. Several
investigators have reported a higher disease penetrance
in males than in females. Sporadic cases also can occur
and are thought to represent spontaneous mutations.
In two reports published simultaneously by laborato-
ries on different continents, the gene for cherubism
was mapped to chromosome 4p16. Mutations subse-
quently were identiﬁed in the SH3BP2 gene within this
locus. The protein encoded by this gene is believed
to function in signal transduction pathways and to
increase the activity of osteoclasts and osteoblasts
during normal tooth eruption. It has been suggested
that mutations in the SH3BP2 gene may lead to patho-
logic activation of osteoclasts and disruption of jaw
morphogenesis. However, the molecular pathogenesis
of cherubism remains poorly understood.
The name cherubism was applied to this condition
because the facial appearance is similar to that of the
plump-cheeked little angels (cherubs) depicted in
Renaissance paintings. Although cherubism also has
been called familial ﬁbrous dysplasia, this term should be
avoided because cherubism has no relationship to
ﬁbrous dysplasia of bone (see page 635).
CLINICAL AND RADIOGRAPHIC
FEATURES
Although some examples of cherubism may develop as
early as 1 year of age, the disease usually occurs
between the ages of 2 and 5 years. In mild cases the
diagnosis may not be made until the patient reaches
10 to 12 years of age. The clinical alterations typically
progress until puberty, then stabilize and slowly
regress.
The cherublike facies arises from bilateral in-
volvement of the posterior mandible that produces
angelic chubby cheeks (Fig. 14-22). In addition, there
is an “eyes upturned to heaven” appearance that is
due to a wide rim of exposed sclerae noted below
the iris. This latter feature is due to involvement of
the infraorbital rim and orbital ﬂoor that tilts the eye-
balls upward, as well as to stretching of the upper
facial skin that pulls the lower lid downward. On occa-
sion, affected patients also reveal marked cervical
lymphadenopathy.
The mandibular lesions typically appear as a pain-
less, bilateral expansion of the posterior mandible that
tends to involve the angles and ascending rami. The
bony expansion is usually bilaterally symmetrical; in
severe cases, most of the mandible is involved. Milder
maxillary involvement occurs in the tuberosity areas;
in severe cases, the entire maxilla can be affected.
Extensive bone involvement causes a marked wid-
ening and distortion of the alveolar ridges. In addition
to the aesthetic and psychologic effect, the enlarge-
ments may cause tooth displacement or failure of erup-
tion, impair mastication, create speech difﬁculties, or
Fig. 14-21 Giant cell tumor. This photomicrograph
shows large giant cells that are distributed in a cellular
mesenchymal tissue. This specimen was from an aggressive
lesion that had destroyed most of the maxilla. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

630 ORAL AND MAXILLOFACIAL PATHOLOGY
rarely lead to loss of normal vision or hearing. Although
there have been rare reports of unilateral cherubism,
it is difﬁcult to accept these as examples of this disease
unless there is a strong family history.
Radiographically, the lesions are typically multiloc-
ular, expansile radiolucencies (Fig. 14-23). The appear-
ance is virtually diagnostic as a result of their bilateral
location. Less commonly, the lesions appear as unilocu-
lar radiolucencies. Although cherubism typically
involves only the jaws, involvement also has been
reported rarely in other bones such as the ribs and
humerus.
No unusual biochemical ﬁndings have been reported
in patients with cherubism. If laboratory results do not
suggest the diagnosis of hyperparathyroidism, then
most children with multiple symmetrical giant cell
granulomas represent examples of cherubism.
However, multiple giant cell lesions may be seen in
association with other conditions, including Ramon
syndrome, Jaffe-Campanacci syndrome, and a Noonan-
like syndrome. It has been suggested that the bony
lesions of cherubism represent a phenotypic picture
common to a number of disease processes that
arise from multiple, distinct, initiating pathogenetic
events.
HISTOPATHOLOGIC FEATURES
The microscopic ﬁndings of cherubism are essentially
similar to those of isolated giant cell granulomas, and
they seldom permit a speciﬁc diagnosis of cherubism
in the absence of clinical and radiologic information.
The lesional tissue consists of vascular ﬁbrous tissue
containing variable numbers of multinucleated giant
cells. The giant cells tend to be small and usually aggre-
gated focally (Fig. 14-24). Like the giant cells in central
giant cell granulomas, the giant cells in cherubism
express markers suggestive of osteoclastic origin. Foci
of extravasated blood are commonly present. The
stroma in cherubism often tends to be more loosely
arranged than that seen in giant cell granulomas. In
some cases, cherubism reveals eosinophilic, cufﬂike
deposits surrounding small blood vessels throughout
the lesion. The eosinophilic cufﬁng appears to be spe-
ciﬁc for cherubism. However, these deposits are not
present in many cases, and their absence does not
exclude a diagnosis of cherubism. In older, resolving
lesions of cherubism, the tissue becomes more ﬁbrous,
the number of giant cells decreases, and new bone
formation is seen.
TREATMENT AND PROGNOSIS
The prognosis in any given case is unpredictable. In
most instances the lesions tend to show varying degrees
of remission and involution after puberty (see Fig.
14-23). By the fourth decade, the facial features of most
patients approach normalcy. In spite of the typical sce-
nario, some patients demonstrate very mild alterations,
whereas others reveal grotesque changes that often are
very slow to resolve. In occasional patients, the defor-
mity can persist.
The question of whether to treat or simply observe
a patient with cherubism is difﬁcult. Excellent results
have been obtained in some cases by early surgical
intervention with curettage of the lesions. Conversely,
early surgical intervention sometimes has been fol-
lowed by rapid regrowth of the lesions and worsening
deformity. A course limited only to observation may
result in extreme and sometimes grotesque facial
deformity, with associated psychologic problems and
functional deformity that may necessitate extensive
surgery. Several investigators have suggested the use of
calcitonin in severe cases, but such therapy awaits
further study. Radiation therapy is contraindicated
because of the risk of development of postirradiation
sarcoma. The optimal therapy for cherubism has not
been determined.
Fig. 14-22 Cherubism. This young girl shows the typical
cherubic facies resulting from bilateral expansile mandibular
and maxillary lesions. (Courtesy of Dr. Román Carlos.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 631
SIMPLE BONE CYST (TRAUMATIC
BONE CYST; HEMORRHAGIC BONE
CYST; SOLITARY BONE CYST;
IDIOPATHIC BONE CAVITY)
The simple bone cyst is a benign, empty, or ﬂuid-
containing cavity within bone that is devoid of an epi-
thelial lining. The lesion is undoubtedly more common
in the jaws than the literature would indicate. The
cause and pathogenesis are uncertain and controver-
sial. Several theories have been proposed, but none of
them explains all of the clinical and pathologic features
of this disease.
The trauma-hemorrhage theory has many advo-
cates, as evidenced by the widely used designation
traumatic bone cyst. This theory suggests that trauma
to the bone that is insufﬁcient to cause a fracture results
in an intraosseous hematoma. If the hematoma does
not undergo organization and repair, it may liquefy and
result in a cystic defect. Some affected patients may
recall an episode of trauma to the affected area, but
this anecdotal information is of uncertain signiﬁcance
and has not been subjected to detailed, controlled
analysis.
Although the trauma-hemorrhage theory appears to
be accepted widely in the dental literature, it has little
support in the orthopedic literature to explain similar
cysts most commonly found in the metaphysis or
diaphysis of the proximal humerus and femur in young
patients. In addition, it cannot explain gnathic simple
bone cysts that have demonstrated progressive enlarge-
ment over several years and, on surgical investigation,
fail to reveal any evidence of continued hemorrhage.
Other etiologic theories include inability of interstitial
ﬂuid to exit the bone because of inadequate venous
drainage, local disturbance in bone growth, ischemic
marrow necrosis, and localized alteration in bone
metabolism resulting in osteolysis.
CLINICAL AND RADIOGRAPHIC
FEATURES
Simple bone cysts have been reported in almost every
bone of the body, but the vast majority involves the long
bones. Simple bone cysts within the jaws are common
A
B
Fig. 14-23 Cherubism. A, Panoramic radiograph of a 7-year-old white boy. Bilateral
multilocular radiolucencies can be seen in the posterior mandible. B, Same patient 6 years
later. The lesions in the mandibular rami demonstrate signiﬁcant resolution, but areas of
involvement are still present in the body of the mandible. (Courtesy of Dr. John R. Cramer.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

632 ORAL AND MAXILLOFACIAL PATHOLOGY
and most frequently encountered in patients between
10 and 20 years of age. The lesion is rare in children
younger than age 5 and is seldom seen in patients older
than age 35. Simple bone cysts of the jaws are essen-
tially restricted to the mandible, although there have
been reports of the lesion in the maxilla. Bilateral
simple bone cysts of the mandible are occasionally
encountered. About 60% of cases occur in males.
The simple bone cyst usually produces no symptoms
and is discovered only when radiographs are taken for
some other reason. About 20% of patients, however,
have a painless swelling of the affected area. Pain and
paresthesia may be noted in a few cases. Although any
area of the mandible may be involved, simple bone
cysts are more common in the premolar and molar
areas.
Radiographically, the lesion most frequently appears
as a well-delineated radiolucent defect. In some areas,
the margins of the defect are sharply deﬁned; in other
areas, the margins are ill deﬁned. The defect may range
from 1 to 10 cm in diameter. When several teeth are
involved in the lesion, the radiolucent defect often
shows domelike projections that scallop upward
between the roots. This feature is highly suggestive but
not diagnostic of a simple bone cyst (Figs. 14-25 and
14-26). In many cases, a cone-shaped outline (pointed
at one or both ends in the anterior-posterior direction)
may be noted, particularly when the lesion is large.
Oval, irregular, or rounded borders are possible as
well. Teeth that appear to be involved in the lesion are
generally vital and do not show root resorption.
A
B
Fig. 14-24 Cherubism. A, Photomicrograph showing
scattered giant cells within a background of cellular,
hemorrhagic mesenchymal tissue. B, High-power view
showing perivascular eosinophilic cufﬁng.
Fig. 14-25 Simple bone cyst. Periapical radiograph
showing a radiolucent area in the apical region of the
anterior mandible. The incisor teeth responded normally to
vitality testing, and no restorations are present.
Fig. 14-26 Simple bone cyst. Panoramic ﬁlm showing a
large simple bone cyst of the mandible in a 12-year-old girl.
The scalloping superior aspect of the cyst between the roots
of the teeth is highly suggestive of, but not diagnostic for, a
simple bone cyst. (Courtesy of Dr. Lon Doles.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 633
Although not characteristic, a simple bone cyst may
appear as a multilocular radiolucency associated with
cortical expansion and slow enlargement. When expan-
sion is present, an occlusal radiograph typically dem-
onstrates a thin shell of cortical bone that exhibits no
further reactive changes. Extensive lesions involving a
substantial portion of the body and ascending ramus
are occasionally encountered (Fig. 14-27).
Similar simple cysts may be associated with lesions
of cemento-osseous dysplasia and other ﬁbro-osseous
proliferations. These typically occur in older patients
and are discussed later (see page 643).
HISTOPATHOLOGIC FEATURES
The walls of the defect may be lined by a thin band of
vascular ﬁbrous connective tissue or demonstrate a
thickened myxoﬁbromatous proliferation that often is
intermixed with trabeculae of cellular and reactive
bone. This lining may exhibit areas of vascularity, ﬁbrin,
erythrocytes, and occasional giant cells adjacent to the
bone surface (Fig. 14-28). Stringy lacelike dystrophic
calciﬁcations occasionally are noted (Fig. 14-29). There
is never any evidence of an epithelial lining. The bony
surface next to the cavity often shows resorptive areas
(Howship’s lacunae) indicative of past osteoclastic
activity.
DIAGNOSIS
The radiographic features of the simple bone cyst,
although often suggestive of the diagnosis, are not
diagnostic and may be confused with a wide variety
of odontogenic and nonodontogenic radiolucent jaw
lesions. Surgical exploration is necessary to establish
the diagnosis.
Because little to no tissue often is obtained at the
time of surgery, the diagnosis of simple bone cyst
is primarily based on the clinical and radiographic
features, together with the surgical ﬁndings. In about
one third of cases, the lytic defect will be found to be
an empty cavity with smooth, shiny bony walls. In
about two thirds of cases, the cavity will contain small
amounts of serosanguineous ﬂuid. The mandibular
neurovascular bundle may be seen lying free in the
cavity.
TREATMENT AND PROGNOSIS
Although the treatment of simple bone cysts of the long
bones often is more aggressive and includes intrale-
sional steroid injections or thorough surgical curettage,
simple surgical exploration to establish the diagnosis is
Fig. 14-27 Simple bone cyst. Panoramic ﬁlm showing a
large multilocular simple bone cyst of the mandible in a
16-year-old white adolescent. (Courtesy of Dr. Amy Bogardus.)
Fig. 14-28 Simple bone cyst. Photomicrograph of the
bony wall of a simple bone cyst. A thin, vascular connective
tissue membrane is adjacent to the bone, and no epithelial
lining is identiﬁed.
Fig. 14-29 Simple bone cyst. Loose vascular connective
tissue exhibiting areas of basophilic lacelike calciﬁcation in
the wall of a simple bone cyst. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

634 ORAL AND MAXILLOFACIAL PATHOLOGY
usually sufﬁcient therapy for gnathic lesions. Even
though the bony walls of the cavity at surgical explora-
tion often appear smooth and shiny, it is wise to curette
them and submit the small amount of tissue obtained
for microscopic examination to rule out more serious
diseases. Rarely, on microscopic examination, a lesion
considered to be a simple bone cyst at surgical explora-
tion will prove to be a thin-walled lesion, such as an
odontogenic keratocyst or cystic ameloblastoma. When
a thickened myxoﬁbromatous wall is encountered,
curettage and submission of this material appears
prudent. After surgical exploration with or without
curettage of the bony walls, obliteration of the defect
by new bone formation is generally rapid. Even large
defects may show normal radiographic ﬁndings within
6 months after exploration. Recurrence or persistence
of the lesion is most unusual, but it has been reported.
Periodic radiographic examination should be contin-
ued until complete resolution has been conﬁrmed. The
prognosis is excellent, however.
ANEURYSMAL BONE CYST
Aneurysmal bone cyst is an intraosseous accumula-
tion of variable-sized, blood-ﬁlled spaces surrounded
by cellular ﬁbrous connective tissue that often is
admixed with trabeculae of reactive woven bone. The
cause and pathogenesis of the aneurysmal bone cyst
are poorly understood. Several investigators have pro-
posed that aneurysmal bone cyst arises from a trau-
matic event, vascular malformation, or neoplasm that
disrupts the normal osseous hemodynamics and leads
to an enlarging, hemorrhagic extravasation. As a corol-
lary of this theory, others have suggested that aneurys-
mal bone cyst and giant cell granuloma are closely
related. An aneurysmal bone cyst may form when an
area of hemorrhage maintains connection with the
disrupted feeding vessels; subsequently, giant cell
granuloma–like areas can develop after loss of connec-
tion with the original vascular source.
Some authors have presented large series of cases
involving the extragnathic skeleton and claim that
none of their cases has shown evidence of a preexisting
lesion. Others have reported similar large series and
contend that a preexisting lesion may be evident in one
third of cases. It is likely that the aneurysmal bone cyst
may occur either as a primary lesion or as a result of
disrupted vascular dynamics in a preexisting intrabony
lesion.
Cytogenetic analysis has demonstrated the presence
of various chromosomal abnormalities in some cases,
particularly those involving 17p11-13 and 16q22.
However, the signiﬁcance of these chromosomal
abnormalities in the molecular pathogenesis of the
aneurysmal bone cyst remains unclear.
CLINICAL AND RADIOGRAPHIC
FEATURES
Aneurysmal bone cysts are located most commonly in
the shaft of a long bone or in the vertebral column in
patients younger than age 30. Gnathic aneurysmal
bone cysts are uncommon, with approximately 2%
reported from the jaws. Within the jaws, a wide age
range is noted; however, most cases arise in children
and young adults, with an approximate mean age of 20
years. No signiﬁcant sex predilection is noted. A man-
dibular predominance is noted, and the vast majority
arises in the posterior segments of the jaws.
The most common clinical manifestation is a swell-
ing that has usually developed rapidly. Pain often is
reported; paresthesia, compressibility, and crepitus
are rarely seen. On occasion, malocclusion, mobility,
migration, or resorption of involved teeth may be
present. Maxillary lesions often bulge into the adjacent
sinus; nasal obstruction, nasal bleeding, proptosis, and
diplopia are noted uncommonly.
Radiographic study shows a unilocular or multilocu-
lar radiolucent lesion often associated with marked
cortical expansion and thinning (Fig. 14-30). The radio-
graphic borders are variable and may be well deﬁned
or diffuse. Frequently, a ballooning or “blow-out” dis-
tention of the contour of the affected bone is described.
Uncommonly, small radiopaque foci, thought to be
small trabeculae of reactive bone, are noted within the
radiolucency.
At the time of surgery, intact periosteum and a thin
shell of bone are typically found covering the lesion.
Cortical perforation may occur, but spread into the
adjacent soft tissue has not been documented. When
the periosteum and bony shell are removed, dark
venous blood frequently wells up and venouslike
Fig. 14-30 Aneurysmal bone cyst. A large radiolucent
lesion involves most of the ascending ramus in a 5-year-old
white boy. (Courtesy of Dr. Samuel McKenna.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 635
bleeding may be encountered. The appearance at
surgery has been likened to that of a “blood-soaked
sponge.”
HISTOPATHOLOGIC FEATURES
Microscopically, the aneurysmal bone cyst is charac-
terized by spaces of varying size, ﬁlled with unclotted
blood surrounded by cellular ﬁbroblastic tissue con-
taining multinucleated giant cells and trabeculae of
osteoid and woven bone. On occasion, the wall con-
tains an unusual lacelike pattern of calciﬁcation that is
uncommon in other intraosseous lesions. The blood-
ﬁlled spaces are not lined by endothelium (Fig. 14-31).
In approximately 20% of the cases, aneurysmal bone
cyst is associated with another pathosis, most com-
monly a ﬁbro-osseous lesion or giant cell granuloma.
TREATMENT AND PROGNOSIS
Aneurysmal bone cysts of the jaws are usually treated
by curettage or enucleation, sometimes supplemented
with cryosurgery. The vascularity of gnathic lesions is
typically low ﬂow, and removal of the bulk of the lesion
is usually sufﬁcient to control the bleeding. Rare cases
require more extensive surgical resection. In most
instances, the surgical defect heals within 6 months to
1 year and does not necessitate bone grafting. Irradia-
tion is contraindicated.
The reported recurrence rates are variable and have
been as low as 8% and as high as 60%. Most recurrent
examples arise from inadequate or subtotal removal on
initial therapy. On occasion, recurrence may be related
to incomplete removal of a coexisting lesion such as
an osteoblastoma or ossifying ﬁbroma. Overall, in
spite of recurrences, the long-term prognosis appears
favorable.
Fibro-Osseous Lesions
of the Jaws
Fibro-osseous lesions are a diverse group of processes
that are characterized by replacement of normal bone
by ﬁbrous tissue containing a newly formed mineral-
ized product. The designation ﬁbro-osseous lesion is not
a speciﬁc diagnosis and describes only a process. Fibro-
osseous lesions of the jaws include developmental
(hamartomatous) lesions, reactive or dysplastic pro-
cesses, and neoplasms.
The pathologic features on a biopsy specimen may
be very similar in lesions of diverse cause, behavior,
and prognosis. Clinical, radiographic, and histopatho-
logic correlation is usually most beneﬁcial in establish-
ing a speciﬁc diagnosis. Commonly included among
the ﬁbro-osseous lesions of the jaws are the following:
● Fibrous dysplasia
● Cemento-osseous dysplasia
●Focal cemento-osseous dysplasia
●Periapical cemento-osseous dysplasia
●Florid cemento-osseous dysplasia
● Ossifying ﬁbroma
Although these processes have been grouped under
the encompassing heading of benign ﬁbro-osseous
lesions, a more speciﬁc diagnosis often is critical
because the treatment of these pathoses varies from
none to surgical recontouring to complete removal.
Although many examples can be diagnosed from the
clinical and radiographic features, others require
knowledge of the histopathologic, clinical, and radio-
graphic features for an appropriate diagnosis.
FIBROUS DYSPLASIA
Fibrous dysplasia is a developmental tumorlike con-
dition that is characterized by replacement of normal
bone by an excessive proliferation of cellular ﬁbrous
connective tissue intermixed with irregular bony tra-
beculae. Although considerable confusion has existed
regarding the nature of ﬁbrous dysplasia, much has
been learned about the genetics of this group of disor-
ders, and this knowledge makes the wide variety of
clinical patterns more understandable.
Fibrous dysplasia is a sporadic condition that results
from a postzygotic mutation in the GNAS1 (guanine
nucleotide–binding protein, α-stimulating activity poly-
peptide 1) gene. Clinically, ﬁbrous dysplasia may mani-
fest as a localized process involving only one bone, as
Fig. 14-31 Aneurysmal bone cyst. Photomicrograph
showing a blood-ﬁlled space surrounded by ﬁbroblastic
connective tissue. Scattered multinucleated giant cells are
seen adjacent to the vascular space. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

636 ORAL AND MAXILLOFACIAL PATHOLOGY
a condition involving multiple bones, or as multiple
bone lesions in conjunction with cutaneous and endo-
crine abnormalities. The clinical severity of the condi-
tion presumably depends on the point in time during
fetal or postnatal life that the mutation of GNAS1
occurs.
If the mutation occurs in one of the undifferentiated
stem cells during early embryologic life, the osteoblasts,
melanocytes, and endocrine cells that represent the
progeny of that mutated cell all will carry that mutation
and express the mutated gene. The clinical presenta-
tion of multiple bone lesions, cutaneous pigmentation,
and endocrine disturbances would result. Skeletal pro-
genitor cells at later stages of embryonic development
are assumed to migrate and differentiate as part of the
process of normal skeletal formation. If the mutation
occurs during this later period, then the progeny of the
mutated cell will disperse and participate in the forma-
tion of the skeleton resulting in multiple bone lesions
of ﬁbrous dysplasia. Finally, if the mutation occurs
during postnatal life, then the progeny of that mutated
cell are essentially conﬁned to one site, resulting in
ﬁbrous dysplasia affecting a single bone.
CLINICAL AND RADIOGRAPHIC
FEATURES
MONOSTOTIC FIBROUS DYSPLASIA
OF THE JAWS
When the disease is limited to a single bone, it is termed
monostotic ﬁbrous dysplasia. This type accounts for
about 80% to 85% of all cases, with the jaws being
among the most commonly affected sites. Although the
postnatal mutation of GNAS1 may occur during infancy,
childhood, or adulthood, most examples of monostotic
ﬁbrous dysplasia are diagnosed during the second
decade of life. Males and females are affected with
about equal frequency. A painless swelling of the
affected area is the most common feature (Fig. 14-32).
Growth is generally slow, and the patient or parents
are often unable to recall when the lesion was noted
ﬁrst. Occasionally, however, the growth may be fairly
rapid. The maxilla is involved more often than the
mandible.
Although mandibular lesions are truly monostotic,
maxillary lesions often involve adjacent bones (e.g.,
zygoma, sphenoid, occipital) and are not strictly mono-
stotic. The designation of craniofacial ﬁbrous dyspla-
sia is appropriate for these lesions. Teeth involved in
the lesion usually remain ﬁrm but may be displaced by
the bony mass.
The chief radiographic feature is a ﬁne “ground-
glass” opaciﬁcation that results from superimposition
of a myriad of poorly calciﬁed bone trabeculae arranged
in a disorganized pattern. Radiographically, the lesions
of ﬁbrous dysplasia are not well demarcated. The
margins blend imperceptibly into the adjacent normal
bone so that the limits of the lesion may be difﬁcult to
deﬁne (Figs. 14-33 to 14-35). In the earlier stages, the
lesion may be largely radiolucent or mottled.
Involvement of the mandible often results not only
in expansion of the lingual and buccal plates but also
bulging of the lower border. Superior displacement of
the inferior alveolar canal is not uncommon. Periapical
radiographs of the involved dentition often demon-
strate narrowing of the periodontal ligament space
with an ill-deﬁned lamina dura that blends with the
abnormal bone pattern.
When the maxilla is involved, the lesional tissue
displaces the sinus ﬂoor superiorly and commonly
obliterates the maxillary sinus. Imaging studies in cases
with maxillary involvement may show increased
density of the base of the skull involving the occiput,
sphenoid, roof of the orbit, and frontal bones (Fig.
14-36). This is said to be the most characteristic radio-
graphic feature of ﬁbrous dysplasia of the skull.
POLYOSTOTIC FIBROUS DYSPLASIA;
JAFFE-LICHTENSTEIN SYNDROME;
MCCUNE-ALBRIGHT SYNDROME
Involvement of two or more bones is termed polyos-
totic ﬁbrous dysplasia, a relatively uncommon condi-
tion. The number of involved bones varies from a few
to 75% of the entire skeleton. When seen with café au
lait (coffee with milk) pigmentation, the process is
termed Jaffe-Lichtenstein syndrome. Polyostotic
ﬁbrous dysplasia also may be combined with café au lait
pigmentation and multiple endocrinopathies, such as
sexual precocity, pituitary adenoma, or hyperthyroid-
ism. This pattern is known as the McCune-Albright
syndrome. Another rare disorder associated with
Fig. 14-32 Fibrous dysplasia. Expansile mass of the left
maxilla in a 45-year-old woman. This lesion was known to
have been present for at least 20 years. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 637
(FGF23), which is produced and released by affected
bone.
When present, the café au lait pigmentation consists
of well-deﬁned, generally unilateral tan macules on the
trunk and thighs. These pigmented lesions may be con-
genital, and pigmented oral mucosal macules also may
be present. The margins of the café au lait spots are
typically very irregular, resembling a map of the coast-
line of Maine (Fig. 14-38). This is in contrast to the café
au lait spots of neuroﬁbromatosis (see page 529), which
have smooth borders (like the coast of California).
In McCune-Albright syndrome, sexual precocity
is the most common endocrine manifestation of the
Fig. 14-33 Fibrous dysplasia. Panoramic radiograph of the patient shown in Fig. 14-32.
A diffuse “ground-glass” radiopacity is evident. (Courtesy of Dr. Richard Brock.)
Fig. 14-34 Fibrous dysplasia. Periapical radiograph
showing a diffuse “ground-glass” radiographic appearance.
Fig. 14-35 Fibrous dysplasia. Occlusal radiograph showing
localized expansion of the mandible and the “ground-glass”
radiographic appearance. The margins of the lesion are not
well deﬁned and blend into the adjacent bone. (From Waldron
CA, Giansanti JS: Benign ﬁbro-osseous lesions of the jaws: a clinical-
radiologic-histologic review of 65 cases. I. Fibrous dysplasia of the jaws, Oral
Surg Oral Med Oral Pathol 35:190-201, 1973.)
ﬁbrous dysplasia is Mazabraud syndrome, character-
ized by ﬁbrous dysplasia in combination with intra-
muscular myxomas.
Although the skull and jaws may be affected with
resultant facial asymmetry, the clinical picture in
patients with polyostotic ﬁbrous dysplasia is usually
dominated by symptoms related to the long bone
lesions (Fig. 14-37). Pathologic fracture with resulting
pain and deformity is frequently noted. Leg length dis-
crepancy is very common as a result of involvement
of the upper portion of the femur (hockey stick
deformity).
Hypophosphatemia caused by renal phosphate
wasting is another fairly common ﬁnding among
patients with polyostotic ﬁbrous dysplasia. The mecha-
nism for this ﬁnding appears to be related to the renal
inﬂuences of circulating ﬁbroblast growth factor 23 `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

638 ORAL AND MAXILLOFACIAL PATHOLOGY
Fig. 14-36 Fibrous dysplasia. Computed tomography (CT)
image showing extensive involvement of the maxilla and
skull.
A B
C
Fig. 14-37 Polyostotic ﬁbrous dysplasia. Jaffe-Lichtenstein syndrome. A, Young man
exhibiting enlargement of the right maxilla and mandible. B, Intraoral photograph showing
unilateral maxillary expansion. C, Panoramic radiograph showing ill-deﬁned lesions of the right
side of both jaws.
Fig. 14-38 Polyostotic ﬁbrous dysplasia. Jaffe-Lichtenstein
syndrome. Café au lait pigmentation of the abdomen. This is
the same patient as shown in Fig. 14-37. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 639
syndrome, particularly in females. Menstrual bleeding
may occur during the ﬁrst few months of life. Breast
development and pubic hair may be apparent within
the ﬁrst few years of life in affected girls.
HISTOPATHOLOGIC FEATURES
The typical microscopic ﬁndings of ﬁbrous dysplasia
consist of irregularly shaped trabeculae of immature
(woven) bone in a cellular, loosely arranged ﬁbrous
stroma. The bone trabeculae are not connected to each
other. They often assume curvilinear shapes, which
have been likened to Chinese script writing. The bone
trabeculae are considered to arise by metaplasia and
are not surrounded by plump appositional osteoblasts
(Fig. 14-39). Tiny calciﬁed spherules may be seen
rarely but are never numerous. In contrast to ossifying
ﬁbroma and cemento-osseous dysplasia, ﬁbrous dys-
plasia typically demonstrates a rather monotonous
pattern throughout the lesion rather than being a hap-
hazard mixture of woven bone, lamellar bone, and
spheroid particles. The lesional bone fuses directly to
normal bone at the periphery of the lesion so that no
capsule or line of demarcation is present. Although
ﬁbrous dysplasia of the long bones does not undergo
maturation, jaw and skull lesions tend to be more ossi-
ﬁed than their counterparts in the rest of the skeleton.
This is particularly true in specimens from older
patients.
Serial biopsy specimens in some cases have shown
that histopathologically classic ﬁbrous dysplasia of the
jaws undergoes progressive maturation to a lesion con-
sisting of lamellar bone in a moderately cellular con-
nective tissue stroma (Fig. 14-40). The bone trabeculae
in these mature lesions tend to run parallel to one
another.
TREATMENT AND PROGNOSIS
Clinical management of ﬁbrous dysplasia of the jaws
may present a major problem. Although smaller
lesions, particularly in the mandible, may be surgically
resected in their entirety without too much difﬁculty,
the diffuse nature and large size of many lesions,
A
B
Fig. 14-39 Fibrous dysplasia. A, Irregularly shaped
trabeculae of woven bone in a ﬁbrous stroma. B, Medium-
power view showing peripheral osteoid without osteoblastic
rimming.
A
B
Fig. 14-40 Mature ﬁbrous dysplasia. A, This long-standing
lesion shows separate, broad trabeculae of bone within
ﬁbrous connective tissue. B, Note the lamellar maturation of
the bone. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

640 ORAL AND MAXILLOFACIAL PATHOLOGY
particularly those of the maxilla, preclude removal
without extensive surgery. In many cases, the disease
tends to stabilize and essentially stops enlarging when
skeletal maturation is reached. Some lesions, however,
continue to grow, although generally slowly, in adult
patients.
Some patients with minimal cosmetic or functional
deformity may not require or desire surgical treatment.
Cosmetic deformity with associated psychologic prob-
lems or functional deformity may dictate surgical inter-
vention in the younger patient. Such a procedure
usually entails surgical reduction of the lesion to an
acceptable contour without attempts to remove the
entire lesion. The cosmetic result is usually good, but
regrowth of the lesion occurs over time.
The prevalence of regrowth after surgical reduction
is difﬁcult to determine, but it has been estimated that
between 25% and 50% of patients show some regrowth
after surgical shave-down of the lesion. The regrowth
is more common in younger patients, and many sur-
geons believe that surgical intervention should be
delayed for as long as possible.
In a few studies, patients with primarily polyostotic
disease have been effectively managed with bisphos-
phonate therapy, such as intravenous pamidronate and
oral alendronate. Bisphosphonates have been shown to
provide pain relief and improve skeletal strength.
However, further studies are needed for adequate
assessment of the risks and beneﬁts of bisphosphonate
therapy.
Malignant change, usually development of an osteo-
sarcoma, has been rarely associated with ﬁbrous dys-
plasia. Most examples have been found in patients who
had received radiation therapy for ﬁbrous dysplasia,
but a few examples of spontaneous sarcomatous
changes have been reported. Radiation therapy for
ﬁbrous dysplasia is contraindicated because it carries
the risk for development of postirradiation bone
sarcoma. It also has been suggested that patients with
Mazabraud syndrome may have a slightly increased
risk of sarcoma development, even in the absence of
radiation exposure.
CEMENTO-OSSEOUS DYSPLASIAS
(OSSEOUS DYSPLASIA)
Cemento-osseous dysplasia occurs in the tooth-
bearing areas of the jaws and is probably the most
common ﬁbro-osseous lesion encountered in clinical
practice. In spite of its frequency, the associated nomen-
clature and diagnostic criteria remain an area of debate.
Because the pathologic features share many similari-
ties with ﬁbrous dysplasia and ossifying ﬁbroma, correct
diagnosis can be problematic but is critical to appropri-
ate management.
Because cemento-osseous dysplasia arises in close
approximation to the periodontal ligament and exhib-
its histopathologic similarities with the structure, some
investigators have suggested these lesions are of
periodontal ligament origin. Others believe cemento-
osseous dysplasia represents a defect in extraligament-
ary bone remodeling that may be triggered by local
factors and possibly correlated to an underlying hor-
monal imbalance.
Based on the clinical and radiographic features, it is
convenient to separate cemento-osseous dysplasias
into three groups: (1) focal, (2) periapical, and (3)
ﬂorid. Although the focal pattern is somewhat differ-
ent from the other two forms, it is likely that these cat-
egories may represent variants of the same pathologic
process.
CLINICAL AND RADIOGRAPHIC
FEATURES
FOCAL CEMENTO-OSSEOUS DYSPLASIA
Focal cemento-osseous dysplasia exhibits single site of
involvement. The concept of focal cemento-osseous
dysplasia was not clariﬁed until the mid 1990s. Before
that time, most cases were misdiagnosed as a variant
of ossifying ﬁbroma.
An examination of this pattern reveals slightly dif-
ferent epidemiology from the other two variants. About
90% of cases of focal cemento-osseous dysplasia occur
in females, with an approximate mean age of 38 years
and a predilection for the third to sixth decades. In
contrast to the periapical and ﬂorid variants, a higher
percentage of cases have been reported in whites.
However, this apparent white predilection may be the
result of a population bias in one of the major reported
case series.
Focal cemento-osseous dysplasia may occur in any
area of the jaws, but the posterior mandible is the
predominant site. The disease is typically asymptom-
atic and is detected only on a radiographic examina-
tion. Most lesions are smaller than 1.5 cm in
diameter.
Radiographically, the lesion varies from completely
radiolucent to densely radiopaque with a thin periph-
eral radiolucent rim. Most commonly, however, there
is a mixed radiolucent and radiopaque pattern (Fig.
14-41). The lesion tends to be well deﬁned, but the
borders are usually slightly irregular. Lesions occur in
dentulous and edentulous areas, with many examples
noted in extraction sites. Occasionally, an apparently
focal lesion may represent an early stage in the transi-
tion to multifocal involvement and, as would be
expected, this is seen most frequently in black
females. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 641
PERIAPICAL CEMENTO-OSSEOUS DYSPLASIA
(OSSEOUS DYSPLASIA; CEMENTAL
DYSPLASIA; CEMENTOMAS)
Periapical cemento-osseous dysplasia predominantly
involves the periapical region of the anterior mandible.
Solitary lesions may occur, but multiple foci are present
more frequently. There is a marked predilection for
female patients (ranging from 10 : 1 to 14 : 1), and
approximately 70% of cases affect blacks. Most patients
are diagnosed initially between the ages of 30 and 50,
with the diagnosis almost never made in individuals
younger than age 20. Teeth associated with the
lesions are almost invariably vital and seldom have
restorations.
Periapical cemento-osseous dysplasia is an asymp-
tomatic condition that is discovered when radiographs
are taken for other purposes. Early lesions appear as
circumscribed areas of radiolucency involving the
apical area of a tooth. At this stage the lesion cannot be
differentiated radiographically from a periapical gran-
uloma or periapical cyst (Fig. 14-42). With time, adja-
cent lesions often fuse to form a linear pattern of
radiolucency that envelops the apices of several teeth
(Fig. 14-43).
Serial radiographic studies reveal that the lesions
tend to “mature” over time to create a mixed radiolu-
cent and radiopaque appearance (Fig. 14-44). In the
end stage, the lesions show a circumscribed dense cal-
ciﬁcation surrounded by a narrow radiolucent rim.
However, the periodontal ligament is intact, and fusion
to the tooth is not seen. Individual lesions seldom
exceed 1.0 cm in diameter. Each lesion is self-limiting
and does not typically expand the cortex. Progressive
growth seldom, if ever, occurs.
FLORID CEMENTO-OSSEOUS DYSPLASIA
Florid cemento-osseous dysplasia appears with multi-
focal involvement not limited to the anterior mandible.
Although many cases demonstrate multifocal lesions
only in the posterior portions of the jaws, many patients
also reveal synchronous involvement of the anterior
mandible (Fig. 14-45). Like the periapical pattern, this
form predominantly involves black women (in some
A B
Fig. 14-41 Focal cemento-osseous dysplasia. A, A radiolucent area involves the edentulous
ﬁrst molar area and the apical area of the second molar. B, Radiograph of the same patient
taken 9 years later showing a mixed radiolucent and radiopaque pattern.
Fig. 14-42 Periapical cemento-osseous dysplasia.
Periapical radiograph showing multiple radiolucent lesions at
the apices of the anterior mandibular teeth. (Courtesy of Dr.
Aaron Carner.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

642 ORAL AND MAXILLOFACIAL PATHOLOGY
Fig. 14-43 Periapical cemento-osseous dysplasia.
Later-stage lesions exhibiting signiﬁcant mineralization.
Fig. 14-44 Periapical cemento-osseous dysplasia.
Later-stage lesions exhibiting signiﬁcant mineralization.
Fig. 14-45 Florid cemento-osseous dysplasia. Multiple mixed radiolucent and radiopaque
lesions involving the anterior and posterior regions of the mandible.
series, more than 90% of patients), with a marked pre-
dilection for middle-aged to older adults. An interme-
diate frequency among East Asian populations also has
been described.
The lesions show a marked tendency for bilateral
and often quite symmetrical involvement, and it is not
unusual to encounter extensive lesions in all four pos-
terior quadrants. The disease may be completely
asymptomatic and, in such cases, is discovered only
when radiographs are taken for some other purpose.
In other instances, the patient may complain of dull
pain, and an alveolar sinus tract may be present, expos-
ing yellowish, avascular bone to the oral cavity
(Fig. 14-46). Although rarely prominent, some degree `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 643
common for the radiopacities to remain separated
from adjacent teeth with an intervening intact peri-
odontal ligament space, in some cases fusion of
cemento-osseous material directly on the tooth root
surface may be observed in end-stage lesions.
Such a process may result in thickened root apices sur-
rounded by radiolucency (or a “hypercementosis-like”
appearance).
Both dentulous and edentulous areas may be
affected, and involvement appears to be unrelated to
the presence or absence of teeth. More sharply deﬁned
radiolucent areas, which on surgical exploration prove
to be simple bone cysts (see page 631), may be inter-
mixed with the other lesional elements. The cysts may
be single or multiple and, in some cases, represent a
sizable portion of the lesion. It has been suggested that
these simple bone cysts arise from obstruction to drain-
age of the normal interstitial ﬂuid by the ﬁbro-osseous
proliferation.
HISTOPATHOLOGIC FEATURES
All three patterns of cemento-osseous dysplasia dem-
onstrate similar histopathologic features. The tissue
consists of fragments of cellular mesenchymal tissue
composed of spindle-shaped ﬁbroblasts and collagen
ﬁbers with numerous small blood vessels (Fig. 14-48).
Free hemorrhage is typically noted interspersed
throughout the lesion.
Fig. 14-46 Florid cemento-osseous dysplasia. Yellowish,
avascular cementum-like material is beginning to exfoliate
through the oral mucosa.
Fig. 14-47 Florid cemento-osseous dysplasia. Multifocal radiopaque lesions of the posterior
areas of the jaws. (Courtesy of Dr. Solomon Israel.)
of expansion may be noted in one or more of the
involved areas.
Radiographically, the lesions typically demonstrate
an identical pattern of maturation noted in the other
two forms. Initially, the lesions are predominantly
radiolucent but with time become mixed, then pre-
dominantly radiopaque with only a thin peripheral
radiolucent rim (Fig. 14-47). On occasion, a lesion can
become almost totally radiopaque and blend with the
adjacent normal-appearing bone. Although it is most `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

644 ORAL AND MAXILLOFACIAL PATHOLOGY
Within this ﬁbrous connective tissue background is
a mixture of woven bone, lamellar bone, and cemen-
tum-like particles (Fig. 14-49). The proportion of each
mineralized material varies from lesion to lesion and
from area to area in individual sites of involvement. As
the lesions mature and become more sclerotic, the
ratio of ﬁbrous connective tissue to mineralized mate-
rial decreases. With maturation, the bone trabeculae
become thick curvilinear structures that have been
said to resemble the shape of ginger roots. With pro-
gression to the ﬁnal radiopaque stage, individual tra-
beculae fuse and form lobular masses composed of
sheets or fused globules of relatively acellular and dis-
organized cemento-osseous material (Fig. 14-50).
DIAGNOSIS
In most instances of periapical or ﬂorid cemento-
osseous dysplasia, the distinctive clinical and radio-
graphic patterns (e.g., a black female patient with
multiquadrant involvement or multiple lesions involv-
ing vital lower incisor teeth) allow a strong presump-
tive diagnosis without the necessity of biopsy. The
features of focal cemento-osseous dysplasia are less
speciﬁc and often mandate surgical investigation. Even
on histopathologic review, distinguishing focal cemen-
to-osseous dysplasia from ossifying ﬁbroma often can
be difﬁcult. The ﬁndings at surgery are very helpful in
discriminating between these two lesions. Before the
ﬁnal sclerotic stage, cemento-osseous dysplasia con-
sists of easily fragmented and gritty tissue that can be
curetted easily from the defect but does not separate
cleanly from the adjacent normal bone. In contrast,
ossifying ﬁbromas tend to separate cleanly from the
bone and are removed in one or several large masses.
Several histopathologic features also can help to
conﬁrm the impression obtained from the surgical and
gross descriptions. Although cemento-osseous dyspla-
sia and ossifying ﬁbroma demonstrate a mixture of
bone and cementum-like particles, the trabeculae in
ossifying ﬁbroma tend to be more delicate and often
demonstrate osteoblastic rimming. The cementum-like
particles in cemento-osseous dysplasia are irregularly
shaped and often exhibit retraction from the adjacent
stroma, whereas those in ossifying ﬁbroma are more
ovoid and often demonstrate brush borders in intimate
association with the adjacent stroma. Although ossify-
ing ﬁbroma can exhibit hemorrhage along the margins
of the specimen, cemento-osseous dysplasia typically
reveals free hemorrhage throughout the lesion and a
sinusoidal vascularity in close association with the bony
trabeculae.
TREATMENT AND PROGNOSIS
The various forms of cemento-osseous dysplasia do not
appear neoplastic; therefore, they generally do not
require removal. However, these lesions can cause
Fig. 14-48 Cemento-osseous dysplasia. Low-power
photomicrograph showing fragments of cellular ﬁbrous
connective tissue containing scattered trabeculae of bone.
Fig. 14-49 Cemento-osseous dysplasia. High-power
photomicrograph showing spicules of bone and cementum-
like hard tissue within moderately cellular ﬁbrous connective
tissue. Note the hemorrhage around the bony trabeculae.
Fig. 14-50 Cemento-osseous dysplasia. Late-stage lesion
showing a sclerotic mass of cemento-osseous material. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 645
signiﬁcant clinical problems for some patients. During
the predominantly radiolucent phase, the lesions cause
few problems. Once signiﬁcant sclerosis is present,
the lesions of cemento-osseous dysplasia tend to be
hypovascular and prone to necrosis with minimal
provocation. For the asymptomatic patient, the best
management consists of regular recall examinations
with prophylaxis and reinforcement of good home
hygiene care to control periodontal disease and
prevent tooth loss.
Because the onset of symptoms is usually associated
with exposure of the sclerotic masses to the oral cavity,
biopsy or elective extraction of teeth should be avoided.
In other instances, symptoms begin after exposure of
the sclerotic masses to the oral cavity as a result of
progressive alveolar atrophy under a denture. Affected
patients should be encouraged to retain their teeth to
prevent development of symptoms later.
Management of the symptomatic patient is more
difﬁcult. At this stage, there is an inﬂammatory com-
ponent to the disease and the process is basically a
chronic osteomyelitis involving dysplastic bone and
cementum. Antibiotics may be indicated but often are
not effective. Sequestration of the sclerotic cementum-
like masses occurs slowly and is followed by healing.
Saucerization of dead bone may speed healing.
Although a single case of a malignant ﬁbrous histiocy-
toma arising within a focus of ﬂorid cemento-osseous
dysplasia has been reported, such neoplastic transfor-
mation appears unique, and the prognosis for patients
with cemento-osseous dysplasia is good.
When simple bone cysts arise within foci of
cemento-osseous dysplasia, surgical exploration is
necessary to establish the diagnosis. These simple
bone cysts often do not heal as rapidly as those noted
in a younger patient who does not have cemento-
osseous dysplasia. In some cases the cysts persist or
enlarge after surgical intervention; when they ﬁll in,
the bone retains an abnormal radiographic appear-
ance. To assist healing, the cyst and the surrounding
ﬁbro-osseous proliferation are usually curetted
thoroughly.
FAMILIAL GIGANTIFORM CEMENTOMA
Although the term gigantiform cementoma has been
used in the past as a synonym for ﬂorid cemento-
osseous dysplasia, most authorities now restrict use of
this term to an uncommon hereditary disorder that is
signiﬁcantly different from conventional cemento-
osseous dysplasia. Familial gigantiform cementoma
is a disorder of gnathic bone that ultimately leads to
the formation of massive sclerotic masses of disorga-
nized mineralized material.
CLINICAL AND RADIOGRAPHIC FINDINGS
Familial gigantiform cementoma is an autosomal dom-
inant disorder that demonstrates high penetrance and
variable expressivity. Although the majority of reported
cases have occurred in whites, well-documented exam-
ples have been seen in African blacks. No sexual pre-
dilection has been observed.
Most affected patients begin to develop radiographic
alterations during the ﬁrst decade of life. By adoles-
cence, clinically obvious alterations are typically noted
and are followed by a rapid and expansive growth
pattern (Fig. 14-51). The osseous pathosis appears
limited to the jaws and typically demonstrates multifo-
cal involvement of both the maxilla and the mandible.
Although the course is variable, the gnathic enlarge-
ment in most patients results in signiﬁcant facial
deformity, as well as impaction, malposition, and mal-
occlusion of the involved dentition. If not treated, then
the osseous enlargement eventually ceases during the
ﬁfth decade.
Radiographically, the initial features resemble those
seen in cemento-osseous dysplasia, appearing as
multiple radiolucencies in the periapical regions. With
progression, the affected sites expand to replace much
of the normal bone within the involved quadrant and
develop a mixed radiolucent and radiopaque pattern.
With further maturation, the lesions become predomi-
nantly radiopaque but often maintain a thin radiolu-
cent rim.
As noted in cemento-osseous dysplasia, the affected
bone during the ﬁnal radiopaque stage is very sensitive
to inﬂammatory stimuli and becomes necrotic with
minimal provocation. Before therapy, some investiga-
tors have reported elevated serum alkaline phospha-
tase that subsequently declines after surgical removal
of the osseous proliferations. Anemia also has been
reported in a number of affected females in different
kindreds. In one family, all affected females demon-
strated multifocal polypoid adenomas of the uterus
that were associated with chronic hemorrhage and
thought responsible for the anemia. A gynecologic
examination appears prudent in all affected females,
especially those with anemia. In two kindreds, bone
fragility and tendency for long bone fractures were
noted. It is not clear whether such patients might fall
within a spectrum that also includes cases reported as
osteogenesis imperfecta with associated ﬁbro-osseous
lesions of the jaws.
Sporadic cases with clinical and radiographic fea-
tures similar to those of familial gigantiform cemen-
toma also have been reported. It is possible that these
cases may represent spontaneous mutations. Some of
these nonfamilial cases have been termed multiple
(cemento-) ossifying ﬁbromas or bilateral ossifying ﬁbromas. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

646 ORAL AND MAXILLOFACIAL PATHOLOGY
Whether such cases are best considered multiple
cemento-ossifying ﬁbromas, sporadic cases of familial
gigantiform cementoma, or unusual progressive forms
of cemento-osseous dysplasia remains unclear. Future
insights into the genetic basis and molecular pathogen-
esis of this problematic spectrum of diseases may
improve the understanding and appropriate classiﬁca-
tion of such cases.
HISTOPATHOLOGIC FEATURES
Histopathologically, familial gigantiform cementoma
shows the same spectrum of changes seen in ﬂorid
cemento-osseous dysplasia, and the two cannot be dis-
tinguished microscopically.
TREATMENT AND PROGNOSIS
Before the ﬁnal sclerotic stage, attempts to improve
aesthetics by shave-down surgical procedures have not
been successful because the dysplastic tissue rapidly
regrows. Once the lesions are predominantly radi-
opaque, partial removal may lead to sequestration of
the remaining affected bone. Therefore, extensive
resection of the altered bone and reconstruction of the
facial skeleton and associated soft tissues have been
recommended and can produce acceptable functional
and aesthetic results. The extent of the required surgi-
cal procedures often is greater for patients who are
treated during the later stages of the disease.
OSSIFYING FIBROMA
(CEMENTIFYING FIBROMA;
CEMENTO-OSSIFYING FIBROMA)
Although it can resemble focal cemento-osseous dys-
plasia radiographically and, to a lesser extent, histo-
pathologically, ossifying ﬁbroma is a true neoplasm
with a signiﬁcant growth potential. Before the reﬁning
of the concept of focal cemento-osseous dysplasia in
the mid 1990s, ossifying ﬁbroma was thought to be a
common neoplasm. In reality, true ossifying ﬁbromas
are relatively rare, with many previously reported
examples actually being focal cemento-osseous
dysplasia.
The neoplasm is composed of ﬁbrous tissue that
contains a variable mixture of bony trabeculae,
cementum-like spherules, or both. Although the lesions
do contain a variety of mineralized structures, most
authorities agree the same progenitor cell produces the
different materials. It has been suggested that the origin
of these tumors is odontogenic or from periodontal
ligament, but microscopically identical neoplasms with
cementum-like differentiation also have been reported
in the orbital, frontal, ethmoid, sphenoid, and temporal
bones, leaving these prior theories of origin open to
A B
Fig. 14-51 Familial gigantiform cementoma. Young woman with massive lesions involving
all four quadrants of the jaws. (A from Abdelsayed RA, Eversole LR, Singh BS et al: Gigantiform cementoma:
clinicopathologic presentation of 3 cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 91:438-444, 2001;
B courtesy of Dr. Raﬁk Abdelsayed.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 647
question. Today, many authorities prefer to designate
the cementum-like material present in ossifying ﬁbro-
mas as a variation of bone. The designations ossifying
ﬁbroma, cemento-ossifying ﬁbroma, and cementifying
ﬁbroma are all appropriate for this tumor and continue
to be used by many. In spite of this, however, it is
agreed that these are the same lesion and are classiﬁed
best as osteogenic neoplasms. In this section, all of
these variations are combined under the term ossifying
ﬁbroma.
Recently, mutations in the tumor suppressor gene
HRPT2 were identiﬁed in patients with a rare condi-
tion known as hyperparathyroidism-jaw tumor syndrome,
which is characterized by parathyroid adenoma or car-
cinoma, ossifying ﬁbromas of the jaws, renal cysts, and
Wilms’ tumors. This discovery led to the subsequent
ﬁnding of HRPT2 gene mutations in two sporadic cases
of ossifying ﬁbroma of the jaws. The function of the
HRPT2 protein product (known as paraﬁbromin) and
the mechanism by which mutations in this gene lead
to tumor formation are not well understood.
CLINICAL AND RADIOGRAPHIC
FEATURES
The epidemiology of ossifying ﬁbroma is unclear
because many previous reports confused focal cemen-
to-osseous dysplasia with true ossifying ﬁbromas. It
appears ossifying ﬁbromas occur across a wide age
range, with the greatest number of cases encountered
during the third and fourth decades of life. There
is a deﬁnite female predilection, with the mandible
involved far more often than the maxilla. The mandi-
bular premolar and molar area is the most common
site.
Small lesions seldom cause any symptoms and are
detected only on radiographic examination. Larger
tumors result in a painless swelling of the involved
bone (Fig. 14-52); they may cause obvious facial asym-
metry, which on occasion reaches grotesque size. Pain
and paresthesia are rarely associated with an ossifying
ﬁbroma.
Radiographically, the lesion most often is well
deﬁned and unilocular. Some examples show a scle-
rotic border. Depending on the amount of calciﬁed
material produced in the tumor, it may appear com-
pletely radiolucent; more often, varying degrees of
radiopacity are noted. True ossifying ﬁbromas that
become largely radiopaque with only a thin radiolu-
cent periphery are uncommon; many reported exam-
ples with this radiographic pattern likely represent
end-stage focal cemento-osseous dysplasia. Root diver-
gence or resorption of roots of teeth associated with the
tumor may be seen. Large ossifying ﬁbromas of the
mandible often demonstrate a characteristic down-
ward bowing of the inferior cortex of the mandible.
HISTOPATHOLOGIC FEATURES
At surgical exploration, the lesion is well demarcated
from the surrounding bone, thus permitting relatively
easy separation of the tumor from its bony bed. A few
ossifying ﬁbromas will show, grossly and microscopi-
cally, a ﬁbrous capsule surrounding the tumor. Most
are not encapsulated but are well demarcated grossly
and microscopically from the surrounding bone.
On gross examination, the tumor is usually submit-
ted in one mass or as a few large pieces (Fig. 14-53).
Ossifying ﬁbromas consist of ﬁbrous tissue that exhibits
varying degrees of cellularity and contains mineralized
A B
Fig. 14-52 Ossifying ﬁbroma. A, Enlargement of the posterior maxilla caused by a large
ossifying ﬁbroma. B, Note the mixed radiolucent and radiopaque lesion expanding the
posterior maxilla. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

648 ORAL AND MAXILLOFACIAL PATHOLOGY
material (Fig. 14-54). The hard tissue portion may be
in the form of trabeculae of osteoid and bone or
basophilic and poorly cellular spherules that resemble
cementum. Admixtures of the two types are typical.
The bony trabeculae vary in size and frequently dem-
onstrate a mixture of woven and lamellar patterns.
Peripheral osteoid and osteoblastic rimming are usually
present. The spherules of cementum-like material
often demonstrate peripheral brush borders that blend
into the adjacent connective tissue (Fig. 14-55). Signiﬁ-
cant intralesional hemorrhage is unusual. Variation in
the types of mineralized material produced may be
helpful in distinguishing ossifying ﬁbroma from ﬁbrous
dysplasia, which has a more uniform pattern of osseous
differentiation.
TREATMENT AND PROGNOSIS
The circumscribed nature of the ossifying ﬁbroma gen-
erally permits enucleation of the tumor with relative
ease. Some examples, however, which have grown
large and destroyed considerable bone, may necessi-
tate surgical resection and bone grafting. The progno-
sis, however, is very good, and recurrence after removal
of the tumor is rarely encountered. There is no evi-
dence that ossifying ﬁbromas ever undergo malignant
change.
JUVENILE OSSIFYING FIBROMA
(JUVENILE ACTIVE OSSIFYING
FIBROMA; JUVENILE AGGRESSIVE
OSSIFYING FIBROMA)
The juvenile ossifying ﬁbroma is a controversial
lesion that has been distinguished from the larger
group of ossifying ﬁbromas on the basis of the age of
the patients, most common sites of involvement,
and clinical behavior. Two different neoplasms have
been reported under the term, and disagreement
exists over the spectrum of what should be accepted as
juvenile ossifying ﬁbromas. Although the two forms
demonstrate different histopathologic and clinical
features, several investigators have chosen to compro-
mise and accept two patterns of juvenile ossifying
ﬁbroma: (1) trabecular and (2) psammomatoid.
Among lesions involving the craniofacial skeleton, the
number of psammomatoid cases reported exceeds
the number of trabecular cases reported by a ratio of
approximately 4:1.
A recent study of three cases of the psammomatoid
variant arising in the orbit of adolescent boys demon-
Fig. 14-53 Ossifying ﬁbroma. Gross specimen showing a
well-circumscribed tumor that shelled out in one piece.
Fig. 14-54 Ossifying ﬁbroma. This low-magniﬁcation
photomicrograph shows a well-circumscribed solid tumor
mass. Trabeculae of bone and droplets of cementum-like
material can be seen forming within a background of cellular
ﬁbrous connective tissue.
Fig. 14-55 Ossifying ﬁbroma. High-power
photomicrograph showing a mixture of woven bone and
cementum-like material. Note the spherules demonstrating
peripheral brush borders (arrow). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 649
strated the presence of nonrandom chromosomal
breakpoints at Xq26 and 2q33 resulting in (X;2)
translocation. Although no similar studies have been
reported with respect to the trabecular variant, it is
possible that future insights into the cytogenetic abnor-
malities of these two variants may aid in deﬁning them
as distinct entities.
CLINICAL AND RADIOGRAPHIC
FEATURES
In most instances, the neoplasms often grow rapidly,
are well-circumscribed, and lack continuity with the
adjacent normal bone. The lesions are circumscribed
radiolucencies that in some cases contain central radi-
opacities (Fig. 14-56). In some cases “ground glass”
opaciﬁcation may be observed. Those present within a
sinus may appear radiodense and often create a cloud-
ing that may be confused with sinusitis.
The age at diagnosis varies, with reported cases
occurring in patients from younger than 6 months to
older than 70 years of age. Although both patterns
reveal similar radiographic features and growth pat-
terns, the trabecular form is diagnosed initially in
younger patients. The mean age of trabecular juvenile
ossifying ﬁbromas is approximately 11 years, whereas
the mean age of patients diagnosed with the psam-
momatoid variant approaches 22 years. Both forms
exhibit a slight male predilection and occur in either
jaw but reveal a maxillary predominance. Although
many of these tumors are initially discovered on routine
radiographic examination, cortical expansion may
result in clinically detectable facial enlargement. The
psammomatoid variant frequently appears outside the
jaws, with more than 70% arising in the orbital and
frontal bones and paranasal sinuses.
Complications secondary to the neoplasm are typi-
cally the result of impingement on neighboring struc-
tures. With persistent growth, lesions arising in the
paranasal sinuses penetrate the orbital, nasal, and
cranial cavities. Nasal obstruction, exophthalmos, or
proptosis may be seen. Rarely, temporary or perma-
nent blindness occurs.
Intracranial extension has been discovered in
neoplasms arising adjacent to the cribriform plates.
Because of the circumscribed growth pattern of the
tumor, the frontal lobe is typically elevated without any
associated neurologic signs. Rarely, intracranial exten-
sion has resulted in meningitis, with one report of a
maxillary tumor leading to convulsions and death from
pneumococcal meningitis.
In some cases of the psammomatoid variant, devel-
opment of an aneurysmal bone cyst has been reported.
Such cystic changes tend to occur in younger patients
in the ﬁrst and second decades of life and have been
associated with large maxillary lesions exhibiting
aggressive behavior.
HISTOPATHOLOGIC FEATURES
Both patterns are typically nonencapsulated but well
demarcated from the surrounding bone. The tumor
consists of cellular ﬁbrous connective tissue that exhib-
its areas that are loose and other zones that are so cel-
lular that the cytoplasm of individual cells is hard to
discern because of nuclear crowding. Myxomatous foci
are not rare and often are associated with pseudocystic
degeneration. Mitotic ﬁgures can be found but are not
numerous. Areas of hemorrhage and small clusters of
multinucleated giant cells are usually seen.
The mineralized component in the two patterns is
very different. The trabecular variant shows irregular
strands of highly cellular osteoid encasing plump and
irregular osteocytes (Fig. 14-57). These strands often
are lined by plump osteoblasts and in other areas
by multinucleated osteoclasts. In contrast, the psam-
momatoid pattern forms concentric lamellated and
spherical ossicles that vary in shape and typically have
basophilic centers with peripheral eosinophilic osteoid
rims (Fig. 14-58). A peripheral brush border blending
into the surrounding stroma is noted in many of
the ossicles. Occasionally, individual ossicles undergo
remodeling and form crescentic shapes.
Fig. 14-56 Juvenile ossifying ﬁbroma. Computed
tomography (CT) scan showing a large tumor involving the
left maxilla and maxillary sinus of a 12-year-old girl.
Clinically, the tumor was growing rapidly. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

650 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The clinical management and prognosis of the juvenile
ossifying ﬁbroma are uncertain. Although many tumors
demonstrate slow but progressive growth, some juve-
nile ossifying ﬁbromas demonstrate rapid enlargement.
The more aggressive neoplasms tend to arise in infants
and young children.
For smaller lesions, complete local excision or thor-
ough curettage appears adequate. For some rapidly
growing lesions, wider resection may be required.
In contrast to the negligible recurrence rate seen in
the common types of ossifying ﬁbromas, recurrence
rates of 30% to 58% have been reported for juvenile
ossifying ﬁbromas. Malignant transformation has not
been documented.
OSTEOMA
Osteomas are benign tumors composed of mature
compact or cancellous bone. Osteomas are essentially
restricted to the craniofacial skeleton and rarely, if
ever, are diagnosed in other bones. There is some
question as to whether osteomas represent true neo-
plasms, and not all lesions designated as an osteoma
may represent a single entity. Some likely repre-
sent the end stage of an injury or inﬂammatory process
or the end stage of a hamartomatous process, such
as ﬁbrous dysplasia. The common palatal and man-
dibular tori and buccal exostoses (see page 19) are
not considered to represent osteomas, although they
are histopathologically identical to osteomas. Be-
cause many osteomas are small, asymptomatic lesions,
there is little reliable information as to their true
frequency.
CLINICAL AND RADIOGRAPHIC
FEATURES
Osteomas of the jaws may arise on the surface of the
bone, as a polypoid or sessile mass (periosteal, periph-
eral, or exophytic osteoma), or they may be located
in the medullary bone (endosteal or central osteoma).
Extraskeletal lesions of soft tissue, typically located
within muscle or the dermis of the skin (osteoma
cutis), also are possible. Most jaw osteomas are detected
in young adults and are generally asymptomatic, soli-
tary lesions. There is little valid information as to
whether there is any gender predilection. The most
common gnathic locations are the body of the mandi-
ble or the condyle. When located in the body, most
osteomas occur posterior to the premolars on the
lingual surface. Less common mandibular locations
include the angle (particularly at the inferior border),
coronoid process, and ramus.
Periosteal osteomas appear as slowly growing masses
on the surface of the mandible or maxilla. Some types
may reach a large size, resulting in facial deformity.
Small endosteal osteomas are asymptomatic, but large
lesions cause a slowly progressive enlargement of the
affected area.
An osteoma involving the mandibular condyle may
cause a slowly progressing shift in the patient’s occlu-
sion, with deviation of the midline of the chin toward
the unaffected side. Other reported signs and symp-
toms include facial swelling, pain, and limited mouth
opening.
Condylar osteomas are considered by some to be a
true neoplasm, whereas others designate them as
hyperostoses. Distinguishing this process from condylar
hyperplasia can be difﬁcult; however, condylar osteo-
mas are typically lobulated, whereas the condyle retains
its original shape when hyperplastic.
Paranasal sinus lesions also are possible and are
actually more common than gnathic lesions. The frontal
sinus is most commonly involved, followed by the
ethmoid and maxillary sinuses. Such lesions are usually
Fig. 14-57 Juvenile ossifying ﬁbroma. Trabeculae of
cellular woven bone are present in a cellular ﬁbrous stroma.
Fig. 14-58 Juvenile ossifying ﬁbroma. Cellular ﬁbrous
connective tissue containing spherical ossicles with basophilic
centers and peripheral eosinophilic rims. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 651
asymptomatic, although pain, swelling, sinusitis, and
nasal discharge are possible. In rare cases, paranasal
sinus osteomas may expand into orbital structures and
result in proptosis, diplopia, and decreased visual
acuity. Infrequently, intracranial extension can lead
to meningitis, cerebral abscesses, and intracranial
mucoceles.
Radiographically, osteomas appear as circumscribed
sclerotic masses. Periosteal osteomas may show a
uniform sclerotic pattern or may demonstrate a scle-
rotic periphery with a central trabecular pattern (Fig.
14-59). Smaller endosteal osteomas are difﬁcult, if not
impossible, to differentiate from foci of sclerotic bone
representing the end stage of an inﬂammatory process
(condensing osteitis, focal chronic sclerosing osteomy-
elitis) or from noninﬂammatory foci of sclerotic bone
(idiopathic osteosclerosis). The true nature of these
osteomas can be conﬁrmed only by documentation of
continued growth.
HISTOPATHOLOGIC FEATURES
Compact osteomas are composed of normal- appearing
dense bone showing minimal marrow tissue (Fig.
14-60). Cancellous osteomas are composed of trabec-
ulae of bone and ﬁbrofatty marrow. Osteoblastic activ-
ity may be fairly prominent.
TREATMENT AND PROGNOSIS
Larger osteomas of the mandibular body causing symp-
toms or cosmetic deformity are treated by conservative
surgical excision. Small, asymptomatic osteomas, par-
ticularly those located endosteally, probably do not
need to be treated but should be observed periodically.
Because of the frequency of associated symptoms, oste-
omas arising in the condyle are usually removed surgi-
cally. Large lesions mandate condylectomy, whereas
peripheral osteomas are treated by local resection.
Paranasal sinus osteomas may not require removal
unless they become large or symptomatic; small, peri-
osteal lesions may be removed endoscopically, whereas
larger lesions typically require an open surgical
approach. Osteomas are completely benign, and
patients do not experience malignant change. Recur-
rence after excision is extremely rare.
GARDNER SYNDROME
Gardner syndrome is a rare disorder that is inherited
as an autosomal dominant trait with near 100% pene-
trance; approximately one third of cases occur sponta-
neously and appear to represent new gene mutations.
The responsible gene has been mapped to the long arm
of chromosome 5 and has been identiﬁed as the adeno-
matous polyposis coli (APC) tumor suppressor gene.
Gardner syndrome is considered to be part of a spec-
trum of diseases characterized by familial colorectal
polyposis. In addition to the colonic manifestations,
other gastrointestinal abnormalities are seen along
with a variety of ﬁndings that may involve the skin, soft
tissues, retina, skeletal system, and teeth. The presence
of extracolonic manifestations and the severity of gas-
trointestinal disease correlate with the speciﬁc position
of mutations within the APC gene. However, the pos-
sibility that additional mutations in undiscovered mod-
iﬁer genes also may inﬂuence the severity and pattern
of disease cannot be excluded. Several of the extraco-
lonic manifestations are distinctive and have led to the
discovery of the syndrome.
Fig. 14-59 Osteoma. The radiograph shows a
pedunculated cancellous osteoma arising from the lingual
surface of the mandible near the crest of the alveolar ridge.
Fig. 14-60 Osteoma. This compact osteoma is composed
of dense bone, with only minimal marrow elements. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

652 ORAL AND MAXILLOFACIAL PATHOLOGY
CLINICAL AND RADIOGRAPHIC
FEATURES
The reported prevalence of Gardner syndrome varies
from 1:8300 to 1:16,000 live births. The associated
colonic polyps typically develop during the second
decade; because these are adenomatous, they ulti-
mately transform into adenocarcinoma. In addition,
detection of extracolonic polyps is not rare in the small
intestine or stomach, with a small percentage exhibit-
ing carcinomatous transformation.
Up to 90% of patients with Gardner syndrome dem-
onstrate skeletal abnormalities, the most common of
which are osteomas. Although the osteomas may affect
any part of the skeleton, the most commonly involved
areas are the skull, paranasal sinuses, and the mandi-
ble. When gnathic lesions are seen, they often occur in
the region of the mandibular angles and are frequently
associated with prominent facial deformity (Fig.
14-61). The osteomas are usually noted during puberty
and precede the development of, or any symptoms
from, the bowel polyps (Fig. 14-62). Most patients dem-
onstrate between three and six osseous lesions. The
osteomas appear as areas of increased radiodensity
that vary from slight thickenings to large masses. On
occasion, large osteomas of the mandible or condyle
will limit the mandibular opening. Dental abnormali-
ties include an increased prevalence of odontomas,
supernumerary teeth, and impacted teeth. Although
up to 20% of affected patients demonstrate supernu-
merary teeth, the frequency of extra teeth is not nearly
as high as that noted in cleidocranial dysplasia.
Most patients show one or several epidermoid cysts
of the skin (Fig. 14-63). Desmoid tumors (locally aggres-
sive ﬁbrous neoplasms) of the soft tissue arise in
approximately 10% of affected patients. These lesions
are three times more frequent in females and often
develop in the abdominal scar that forms after
colectomy.
Although lesser known, an increased prevalence of
thyroid carcinoma also is noted, with females demon-
strating a 100-fold increase. In addition, pigmented
lesions of the ocular fundus are evident in nearly
90% of affected patients. Identiﬁcation of this ocular
abnormality is useful when evaluating patients for the
syndrome.
HISTOPATHOLOGIC FEATURES
Histopathologically, the osteomas are generally of the
compact type. An individual lesion cannot be differen-
tiated microscopically from a solitary osteoma.
Fig. 14-61 Gardner syndrome. Panoramic radiograph showing multiple osteomas of the
mandible.
Fig. 14-62 Gardner syndrome. A segment of resected
large bowel showing polyp formation (arrow). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 653
TREATMENT AND PROGNOSIS
The major problem for patients with Gardner syn-
drome is the high rate of malignant transformation of
bowel polyps into invasive adenocarcinoma. By age 30,
about 50% of patients with Gardner syndrome will
develop colorectal carcinoma. The frequency of malig-
nant change approaches 100% in older patients.
Prophylactic colectomy is usually recommended.
Removal of jaw osteomas and epidermoid cysts for
cosmetic reasons sometimes may be indicated, but the
long-term prognosis depends on the behavior of the
bowel adenocarcinomas.
OSTEOBLASTOMA AND
OSTEOID OSTEOMA
Osteoblastoma and osteoid osteoma are closely
related benign bone tumors that arise from osteoblasts.
There is general agreement that the histopathologic
features of these two lesions are identical, but it has
been shown that the tumor nidus in osteoid osteomas
contains a concentration of peripheral nerves not seen
in other ﬁbro-osseous neoplasms. In addition, the
tumor produces prostaglandins that result in signiﬁ-
cant pain that is relieved by prostaglandin inhibitors
such as aspirin. Classically, the distinction depends on
the size of the lesion, with osteoid osteoma being
smaller than 2 cm and osteoblastoma being larger than
2 cm. Some authors prefer to classify both of these
lesions as osteoblastomas.
The features of the cementoblastoma closely resem-
ble those present in the osteoblastoma. A number of
noted authorities in orthopedic pathology consider
cementoblastoma and osteoblastoma to be identical
lesions and prefer to designate both as osteoblastomas.
Because of signiﬁcant radiographic and histopatho-
logic similarities, the primary difference between an
osteoblastoma and a cementoblastoma depends on
whether the lesion is fused to a tooth or not, and this
ability is most likely because of the ﬁnal histodifferen-
tiation of the tumor cells. Because of these similarities,
cementoblastoma is presented in the next section of
this chapter rather than in Chapter 15.
CLINICAL AND RADIOGRAPHIC
FEATURES
OSTEOBLASTOMA
Osteoblastomas are rarely encountered and represent
less than 1% of all bone tumors. The most frequently
affected bones are the vertebral column, sacrum, cal-
varium, long bones, and the small bones of the hands
and feet. For those developing within the jaws, there is
a slight mandibular predilection, with most examples
arising in the posterior regions. Approximately 85% of
gnathic osteoblastomas occur before age 30, and there
is a slight female predominance among reported
cases.
Most osteoblastomas are between 2 and 4 cm, but
they may be as large as 10 cm. Pain, tenderness, and
swelling are common presenting features. In contrast
to the osteoid osteoma, aspirin usually does not relieve
the pain associated with an osteoblastoma. In many
Fig. 14-63 Gardner syndrome. This patient has multiple,
large epidermoid cysts. (Courtesy of Dr. William Welton.)
Fig. 14-64 Osteoblastoma. Computed tomography (CT)
image showing a large, destructive radiolucent and
radiopaque lesion of the mandible. (Courtesy of Dr. Ed Marshall.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

654 ORAL AND MAXILLOFACIAL PATHOLOGY
cases, pain may be misinterpreted as evidence of odon-
togenic infection. Lesions adjacent to teeth may lead to
tooth mobility, root resorption, or tooth displacement.
Radiographically, the osteoblastoma may appear as a
well-deﬁned or ill-deﬁned radiolucent lesion often
with patchy areas of mineralization (Fig. 14-64). Other
lesions demonstrate considerable mineralization.
Although frequently noted in osteoid osteomas, reac-
tive sclerosis surrounding the lesion is not a constant
feature. Most osteoblastomas arise within medullary
bone; however, in some instances, an osteoblastoma
may present as a bony outgrowth projecting from
the periosteum without evidence of a more central
destructive process. Such lesions are termed periosteal
osteoblastomas.
A small group of osteoblastomas (aggressive osteo-
blastomas) is characterized by more atypical histo-
pathologic features and locally aggressive behavior.
These tumors usually occur in older patients, with most
being older than 30 years of age. A variety of bones,
including the mandible, may be involved. Aggressive
osteoblastomas tend to be larger than conventional
osteoblastomas and typically measure greater than 4
cm in diameter. Pain is a common symptom and may
be severe. Radiographically, these lesions show the fea-
tures of conventional osteoblastomas but tend to be
larger.
OSTEOID OSTEOMA
Osteoid osteomas occur most often in the femur, tibia,
and phalanges. They are very rare in the jaws. Pain is
the most common presenting symptom. It is usually
nocturnal in nature and alleviated by salicylates.
However, nocturnal pain relieved by aspirin has been
documented more often among extragnathic lesions
than jaw lesions. Radiographically, the osteoid osteoma
appears as a well-circumscribed radiolucent defect,
usually less than 1 cm in diameter, with a surrounding
zone of reactive sclerosis of varying thickness. A small
radiopaque nidus may be present, resulting in a target-
like appearance radiographically (Fig. 14-65).
HISTOPATHOLOGIC FEATURES
The lesions reveal mineralized material that demon-
strates prominent reversal lines. The material may be
present in large sheets or irregular trabeculae. At the
periphery of the large masses and surrounding the
trabeculae are scattered multinucleated osteoclast-like
cells and numerous osteoblasts that have ample cyto-
plasm and hyperchromatic nuclei (Fig. 14-66). The
supporting stroma consists of loose ﬁbrous connective
tissue that contains scattered dilated vascular chan-
nels. Focal areas of hemorrhage are not rare, and
osteoblastomas occasionally exhibit a central zone of
increased vascularity.
Microscopically, aggressive osteoblastomas are char-
acterized by the presence of large (epithelioid) osteo-
blasts with increased mitotic activity and nontrabecular
sheets or lacelike areas of osteoid production. On occa-
sion, osteoblastomas may demonstrate a rich cellular-
ity that has led to erroneous diagnoses of osteosarcoma.
Differentiation between some osteoblastomas and
low-grade osteosarcomas may be very difﬁcult. Some
low-grade osteosarcomas may closely resemble the
microscopic appearance of osteoblastomas, and some
lesions may have microscopic features intermediate
between osteoblastoma and osteosarcoma.
Fig. 14-65 Osteoid osteoma. A circumscribed, mixed
radiolucent and radiopaque lesion near the apex of mesial
root of mandibular ﬁrst molar. The patient had dull,
nocturnal pain that was relieved by aspirin. (Courtesy of Dr. Ellen
Eisenberg.)
Fig. 14-66 Osteoblastoma. High-power photomicrograph
showing irregular bony trabeculae with prominent
osteoblastic rimming and osteoclasts. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 655
TREATMENT AND PROGNOSIS
Most cases of osteoid osteoma and osteoblastoma are
treated by local excision or curettage. The prognosis is
good, and some lesions will regress even after incom-
plete excision. A small number of lesions will recur; in
rare instances, an osteoblastoma may undergo trans-
formation into an osteosarcoma. Although about 50%
of aggressive osteoblastomas will recur, metastasis or
death from the tumor has not been reported.
CEMENTOBLASTOMA
(TRUE CEMENTOMA)
Cementoblastoma is an odontogenic neoplasm of
cementoblasts, and many authorities believe this
neoplasm represents the only true neoplasm of
cementum.
CLINICAL AND RADIOGRAPHIC
FEATURES
Cementoblastomas are rare neoplasms, representing
less than 1% of all odontogenic tumors. Greater than
75% arise in the mandible, with 90% arising in the
molar and premolar region. Almost 50% involve the
ﬁrst permanent molar. Impacted or unerupted teeth
rarely may be affected as well. Cementoblastomas
rarely affect deciduous teeth. There is no signiﬁcant sex
predilection. The neoplasm occurs predominantly in
children and young adults, with about 50% arising
before the age of 20 years and 75% occurring before
the age of 30 years. Pain and swelling are present in
approximately two thirds of reported patients. Although
most investigators consider the cementoblastoma to
represent a rather innocuous neoplasm, signs of locally
aggressive behavior may be observed, including bony
expansion, cortical erosion, displacement of adjacent
teeth, envelopment of multiple adjacent teeth, maxil-
lary sinus involvement, and inﬁltration into the pulp
chamber and root canals.
Radiographically, the tumor appears as a radiopaque
mass that is fused to one or more tooth roots and is
surrounded by a thin radiolucent rim (Fig. 14-67). The
outline of the root or roots of the involved tooth is
usually obscured as a result of root resorption and
fusion of the tumor with the tooth.
HISTOPATHOLOGIC FEATURES
The histopathologic presentation of cementoblastoma
closely resembles that of osteoblastoma, with the
primary distinguishing feature being tumor fusion with
the involved tooth (Fig. 14-68). The majority of the
tumor consists of sheets and thick trabeculae of miner-
alized material with irregularly placed lacunae and
prominent basophilic reversal lines. Cellular ﬁbrovas-
cular tissue is present between the mineralized tra-
beculae. Multinucleated giant cells often are present,
and prominent blastlike cells frequently line the min-
eralized trabeculae (Fig. 14-69). The periphery of the
lesion, corresponding to the radiolucent zone seen on
the radiograph, is composed of uncalciﬁed matrix,
which often is arranged in radiating columns. In few
instances, the lesion may inﬁltrate the pulp chamber
and root canals of the involved tooth.
TREATMENT AND PROGNOSIS
Treatment of a cementoblastoma usually consists of
surgical extraction of the tooth together with the
attached calciﬁed mass. Surgical excision of the mass
A B
Fig. 14-67 Cementoblastoma. A, A densely mineralized mass is seen at the apex of the
distal root of the ﬁrst molar. The root is partially resorbed. B, The surgical specimen shows
that the mass is attached to the root. (Courtesy of Dr. John Wright.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

656 ORAL AND MAXILLOFACIAL PATHOLOGY
with root amputation and endodontic treatment of the
involved tooth may be considered. In the past, this
tumor has been considered to exhibit a very low recur-
rence rate, although a recently reported series of a
large number of cases suggests recurrences may be
more common than previously thought, with an overall
recurrence rate as high as 22%. Completeness of
removal is most closely related to recurrence. Total
removal of the mass and the associated tooth mini-
mizes but does not completely eliminate the chance of
recurrence. Progressive growth of the tumor after
extraction of the involved tooth and incomplete
removal of the mass has been documented.
CHONDROMA
Chondromas are benign tumors composed of mature
hyaline cartilage. Chondromas are one of the more
common bone tumors and are located most often in
the short tubular bones of the hands and feet. However,
a diagnosis of chondroma in the jaws, facial bones, and
base of the skull should be viewed with great skepti-
cism because many so-called benign chondromas of
the craniofacial complex have recurred and acted in a
malignant manner. No major series has reported
enchondromas arising in the craniofacial bones. In
spite of this, individual reports and small series of
gnathic chondromas can be found, with most examples
thought to arise from vestigial cartilaginous rests. Such
rests are located in the anterior maxilla, symphysis,
coronoid process, and condyle.
CLINICAL AND RADIOGRAPHIC
FEATURES
Chondromas usually arise in the third and fourth
decades without a signiﬁcant sex predilection. Most
gnathic examples have been found in the condyle or
anterior maxilla of adult patients. When arising in the
jaw, most chondromas are painless and slowly growing
tumors. Tooth mobility and root resorption are noted
occasionally. Radiographically, chondromas typically
appear as radiolucencies with central areas of
radiopacity.
In most cases, chondromas arise in a single site.
Multiple and widespread involvement with a tendency
to be unilateral is termed Ollier disease. In another
presentation, termed Maffucci syndrome, skeletal
chondromatosis is seen in association with soft tissue
angiomas.
HISTOPATHOLOGIC FEATURES
Histopathologically, a chondroma appears as a circum-
scribed mass of mature hyaline cartilage that typically
demonstrates well-formed lacunae containing small
chondrocytes with pale cytoplasm and small, round
nuclei. On occasion, the microscopic distinction
between a benign chondroma and a low-grade chon-
drosarcoma of the jaws is difﬁcult (see page 664).
TREATMENT AND PROGNOSIS
It is wise to consider any lesion diagnosed as chon-
droma of the jaws to represent a potential chondrosar-
coma. Treatment is directed toward total surgical
Fig. 14-68 Cementoblastoma. Low-power photomicro-
graph showing the tumor attached to the roots of the tooth.
Fig. 14-69 Cementoblastoma. Mineralized tissue
containing numerous plump cementoblasts. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 657
removal of the tumor. Condylar examples are usually
treated by condylectomy.
CHONDROMYXOID FIBROMA
The chondromyxoid ﬁbroma is an uncommon
benign neoplasm accounting for less than 1% of all
primary bone tumors. It is located most commonly in
the metaphyseal region of the long bones. Chondro-
myxoid ﬁbromas rarely involve the jaws. Cytogenetic
analysis in several cases has demonstrated the presence
of nonrandom, clonal abnormalities of chromosome 6,
where a number of candidate genes important in carti-
lage development are located. Further characterization
of these chromosomal abnormalities may aid in differ-
entiating chondromyxoid ﬁbroma from chondrosar-
coma, a distinction that at times can be difﬁcult.
CLINICAL AND RADIOGRAPHIC
FEATURES
Chondromyxoid ﬁbromas of the jaws have been en-
countered in patients ranging in age from 10 to 67
years. The mean age of occurrence is approximately 30
years, with the majority discovered in the second and
third decades. There is no sex predilection. Of the re-
ported cases in the jaws, about three quarters occurred
in the mandible. In about one fourth, pain was an initial
symptom, and swelling was noted in approximately
three fourths. Some cases have been asymptomatic,
being detected only on a radiographic examination.
Radiographically, the lesion is a circumscribed
radiolucent defect with sclerotic or scalloped margins.
Central radiopacities sometimes are present within the
lesion. On initial presentation, the size of reported
chondromyxoid ﬁbromas varied from 1.0 to 6.5 cm.
HISTOPATHOLOGIC FEATURES
The tumor consists of lobulated areas of spindle-shaped
or stellate cells with abundant myxoid or chondroid
intercellular substance. The lobules characteristically
are separated by zones of a more cellular tissue com-
posed of spindle-shaped or round cells with varying
numbers of multinucleated giant cells (Fig. 14-70).
Large pleomorphic cells that may cause confusion
with chondrosarcoma may be seen. Focal areas of cal-
ciﬁcation and spicules of residual bone also may be
present within the tumor.
TREATMENT AND PROGNOSIS
Although the chondromyxoid ﬁbroma is a benign
tumor, approximately 25% of cases in the long bones
recur after curettage. Some orthopedic surgeons rec-
ommend block excision as the initial treatment. Gener-
ally, chondromyxoid ﬁbromas of the jaws have been
small and treated by curettage; recurrence is uncom-
mon. Because of the lobular growth and associated
scalloped margins, larger gnathic lesions appear to
justify resection in an attempt to prevent recurrence.
Radiation therapy is contraindicated because of
the risk of inducing malignant transformation or
osteoradionecrosis.
Distinguishing between a chondromyxoid ﬁbroma
and myxoid chondrosarcoma histopathologically may
be difﬁcult. Examples of both underdiagnosis and
overdiagnosis, with resultant improper treatment, have
been described.
SYNOVIAL CHONDROMATOSIS
(CHONDROMETAPLASIA)
Synovial chondromatosis is a rare, benign, nonneo-
plastic arthropathy characterized by the metaplastic
development of cartilaginous nodules within the syno-
vial membrane. The exact cause is unknown. In many
cases an association with other joint conditions (e.g.,
inﬂammatory joint disease, noninﬂammatory arthrop-
athy, joint overuse or other trauma) has been described,
and thus the development of synovial chondromatosis
appears to represent a secondary reactive phenome-
non. Less commonly, no identiﬁable etiologic factors
are identiﬁed, and such cases have been designated as
primary synovial chondromatosis.
The process typically proceeds through three stages.
In the ﬁrst stage, foci of metaplastic cartilage arise in
the synovial lining. With time, these foci increase in
size and begin to detach, with cartilaginous material
present in both the synovial membrane and the joint.
Fig. 14-70 Chondromyxoid ﬁbroma. Myxoid connective
tissue with scattered giant cells and foci of cartilaginous
differentiation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

658 ORAL AND MAXILLOFACIAL PATHOLOGY
In the ﬁnal stage, metaplastic cartilage is found only in
the joint.
CLINICAL AND RADIOGRAPHIC
FEATURES
The disease most commonly affects large joints, such as
the knee, elbow, hip, and shoulder. The number of
reported cases involving the temporomandibular joint
(TMJ) is less than 100. In recent years, there has been an
increase in reported cases, possibly because of improved
imaging techniques and increased awareness of the
disease. The condition is usually limited to one joint.
Synovial chondromatosis of the TMJ occurs across a
wide age range, but most affected patients are middle-
aged. In contrast to the ﬁndings in other joints, there is
a predilection for females. Periarticular swelling, pain,
crepitus, and limitation of joint motion are usually
present. These features are common to a number of
pathoses involving the TMJ and are not diagnostic for
synovial chondromatosis. In rare instances, the disease
may produce no symptoms. The process is usually
limited to the joint, although extraarticular extension
and even intracranial extension have been reported in
a few more aggressive cases.
Radiographically, the most common feature is the
presence of loose bodies in the joint. These consist of
rounded, irregularly shaped, and variably sized radi-
opaque structures in the region of the joint. Other fea-
tures include irregularity of the joint space, widened
joint space, and irregularity of the condylar head.
These ﬁndings, however, are not diagnostic of syno-
vial chondromatosis and may be seen in other degen-
erative joint diseases. The absence of loose bodies does
not preclude a diagnosis of synovial chondromatosis.
Computed tomography (CT) scans and magnetic reso-
nance imaging (MRI) have been advocated as more
sensitive diagnostic imaging procedures.
HISTOPATHOLOGIC FEATURES
Nodules of cartilage are present within the synovium and
lie loose in the joint space. As many as 100 nodules may
be present. These cartilaginous nodules often become
calciﬁed and may ossify. The cartilage may appear atypi-
cal with hyperchromatic and binucleated chondrocytes,
particularly in primary lesions (Fig. 14-71). In another
clinical situation, these features would suggest a diagnosis
of chondrosarcoma, but these changes are not considered
signiﬁcant in synovial chondromatosis.
TREATMENT AND PROGNOSIS
For patients with synovial chondromatosis, the involved
synovium and all loose bodies are removed surgically.
Some surgeons advocate total synovectomy to prevent
recurrence. Meniscectomy may be necessary if the disc
cannot be repaired. A few cases of erosion of the glenoid
fossa and cranial extension of the process have been
reported. Surgery is performed most commonly via
open arthrotomy, although arthroscopy may be used
for biopsy and occasionally for treatment of limited
disease with loose bodies less than 3 mm in diameter.
A wider approach is typically necessary for the rare
cases with extensive extraarticular involvement.
The prognosis is good, with an overall low frequency
of recurrence after surgical excision. However, some
investigators have noted that the less common primary
lesions may exhibit more aggressive behavior with a
higher recurrence rate, even after synovectomy. Thus
periodic follow-up examinations would appear to be
prudent. Malignant transformation of synovial chon-
dromatosis of the TMJ has not been noted. Most patients
experience improved joint function and pain relief
after surgery.
DESMOPLASTIC FIBROMA
The desmoplastic ﬁbroma of bone is an uncommon
tumor of ﬁbroblastic origin. It is thought to be the
osseous counterpart of the soft tissue ﬁbromatosis
(desmoid tumor) (see page 515). In a few cases, des-
moplastic ﬁbroma-like lesions of the jaws have been
reported in association with tuberous sclerosis.
CLINICAL AND RADIOGRAPHIC
FEATURES
Most examples of desmoplastic ﬁbroma of bone are
discovered in patients younger than 30 years of age.
The age range of reported gnathic examples is from 10
Fig. 14-71 Synovial chondromatosis. Photomicrograph
from one of many nodules removed at the time of
synovectomy. The cartilage shows some degree of atypia, and
in a different clinical setting this histopathology could be
interpreted to represent a low-grade chondrosarcoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 659
months to 59 years, with a mean of approximately 16
years. There is no signiﬁcant sex predilection. The most
common locations are the mandible, femur, pelvic
bones, radius, and tibia. Of the reported cases involving
the jaws, 84% have occurred in the mandible, most
often in the molar angle-ascending ramus area.
Although some tumors are associated with limited
opening, with or without malocclusion, a painless
swelling of the affected area is the most common initial
complaint. Tooth mobility, proptosis, concurrent infec-
tion, and dysesthesia have been reported infrequently.
Radiographically, the lesion appears as a multilocular
or occasionally unilocular radiolucent area. The
margins may be well deﬁned or ill deﬁned (Fig. 14-72).
The bone is expanded, and the cortex is thinned; corti-
cal reaction mimicking the appearance of an osteosar-
coma is rare. If the lesion erodes through the cortex,
then an accompanying soft tissue mass will be present.
When this occurs, it may be difﬁcult to determine
whether the lesion is a desmoplastic ﬁbroma of bone
with soft tissue extension or a soft tissue ﬁbromatosis
with secondary extension into bone. Adjacent teeth
may exhibit displacement and root resorption.
HISTOPATHOLOGIC FINDINGS
The tumor is composed of small elongated ﬁbroblasts
and abundant collagen ﬁbers (Fig. 14-73). The degree
of cellularity may vary from area to area in a given
lesion, and the cellular areas may show plumper ﬁbro-
blasts and less collagen. The ﬁbroblasts are not atypical,
however, and mitoses are essentially absent. Bone
spicules may be present at the interface between the
tumor and adjacent bone but are never an integral part
of the lesion.
Some authors have recommended that diagnostic
biopsies be sampled generously from the center rather
than the periphery of the lesion, because reactive bone
at the periphery may be mistaken for osteoid produc-
tion, which may lead to a mistaken diagnosis of a
benign ﬁbro-osseous lesion or osteosarcoma.
TREATMENT AND PROGNOSIS
Although the desmoplastic ﬁbroma is considered to be
a benign tumor, it often behaves in a locally aggressive
fashion, with extensive bone destruction and soft tissue
extension; therefore, radical surgery may be required
to control the disease. Some surgeons prefer curettage,
whereas others prefer wide local excision or resection
with a wide margin. Curettage may be adequate for
localized lesions without cortical perforation or soft
tissue extension, but segmental resection is preferred
for lesions exhibiting rapid growth, an ill-deﬁned radio-
graphic appearance, cortical perforation, or soft tissue
extension. The recurrence rate for lesions treated by
curettage alone is approximately 70%, compared with
approximately 20% for those treated by resection.
Given these high recurrence rates, patients should be
monitored postoperatively for a minimum of 3 years.
Although metastases do not occur and the long-term
prognosis is good, the lesion may be associated with
considerable morbidity.
It may be very difﬁcult to distinguish desmoplastic
ﬁbroma of bone from well-differentiated ﬁbrosarcoma.
Fig. 14-72 Desmoplastic ﬁbroma. Ill-deﬁned, destructive
radiolucency of the anterior maxilla. (Courtesy of Dr. H.T. Daniel.)
Fig. 14-73 Desmoplastic ﬁbroma. The tumor consists of a
cellular proliferation of ﬁbroblasts arranged in interlacing
fascicles. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

660 ORAL AND MAXILLOFACIAL PATHOLOGY
Some authorities suggest that all desmoplastic ﬁbro-
mas of bone be considered potentially malignant.
OSTEOSARCOMA (OSTEOGENIC
SARCOMA)
Osteosarcoma is a malignancy of mesenchymal cells
that have the ability to produce osteoid or immature
bone. Excluding hematopoietic neoplasms, osteosar-
coma is the most common type of malignancy to
originate within bone. The majority of osteosarcomas
demonstrate intramedullary origin, but a small number
may be juxtacortical (discussed in the following section)
or rarely, extraskeletal.
CLINICAL AND RADIOGRAPHIC
FEATURES
Extragnathic osteosarcoma demonstrates a bimodal
age distribution. Most arise in patients between the
ages of 10 and 20 years, with a lesser number diag-
nosed in adults older than age 50. The initial peak
occurs during the period of greatest bone growth;
accordingly, most of these osteosarcomas arise in the
distal femoral and proximal tibial metaphyses. In older
patients, the axial skeleton and ﬂat bones are involved
most frequently; Paget’s disease and previous irradia-
tion are associated with an increased prevalence.
Osteosarcomas of the jaws are uncommon and rep-
resent 6% to 8% of all osteosarcomas. These gnathic
tumors have been diagnosed in patients ranging from
young children to older adults, but they occur most
often in the third and fourth decades of life. The mean
age for patients with osteosarcoma of the jaw is about
33 years, which is 10 to 15 years older than the mean
age for osteosarcomas of the long bones. As is seen in
extragnathic locations, a slight male predominance is
noted.
The maxilla and mandible are involved with about
equal frequency. Mandibular tumors arise more fre-
quently in the posterior body and horizontal ramus
rather than the ascending ramus. Maxillary lesions are
discovered more commonly in the inferior portion
(alveolar ridge, sinus ﬂoor, palate) than the superior
aspects (zygoma, orbital rim).
Swelling and pain are the most common symptoms
(Fig. 14-74). Loosening of teeth, paresthesia, and nasal
obstruction (in the case of maxillary tumors) also may
be noted. Some patients report symptoms for relatively
long periods before diagnosis, which indicates that
some osteosarcomas of the jaws grow rather slowly
(Fig. 14-75).
The radiographic ﬁndings vary from dense sclerosis
to a mixed sclerotic and radiolucent lesion to an entirely
radiolucent process. The peripheral border of the
lesion is usually ill deﬁned and indistinct, making it
difﬁcult to determine the extent of the tumor radio-
graphically. In some cases, an extensive osteosarcoma
may show only minimal and subtle radiographic
change with only slight variation in the trabecular
pattern. Occasionally, there is resorption of the roots of
teeth involved by the tumor. This feature is often
described as “spiking” resorption as a result of the
tapered narrowing of the root. The “classic” sunburst
or sun ray appearance caused by osteophytic bone pro-
duction on the surface of the lesion is noted in about
25% of jaw osteosarcomas. Often this is appreciated
best on an occlusal projection (Fig. 14-76). In few cases
a triangular elevation of the periosteum, referred to as
Codman’s triangle, may be observed.
A B
Fig. 14-74 Osteosarcoma. A, This patient shows a ﬁrm, painful swelling of the left maxilla
of recent onset. B, The periapical radiograph shows a dense sclerotic change in the bone
pattern. (Courtesy of Dr. Len Morrow.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 661
A B
C
Fig. 14-75 Osteosarcoma. A, This massive tumor had been present for many months before
the patient sought treatment. B, Intraoral photograph of the tumor mass. C, The panoramic
radiograph shows a “sunburst” pattern of trabeculation within the tumor.
Fig. 14-76 Osteosarcoma. Occlusal radiograph
demonstrating prominent exophytic tumor bone production
on the buccal surface of the mandible, resulting in the
“sunburst” pattern. (Courtesy of Dr. Lewis Gilbert.)
An important early radiographic change in patients
with osteosarcoma consists of a symmetrical widening
of the periodontal ligament space around a tooth or
several teeth. This is the result of tumor inﬁltration
along the periodontal ligament space (Fig. 14-77).
Widening of the periodontal ligament space is not spe-
ciﬁc for osteosarcoma and may be seen associated with
other malignancies. This radiographic ﬁnding, when
accompanied by pain or discomfort and other minimal
radiographic changes, may be of great importance in
the early diagnosis of jaw osteosarcomas.
Although periapical, occlusal, and panoramic radio-
graphs often lead to the initial diagnosis, CT scans are
excellent for demonstrating the degree of intramedul-
lary extension, tumor calciﬁcation, cortical involve-
ment, and soft tissue involvement. These scans prove
invaluable for determining the extent of surgery. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

662 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Osteosarcomas of the jaws display considerable histo-
pathologic variability. The essential microscopic crite-
rion is the direct production of osteoid by malignant
mesenchymal cells (Fig. 14-78). In addition to osteoid,
the cells of the tumor may produce chondroid material
and ﬁbrous connective tissue. The tumor cells may vary
from relatively uniform round or spindle-shaped cells
to highly pleomorphic cells with bizarre nuclear and
cytoplasmic shapes. The amount of matrix material
produced in the tumor may vary considerably. In some
instances, osteoid production may be very minimal and
difﬁcult to demonstrate. Most osteosarcomas of the
jaws tend to be better differentiated than osteosarco-
mas of the extragnathic skeleton.
Depending on the relative amounts of osteoid, car-
tilage, or collagen ﬁbers produced by the tumor, many
pathologists subclassify osteosarcomas into the follow-
ing types:
● Osteoblastic
● Chondroblastic
● Fibroblastic
These histopathologic subtypes, however, do not
have any great bearing on the prognosis. Other less
commonly encountered histopathologic variations
include malignant ﬁbrous histiocytoma-like, small cell,
epithelioid, telangiectatic, and giant cell–rich.
Chondroblastic osteosarcomas constitute a substan-
tial proportion of all osteosarcomas of the jaws. Some
examples may be composed almost entirely of malig-
nant cartilage growing in lobules with only small
foci of direct osteoid production by tumor cells
being identiﬁed (Fig. 14-79). Such lesions, however,
should be classiﬁed as osteosarcomas rather than
chondrosarcomas.
Low-grade, well-differentiated osteosarcomas may
show only minimal cellular atypia of the lesional cells
and abundant bone formation. On microscopic exami-
nation, these lesions may be difﬁcult to differentiate
from benign bone lesions, such as ﬁbrous dysplasia or
ossifying ﬁbroma.
TREATMENT AND PROGNOSIS
Many past and present investigators believe osteosar-
coma of the jaws is less aggressive than those occurring
in the long bones. Most gnathic osteosarcomas are low-
grade, and metastases are seen less frequently. Despite
Fig. 14-77 Osteosarcoma. This 26-year-old woman had a
6-cm painful tumor of the anterior mandible. The periapical
radiograph shows widening of the periodontal ligament
spaces and a mottled radiopacity superimposed on the teeth.
(Courtesy of Dr. Charles Ferguson.)
Fig. 14-78 Osteosarcoma. Anaplastic tumor cells forming
cellular disorganized bone.
Fig. 14-79 Osteosarcoma. This tumor produced a
combination of malignant cartilage and bone. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 663
these ﬁndings, many current clinicopathologic studies
fail to support this contention and suggest that osteo-
sarcomas of the jaws are aggressive neoplasms. The
most important prognostic indicator is the ability to
achieve initial complete surgical removal, a feat that is
much more difﬁcult to achieve in the jaws than the
long bones. In particular, maxillary lesions often are
more difﬁcult to resect completely than mandibular
lesions. The aggressiveness of gnathic osteosarcoma
remains an area of controversy that is difﬁcult to resolve
because of the rarity of the neoplasm and the lack of
consistently applied diagnostic criteria.
Multicenter investigations of different therapies to
osteosarcoma of long bones have led to an improved
prognosis that now appears superior to that associated
with gnathic neoplasms. These protocols involve neo-
adjuvant (preoperative) chemotherapy followed by
radical surgical excision with careful pathologic exami-
nation of the specimen to evaluate the chemotherapeu-
tic effects on the tumor. Adjuvant (postoperative)
chemotherapy is used and may be modiﬁed if poor
histopathologic response to the neoadjuvant regimen
is noted. Some investigators have demonstrated 4-year
survival rates exceeding 80% with this approach.
Limited numbers of patients with jaw osteosarcomas
have been treated with these protocols, and superior
results have been claimed compared with surgical
treatment alone. In addition, a systematic literature
review of 201 patients with craniofacial osteosarcoma
demonstrated that patients treated with chemotherapy
exhibited an improved long-term survival regardless of
the ability to achieve complete surgical removal.
In spite of the improved prognosis in patients receiv-
ing chemotherapy, radical surgical excision remains
the mainstay of therapy. Because the tumor may extend
for some distance beyond the apparent clinical and
radiographic margins, local recurrence after surgery is
a major problem. Local uncontrolled disease is more
often the cause of death for patients with jaw osteosar-
coma than are the effects of distant metastases. Most
deaths from uncontrolled local disease occur within 2
years of the initial treatment. Jaw osteosarcomas have
less tendency to metastasize than do osteosarcomas of
long bones. Although regional lymph nodes may be
infrequently involved, metastases most often affect the
lungs and brain. When comparing mandibular and
maxillary osteosarcomas, metastasis is noted more fre-
quently from mandibular neoplasms, whereas local
recurrence is associated more frequently with maxil-
lary tumors.
The prognosis remains serious. Various studies indi-
cate a 30% to 70% survival rate. Survival rates of up to
80% have been reported for patients receiving initial
radical surgery, the best hope for permanent cure.
Additional prospective investigations of gnathic osteo-
sarcoma treated by neoadjuvant chemotherapy fol-
lowed by surgical removal and adjuvant chemotherapy
are necessary in an attempt to conﬁrm the most appro-
priate approach.
PERIPHERAL (JUXTACORTICAL)
OSTEOSARCOMA
In contrast to the usual forms of intramedullary osteo-
sarcoma, several varieties originate adjacent to the
cortex of the bone, initially grow outward from the
surface, and do not involve the underlying medullary
cavity. The terminology used for these lesions by differ-
ent authors is somewhat confusing. These peripheral
(juxtacortical) osteosarcomas usually occur in the
long bones, but examples involving the jaws have been
reported.
The parosteal type of osteosarcoma is a lobulated
nodule attached to the cortex by a short stalk (Fig.
14-80). There is no elevation of the periosteum and no
peripheral periosteal reaction. Histopathologically, the
exophytic mass demonstrates a spindle cell ﬁbroblast-
like proliferation that contains well-developed trabecu-
lae of bone. With time, the trabeculae often coalesce
and form a large mass of solid bone. Parosteal osteo-
sarcoma is a low-grade sarcoma that has a small risk
of recurrence and metastasis if treated by radical
excision. With inadequate surgery, the tumor may
Parosteal
Periosteal
Elevated
periosteum with
new bone formation
No
elevation of
periosteum
No new
bone
formation
Fig. 14-80 Peripheral (juxtacortical) osteosarcoma.
Illustration comparing different types of peripheral
osteosarcoma. Parosteal osteosarcoma presents as a
lobulated nodule without a peripheral periosteal reaction.
Periosteal osteosarcoma presents as a sessile mass associated
with signiﬁcant periosteal new bone formation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

664 ORAL AND MAXILLOFACIAL PATHOLOGY
eventually develop into a higher-grade osteosarcoma,
with a resultant poor prognosis.
The periosteal form of osteosarcoma is a sessile
lesion that arises within the cortex and elevates the
overlying periosteum, which provokes the production
of signiﬁcant peripheral periosteal new bone formation
(see Fig. 14-80). Often the leading edge of the tumor
mass perforates the surface of the periosteum and
extends into the surrounding soft tissue. Histopatho-
logically, the tumor demonstrates primitive sarcoma-
tous cells within a tumor that demonstrates signiﬁcant
chondroblastic differentiation. Close inspection will
reveal foci of tumor osteoid and immature bone forma-
tion. Radical surgical excision with wide margins is the
therapy of choice. Although the prognosis is better than
that associated with intramedullary tumors, periosteal
osteosarcoma has a poorer outcome than the parosteal
variant. In reviews of patients with periosteal osteosar-
comas, approximately 25% died from metastatic
disease.
POSTIRRADIATION BONE SARCOMA
Sarcoma arising in a bone that has been previously
subjected to radiation therapy is a well-recognized phe-
nomenon. The jaws are situated closely to tissues that
commonly receive therapeutic radiation and are a
common site for postirradiation bone sarcomas. Postir-
radiation sarcomas may develop as early as 3 years
after radiation, but the average latent period is about
14 years. The frequency of development of sarcoma is
related to radiation dose. Postirradiation sarcoma
develops in about 0.2% of patients receiving 7000 cGy;
there is no increased prevalence of sarcoma for those
receiving less than 1000 cGy.
Osteosarcoma is the most common type of postir-
radiation sarcoma, accounting for 50% of all cases.
About 40% of postirradiation sarcomas are ﬁbrosarco-
mas, with chondrosarcomas and other histopatho-
logic types making up the rest. Postirradiation bone
sarcomas have no distinctive histopathologic features
that allow them to be distinguished from other bone
sarcomas of the same type that arise de novo.
The prognosis for postirradiation sarcomas is about
the same as for de novo tumors of the same type.
CHONDROSARCOMA
Chondrosarcoma is a malignant tumor characterized
by the formation of cartilage, but not bone, by the
tumor cells. Chondrosarcomas comprise about 10% of
all primary tumors of the skeleton but are considered
by most authorities to involve the jaws only rarely.
Chondrosarcoma is about half as common as osteosar-
coma and about twice as common as Ewing sarcoma.
Approximately 1% to 3% of all chondrosarcomas arise
in the head and neck area, and such lesions comprise
only 0.1% of all head and neck malignancies. Some
institutions report a somewhat greater frequency
of chondrosarcomas in the jaws. This may be the
result of differing criteria used by the pathologists
for distinguishing chondroblastic osteosarcomas from
chondrosarcomas.
CLINICAL AND RADIOGRAPHIC FINDINGS
In extragnathic bones, chondrosarcoma is primarily a
neoplasm of adulthood, with peak prevalence in the
sixth and seventh decades of life. Although chondro-
sarcoma arises across a wide age range, the majority of
affected patients are older than 50 years of age; tumors
arising in patients younger than age 45 are uncommon.
No signiﬁcant sex or race predilection is noted. The
most frequently involved bones are the ileum, femur,
and humerus. Involvement of the head and neck is
seen infrequently.
When occurring in the head and neck, chondrosar-
comas arise most frequently in the maxilla; less
common sites of involvement are the mandibular body,
ramus, nasal septum, and paranasal sinuses. Although
chondrosarcomas most often develop in osseous loca-
tions, approximately one third of head and neck lesions
are extraosseous and originate in either laryngotra-
cheal cartilage or soft tissue. Because of the rarity of
chondrosarcoma, large series of jaw and facial bone
lesions are uncommon. In one of the larger series, the
Mayo Clinic reviewed 56 patients with chondrosar-
coma of the jaws and facial bones, and a pattern of
occurrence similar to the extragnathic bones was
observed. In this series the peak prevalence was noted
in the seventh decade, but the age at initial diagnosis
had a wide range, with approximately 20% noted in
patients younger than 20 years of age. The mean patient
age at the time of diagnosis was 41.6 years. No sex or
race predilection was noted. Involvement of the maxilla
and maxillary sinus outnumbered those in the mandi-
ble by 4 to 1.
In a recent review of 400 head and neck chondro-
sarcomas from the American College of Surgeons’
National Cancer Database, the age distribution for
patients with conventional-type tumors was similar to
that previously reported by the Mayo Clinic series.
However, review of prior publications presents a con-
ﬂicting picture in which the mean age is variable and
often reveals a peak prevalence as early as the third
decade. Some investigators have suggested that such
conﬂicting results may be the result of difﬁculty in
performing literature reviews that may contain
chondroblastic osteosarcomas intermixed with true
chondrosarcomas. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 665
A painless mass or swelling is the most common
presenting sign. This may be associated with separation
or loosening of teeth. In contrast to osteosarcoma, pain
is an unusual complaint. Maxillary tumors may cause
nasal obstruction, congestion, epistaxis, photophobia,
or visual loss.
Radiographically, the tumor usually shows features
suggestive of a malignancy, consisting of a radiolucent
process with poorly deﬁned borders. The radiolucent
area often contains scattered and variable amounts of
radiopaque foci, which are caused by calciﬁcation or
ossiﬁcation of the cartilage matrix (Fig. 14-81). Some
chondrosarcomas show extensive calciﬁcation and
radiographically appear as a densely calciﬁed mass
with irregular peripheral margins. Penetration of the
cortex can result in a sunburst pattern similar to that
seen in some osteosarcomas.
Chondrosarcomas often demonstrate extensive
inﬁltration between the osseous trabeculae of the pre-
existing bone without causing appreciable resorption.
In such cases the extent of the tumor is difﬁcult to
determine by radiographic examination. Root resorp-
tion or symmetrical widening of the periodontal liga-
ment space of the teeth involved by the tumor also may
be noted. Chondrosarcomas may grow in a lobular
pattern with minimal or no foci of calciﬁcation. In such
instances, the lesion can appear as a multilocular radio-
lucency and mimic a benign process.
HISTOPATHOLOGIC FEATURES
Chondrosarcomas are composed of cartilage showing
varying degrees of maturation and cellularity. In most
cases, typical lacunar formation within the chondroid
matrix is visible, although this feature may be scarce in
poorly differentiated tumors. The tumor often shows a
lobular growth pattern, with tumor lobules separated
by thin ﬁbrous connective tissue septa. The central
areas of the lobules demonstrate the greatest degree of
maturation. The peripheral areas consist of immature
cartilage and mesenchymal tissue consisting of round
or spindle-shaped cells. Calciﬁcation or ossiﬁcation
may occur within the chondroid matrix. Neoplastic
cartilage may be replaced by bone in a manner similar
to normal endochondral ossiﬁcation.
Chondrosarcomas may be divided into three histo-
pathologic grades of malignancy. This grading system
correlates well with the rate of tumor growth and
prognosis for chondrosarcomas of the extragnathic
skeleton.
GRADES
Grade I chondrosarcomas closely mimic the appear-
ance of a chondroma, composed of chondroid matrix
and chondroblasts that show only subtle variation from
the appearance of normal cartilage. The distinction
between benign and well-differentiated malignant car-
tilaginous tumors is notoriously difﬁcult. Many believe
that a tumor should be considered malignant when
large, plump chondroblasts and binucleated chondro-
cytes are present, even in only scattered microscopic
ﬁelds. Calciﬁcation or ossiﬁcation of the cartilaginous
matrix often is prominent, and mitoses are rare.
Grade II chondrosarcomas show a greater pro-
portion of moderately sized nuclei and increased cel-
lularity, particularly about the periphery of the lobules.
The cartilaginous matrix tends to be more myxoid,
with a less prominent hyaline matrix. The mitotic rate,
however, is low (Fig. 14-82).
Grade III chondrosarcomas are highly cellular
and may show a prominent spindle cell proliferation.
Mitoses may be prominent. Easily recognizable carti-
laginous matrix containing cells within lacunae may be
scarce.
Fig. 14-81 Chondrosarcoma. Ill-deﬁned radiolucent lesion
of posterior mandible containing radiopaque foci. (Courtesy of
Dr. Ben B. Henry.)
Fig. 14-82 Chondrosarcoma. This grade II
chondrosarcoma shows a variation in size of chondrocyte
nuclei. Occasional double nuclei are seen in the lacunae. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

666 ORAL AND MAXILLOFACIAL PATHOLOGY
Chondrosarcomas of the jaws are predominantly of
the histopathologic grades I and II. Grade III tumors
are very uncommon. In the 56 cases reviewed by the
Mayo Clinic, more than 75% were grade I, with the
remainder being grade II; no grade III chondrosarco-
mas were noted in this series.
VARIANTS
Several uncommon microscopic variants of chondro-
sarcoma are also recognized.
The clear cell chondrosarcoma shows cells with
abundant clear cytoplasm; this may lead to problems
in differentiation from a metastatic clear cell carci-
noma. The clear cell chondrosarcoma is considered to
be a low-grade lesion.
Dedifferentiated chondrosarcoma is a high-
grade malignancy that shows an admixture of well-
differentiated chondrosarcoma and a malignant
mesenchymal tumor resembling ﬁbrosarcoma. If these
variants occur in the jaws, then they are exceedingly
rare.
Myxoid chondrosarcoma classically is described
as a soft tissue tumor, although intraosseous lesions
have been reported within the head and neck and else-
where. This variant is characterized by a proliferation
of cells with clear, vacuolated, or eosinophilic cyto-
plasm within a background of mucoid material.
Mesenchymal chondrosarcoma is discussed in
the next section.
TREATMENT AND PROGNOSIS
The prognosis for chondrosarcoma is related to the
size, location, and grade of the lesion. The most impor-
tant factor is the location of the tumor because this has
the greatest inﬂuence on the ability to achieve com-
plete resection. The most effective treatment for chon-
drosarcoma is radical surgical excision. Radiation and
chemotherapy are less effective when compared with
osteosarcoma and are primarily used for unresectable
high-grade chondrosarcomas.
Although aggressive tumors are occasionally seen,
gnathic chondrosarcomas are usually slowly growing
neoplasms with a lower potential for metastasis than
osteosarcoma. Local recurrence leads to death by direct
extension of the tumor into vital structures of the head
and neck. Maxillary and antral tumors often are located
centrally, obtain a larger size before diagnosis, occur
adjacent to the central nervous system (CNS), and
create more difﬁculty in surgical eradication; there-
fore, they are less amenable to cure. In the National
Cancer Database series of 400 head and neck chon-
drosarcomas, only approximately 12% of patients had
regional or distant metastasis at the time of diagnosis,
with a tendency for metastasis in higher-grade and
sinonasal lesions. The overall 5- and 10-year disease-
speciﬁc survival rates in this series were 87.2% and
70.6%, respectively. Survival was greater for patients
with conventional chondrosarcoma than for those with
the myxoid or mesenchymal variants. In the Mayo
Clinic review, no distant metastases occurred in the 56
reported patients; the 5-, 10-, and 15-year survivals
were 67.6%, 53.7%, and 43.9%, respectively. As is
obvious from these data, the importance of 5-year sur-
vival is minimal because recurrence often is a late
sequela. Patients must be followed for their lifetime.
Although these two large series suggest that the prog-
nosis of gnathic and craniofacial chondrosarcoma is
better than that associated with osteosarcoma, previ-
ous studies have suggested that the prognosis of chon-
drosarcoma is worse. This disagreement may be related
to differences in the diagnostic categorization of many
cartilage-producing tumors (chondrosarcoma versus
chondroblastic osteosarcoma).
MESENCHYMAL CHONDROSARCOMA
The mesenchymal chondrosarcoma, an uncommon
and distinctive tumor of bone and soft tissue, shows a
biphasic histopathologic pattern. This aggressive form
of chondrosarcoma represents only 3% to 9% of all
chondrosarcomas.
CLINICAL AND RADIOGRAPHIC
FEATURES
In contrast to other types of chondrosarcoma, the mes-
enchymal variant is unusual in that it most frequently
affects individuals in the second or third decade of life
and the jaws are among the most frequently involved
bones (25% to 30%). Other commonly affected sites are
the ribs, shoulder, pelvic girdle, and vertebrae. About
one third to one fourth of all examples arise in the soft
tissues rather than in bone.
Swelling and pain, often of fairly short duration, are
the most common symptoms. Radiographically, the
tumor demonstrates a radiolucency with inﬁltrative
margins (Fig. 14-83). Stippled calciﬁcation may be
present within the radiolucent area.
HISTOPATHOLOGIC FEATURES
Microscopically, the mesenchymal chondrosarcoma
reveals sheets or patternless masses of small, undiffer-
entiated spindle or round cells surrounding discrete
nodules of cartilage (Fig. 14-84). The chondroid tissue
is well differentiated, and its degree of cellularity and
atypia may vary from that of a benign chondroma to
a low-grade chondrosarcoma. The noncartilaginous
component of the tumor is difﬁcult to differentiate `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 667
from, and may be confused with, a variety of small cell
tumors of bone, such as Ewing sarcoma, lymphoma,
and metastatic small cell carcinoma. In some cases a
prominent, branching vascular pattern is present in the
soft tissue component of a mesenchymal chondrosar-
coma. If cartilaginous foci are sparse, then the tumor
may be misdiagnosed as a hemangiopericytoma.
TREATMENT AND PROGNOSIS
Surgical excision with wide margins is the most appro-
priate therapy. Radiation and chemotherapy have not
prolonged survival in a predictable manner. Local
recurrence and metastasis are not rare. When metas-
tasis occurs, hematogenous spread is seen more fre-
quently than lymphatic involvement, with the lung
being a favored site for metastatic deposits. Recurrent
or metastatic disease may be discovered as long as 20
years after initial therapy. The 10-year survival rate is
approximately 28%.
EWING SARCOMA
Ewing sarcoma is a distinctive primary malignant
tumor of bone that is composed of small, undifferenti-
ated round cells of uncertain histogenesis. Recent
studies have provided data showing that most cases of
Ewing sarcoma exhibit features consistent with neuro-
ectodermal origin. In 85% to 90% of the cases, the
tumor cells demonstrate a reciprocal translocation
between chromosomes 11 and 22 [t(11;22) (q24;q12)].
Ewing sarcoma constitutes 6% to 8% of all primary
malignant bone tumors and represents the third most
common osseous neoplasm after osteosarcoma and
chondrosarcoma. In addition, extraskeletal examples
have been well documented.
CLINICAL AND RADIOGRAPHIC
FEATURES
The peak prevalence of Ewing sarcoma is in the second
decade of life, with approximately 80% of patients
being younger than 20 years of age at the time of
diagnosis and 50% of these tumors being detected in
the second decade. A slight male predominance is
noted. The vast majority of affected patients are white,
with blacks almost never developing this tumor. The
long bones, pelvis, and ribs are affected most frequently,
but almost any bone can be affected. Jaw involvement
is uncommon, with only 1% to 2% occurring in the
gnathic or craniofacial bones.
Pain, often associated with swelling, is the most
common symptom. It is usually intermittent and varies
from dull to severe. Fever, leukocytosis, and an ele-
vated erythrocyte sedimentation rate also may be
present and may lead to an erroneous diagnosis of
osteomyelitis. The tumor commonly penetrates the
cortex, resulting in a soft tissue mass overlying the
affected area of the bone (Fig. 14-85). Jaw involvement
is more common in the mandible than the maxilla.
Paresthesia and loosening of teeth are common ﬁnd-
ings in Ewing sarcomas of the jaws.
Fig. 14-83 Mesenchymal chondrosarcoma. Periapical
radiograph showing a radiolucent lesion between the roots
of the central incisors in a 29-year-old woman. The roots of
the incisors show resorption. At surgery, the lesion was
considerably larger than indicated on the radiograph.
(Courtesy of Dr. Gary Baker.)
Fig. 14-84 Mesenchymal chondrosarcoma. Medium-
power photomicrograph showing sheets of small basophilic
cells with focal areas of cartilaginous differentiation (right). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

668 ORAL AND MAXILLOFACIAL PATHOLOGY
Radiographically, there is irregular lytic bone
destruction with ill-deﬁned margins. Cortical destruc-
tion or expansion may or may not be present. The char-
acteristic “onionskin” periosteal reaction, commonly
observed in Ewing sarcoma of long bones, is seldom
seen in jaw lesions. Although plain radiographs often
are used for initial evaluation, computed tomography
(CT) is the radiographic study of choice for assessment
of lesion extent.
HISTOPATHOLOGIC FEATURES
Ewing sarcoma is composed of small round cells with
well-delineated nuclear outlines and ill-deﬁned cellu-
lar borders (Fig. 14-86). The tumor cells often are
arranged in broad sheets without any distinct pattern.
In some cases, variable-sized nests of tumor cells are
separated by ﬁbrovascular septa, creating a lobular
pattern. Large areas of necrosis and hemorrhage are
commonly present. Ewing sarcomas are not as mor-
phologically homogeneous as once was believed. Some
examples contain foci or may be composed mostly
of larger cells. These are designated as large cell
(atypical) Ewing sarcomas.
About 75% of cases contain glycogen granules in the
cytoplasm of the tumor cells. This is a helpful diagnos-
tic feature, but it is not speciﬁc because glycogen also
can be demonstrated in some other primitive tumors.
About 25% of well-documented Ewing tumors do not
show glycogen.
Diagnosis of Ewing sarcoma may be difﬁcult. The
tumor must be differentiated from other primitive
small cell tumors involving bone and soft tissues in
young patients. These include metastatic neuroblas-
toma, malignant lymphoma, small cell osteosarcoma,
embryonal rhabdomyosarcoma, and the primitive neu-
roectodermal tumor. Metastatic small cell carcinoma
also must be considered in the differential diagnosis of
a suspected Ewing sarcoma in an older patient.
A battery of immunohistochemical reactions and
electron microscopy may be required for conﬁrmation
of the diagnosis of Ewing sarcoma in some cases. Ewing
sarcoma expresses high levels of an antigen determined
by the MIC2 gene. The product of MIC2 is a glycopro-
tein designated CD99 that can be detected by the
immunoperoxidase technique. Although useful in con-
ﬁrmation of Ewing sarcoma, positive reactivity to CD99
also is noted in other tumors and some normal tissues.
Reverse transcription polymerase chain reaction
(RT-PCR) or ﬂuorescence in situ hybridization (FISH)
may be used as more sensitive and speciﬁc methods
for detecting the genetic translocation and conﬁrming
the diagnosis.
TREATMENT AND PROGNOSIS
The prognosis for patients with Ewing sarcoma has
improved dramatically in recent years. Formerly, fewer
than 5% of patients survived more than 5 years. Current
treatment, consisting of combined surgery, radiother-
apy, and multidrug chemotherapy, has led to 40% to
80% survival rates. Because of the risk for postirradia-
tion sarcomas, some clinicians do not recommend
radiation except when surgical resection of the primary
site is not possible.
At the time of initial diagnosis, seemingly localized
disease often is associated with occult micrometastases,
making systemic chemotherapy appropriate in most
cases. Ewing sarcomas frequently metastasize to the
lungs, liver, lymph nodes, and other bones. The ana-
tomic location of the tumor is a critical factor in progno-
sis. Pelvic lesions are associated with the poorest
prognosis. Distal lesions have a better prognosis than
those in a proximal location. With modern therapy,
patients with Ewing sarcoma of the jaws probably have
Fig. 14-85 Ewing sarcoma. A rapidly growing, ulcerated
tumor of the right posterior mandible. (Courtesy of Dr. George
Blozis.)
Fig. 14-86 Ewing sarcoma. Broad sheets of small round
cells with well-deﬁned nuclear outlines and ill-deﬁned
cytoplasmic borders. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 669
an improved prognosis; however, there is a scarcity of
good information because of the small number of cases.
METASTATIC TUMORS TO THE JAWS
Metastatic carcinoma is the most common form of
cancer involving bone. Autopsy studies have shown
that more than two thirds of breast carcinomas, one
half of all prostate carcinomas, and one third of all lung
and kidney carcinomas spread to one or more bones
before a patient dies. Although metastasis to a jaw bone
may arise from primary carcinomas of any anatomic
site, carcinomas of the breast, lung, thyroid, prostate,
and kidney give rise to the majority of gnathic metas-
tases. Metastatic spread of a carcinoma to the jaws
usually occurs by the hematogenous route. Sarcomas
arising in soft tissues or other bones may metastasize
to the jaws, but this is very rare.
CLINICAL AND RADIOGRAPHIC
FEATURES
Most patients with metastatic carcinoma are older;
children are affected rarely. This ﬁnding is a reﬂection
of the greater prevalence of carcinoma in older adults.
Although metastatic lesions may be observed in any
bone, the vertebrae, ribs, pelvis, and skull are the most
frequent sites for metastasis.
The jaws are usually considered to be uncommon
sites for metastasis but may be involved more often
than generally appreciated. A study of carcinomas
arising in various extraoral sites demonstrated that 10
(16%) of 62 autopsied cases of carcinoma showed his-
topathologic evidence of metastasis to the mandible,
even though radiographic study of the mandibles
removed at autopsy in these cases failed to show evi-
dence of metastatic disease. Metastasis to the maxilla
is uncommon, and more than 80% of reported metas-
tases to the jaws have occurred in the mandible.
Metastatic involvement of the jaws exhibits a wide
variety of symptoms. Often the patient experiences
pain, swelling, loosening of teeth, a mass, or paresthe-
sia. Metastasis to the mandible with involvement of the
inferior alveolar nerve occasionally produces a distinc-
tive pattern of anesthesia termed numb-chin syn-
drome in which there is an unexplained loss of
sensation in the lower lip and chin. These symptoms,
however, are not speciﬁc for metastatic disease and
may be associated with primary inﬂammatory or neo-
plastic diseases of the jaws. In some instances, the
patient may be completely asymptomatic, and the
diagnosis of metastatic carcinoma occurs only after
microscopic study of a lesion noted on radiographic
examination. Not uncommonly, an osseous metastasis
is discovered in a nonhealing extraction site from
which the tooth was recently removed because of com-
plaints of local pain or signiﬁcant mobility.
Of particular interest are those cases in which diag-
nosis of a jaw metastasis is the ﬁrst indication that the
patient has a primary malignancy at some other ana-
tomic site. On occasion, the oral lesion is the ﬁrst indi-
cation of an undiscovered and distant malignancy.
Location of the occult primary tumor may be difﬁcult,
requiring extensive evaluation.
Radiographically, metastatic deposits in the jaws
usually appear as radiolucent defects. The defect may
be well circumscribed, resembling a cyst, but more
often it is ill deﬁned with a “moth-eaten” appearance.
Involvement of the alveolus may resemble periodontal
disease clinically and radiographically (Fig. 14-87). On
occasion, a metastatic tumor may cause widening of
the periodontal ligament (Fig. 14-88). Some carcino-
mas, particularly from the prostate and breast, may
stimulate new bone formation in the metastatic site,
resulting in radiopaque or mixed radiolucent and radi-
opaque lesions.
Not uncommonly, patients with gnathic metastases
will have symptoms at a time when conventional radio-
graphs fail to demonstrate detectable alterations. In
these instances, bone scintigraphy is occasionally used
because it has a higher sensitivity and a greater ability
to detect subtle osseous metastases. Some investigators
recommend this technique for patients with prolonged,
unexplained pain who have a history of cancer that is
frequently associated with osseous metastases.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of metastatic carcinoma
in bone varies. In some instances, the metastatic tumor
is well differentiated and closely resembles a carci-
Fig. 14-87 Carcinoma metastatic to the jaws. Panoramic
radiograph showing destruction of the alveolar bone
surrounding the roots of the mandibular second molar. Such
changes may mimic advanced periodontal disease. In this
patient, the lesion originated from an occult carcinoma of the
lung. (Courtesy of Dr. J.M. Sarnovsky.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

670 ORAL AND MAXILLOFACIAL PATHOLOGY
noma of a speciﬁc site, such as the kidney, colon, or
thyroid. In such instances, the pathologist can say with
reasonable certainty that a given metastatic tumor
comes from a speciﬁc primary site (Fig. 14-89). More
often, however, metastatic carcinomas are poorly dif-
ferentiated and histopathologic study of the metastatic
deposit gives little clue as to the primary site of the
tumor. Poorly differentiated metastatic carcinoma may
be difﬁcult to differentiate from anaplastic small cell
sarcomas, malignant lymphomas, and malignant mela-
noma. Immunohistochemical reactions are usually
necessary in such cases to establish the diagnosis.
Although the diagnosis of metastatic carcinoma can
usually be determined by microscopic examination,
the ﬁnal diagnosis depends mostly on a careful medical
history and complete physical examination, with appro-
priate laboratory studies.
TREATMENT AND PROGNOSIS
The prognosis for metastatic carcinoma of the jaws
is poor because, by deﬁnition, osseous metastasis
automatically places the patient in stage IV disease.
Although a solitary metastatic focus may be treated by
excision or radiation therapy, jaw involvement almost
always is associated with widely disseminated disease.
Five-year survival after detection of metastatic carci-
noma involving the jaws is exceedingly rare, and most
patients do not survive more than 1 year.
BIBLIOGRAPHY
Osteogenesis Imperfecta
Ablin DS: Osteogenesis imperfecta: a review, Can Assoc Radiol J
49:110-123, 1998.
Binger T, Rücker M, Spitzer WJ: Dentofacial rehabilitation by
osteodistraction, augmentation and implantation despite
osteogenesis imperfecta, Int J Oral Maxillofac Surg 35:559-
562, 2006.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes affecting
bone: the osteogenesis imperfectas. In Syndromes of the head
and neck, ed 4, pp 178-191, New York, 2001, Oxford Univer-
sity Press.
Lee CYS, Ertel SK: Bone graft augmentation and dental implant
treatment in a patient with osteogenesis imperfecta: review
of the literature with a case report, Implant Dent 12:291-295,
2003.
Levin LS, Wright JM, Byrd DL et al: Osteogenesis imperfecta
with unusual skeletal lesions: report of three families, Am J
Med Genet 21:257-269, 1985.
O’Connell AC, Marini JC: Evaluation of oral problems in an
osteogenesis imperfecta population, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 87:189-196, 1999.
Ormiston IW, Tideman H: Orthognathic surgery in osteogenesis
imperfecta: a case report with management considerations,
J Craniomaxillofac Surg 23:261-265, 1995.
Rauch F, Glorieux FH: Osteogenesis imperfecta, Lancet 363:1377-
1385, 2004.
Schwartz S, Tsipouras P: Oral ﬁndings in osteogenesis
imperfecta, Oral Surg Oral Med Oral Pathol 57:161-167,
1984.
Sillence DO, Senn A, Danks PM: Genetic heterogeneity in osteo-
genesis imperfecta, J Med Genet 16:101-116, 1979.
Osteopetrosis
Albuquerque MA, Melo ES, Jorge WA et al: Osteomyelitis of the
mandible associated with autosomal dominant osteopetrosis:
a case report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
102:94-98, 2006.
Fig. 14-88 Carcinoma metastatic to the jaws. Periapical
radiograph showing widening of the periodontal ligament
spaces.
Fig. 14-89 Carcinoma metastatic to the jaws. Islands of
malignant cells can be seen ﬁlling the marrow spaces. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 671
Bakeman RJ, Abdelsayed RA, Sutley SH et al: Osteopetrosis: a
review of the literature and report of a case complicated by
osteomyelitis of the mandible, J Oral Maxillofac Surg 56:1209-
1213, 1998.
Balemans W, Van Wesenbeeck L, Van Hul W: A clinical and
molecular overview of the human osteopetroses, Calcif Tissue
Int 77:263-274, 2005.
Barbaglio A, Cortelazzi R, Martignoni G et al: Osteopetrosis com-
plicated by osteomyelitis of the mandible: a case report
including gross and microscopic ﬁndings, J Oral Maxillofac
Surg 56:393-398, 1998.
Filho AM, de Castro Domingos A, de Freitas DQ et al:
Osteopetrosis—a review and report of two cases, Oral Dis
11:46-49, 2005.
Key LL Jr, Ries WL: Osteopetrosis. In Bilezikian JP, Raisz LG,
Rodan GA, editors: Principles of bone biology, ed 2, pp 1217-
1227, San Diego, 2002, Academic Press.
Satomura K, Kon M, Tokuyama R et al: Osteopetrosis compli-
cated by osteomyelitis of the mandible: a case report includ-
ing characterization of the osteopetrotic bone, Int J Oral
Maxillofac Surg 36:86-93, 2007.
Tolar J, Teitelbaum SL, Orchard PJ: Osteopetrosis, N Engl J Med
351:2839-2849, 2004.
Younai F, Eisenbud L, Sciubba JJ: Osteopetrosis: a case report
including gross and microscopic ﬁndings in the mandible at
autopsy, Oral Surg Oral Med Oral Pathol 65:214-221, 1988.
Cleidocranial Dysplasia
Camilleri S, McDonald F: Runx2 and dental development, Eur J
Oral Sci 114:361-373, 2006.
Counts AL, Rohrer MD, Prasad H et al: An assessment of root
cementum in cleidocranial dysplasia, Angle Orthod 71:293-
298, 2001.
Daskalogiannakis J, Piedade L, Lindholm TC et al: Cleidocranial
dysplasia: 2 generations of management, J Can Dent Assoc
72:337-342, 2006.
Furuuchi T, Kochi S, Sasano T et al: Morphologic characteristics
of masseter muscle in cleidocranial dysplasia: a report of 3
cases, Oral Med Oral Pathol Oral Radiol Endod 99:185-190,
2005.
Golan I, Baumert U, Hrala BP et al: Dentomaxillofacial variabil-
ity of cleidocranial dysplasia: clinicoradiological presentation
and systematic review, Dentomaxillofac Radiol 32:347-354,
2003.
Golan I, Baumert U, Hrala BP et al: Early craniofacial signs of
cleidocranial dysplasia, Int J Paediatr Dent 14:49-53, 2004.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Cleidocranial dys-
plasia. In Syndromes of the head and neck, ed 4, pp 306-310,
New York, 2001, Oxford University Press.
Ishii K, Nielsen IL, Vargervik K: Characteristics of jaw growth in
cleidocranial dysplasia, Cleft Palate Craniofac J 35:161-166,
1998.
Jansen BL, Kreiborg S: Dental treatment strategies in cleidocra-
nial dysplasia, Br Dent J 172:243-247, 1992.
McNamara CM, O’Riordan BC, Blake M et al: Cleidocranial dys-
plasia: radiological appearances on dental panoramic radiog-
raphy, Dentomaxillofac Radiol 28:89-97, 1999.
Mundlos S: Cleidocranial dysplasia: clinical and molecular
genetics, J Med Genet 36:177-182, 1999.
Visosky AMB, Johnson J, Bingea B: Otolaryngological manifesta-
tions of cleidocranial dysplasia, concentrating on audiological
ﬁndings, Laryngoscope 113:1508-1514, 2003.
Focal Osteoporotic Marrow Defect
Barker BF, Jensen JL, Howell FV: Focal osteoporotic marrow
defects of the jaws, Oral Surg Oral Med Oral Pathol 38:404-
413, 1974.
Crawford BE, Weathers DR: Osteoporotic marrow defects of the
jaws, J Oral Surg 28:600-603, 1970.
Makek M, Lello GE: Focal osteoporotic bone marrow defects of
the jaws, J Oral Maxillofac Surg 44:268-273, 1986.
Schneider LC, Mesa ML, Fraenkel D: Osteoporotic bone marrow
defect: radiographic features and pathogenic factors, Oral
Surg Oral Med Oral Pathol 65:127-129, 1988.
Standish SM, Shafer WG: Focal osteoporotic bone marrow
defects of the jaws, J Oral Surg 20:123-128, 1962.
Idiopathic Osteosclerosis
Geist JR, Katz JO: The frequency and distribution of idiopathic
osteosclerosis, Oral Surg Oral Med Oral Pathol 69:388-393,
1990.
Halse A, Molven O: Idiopathic osteosclerosis of the jaws followed
through a period of 20-27 years, Int Endod J 35:747-751,
2002.
Kawai T, Hirakuma H, Murakami S et al: Radiographic investiga-
tion of idiopathic osteosclerosis of the jaws in Japanese dental
outpatients, Oral Surg Oral Med Oral Pathol 74:237-242,
1992.
MacDonald-Jankowski DS: Idiopathic osteosclerosis in the
jaws of Britons and of the Hong Kong Chinese: radiology
and systematic review, Dentomaxillofac Radiol 28:357-363,
1999.
McDonnell D: Dense bone island: a review of 107 patients, Oral
Surg Oral Med Oral Pathol 76:124-128, 1993.
Petrikowski CG, Peters E: Longitudinal radiographic assessment
of dense bone islands of the jaws, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 83:627-634, 1997.
Williams TP, Brooks SL: A longitudinal study of idiopathic
osteosclerosis and condensing osteitis, Dentomaxillofac Radiol
27:275-278, 1998.
Yonetsu K, Yuasa K, Kanda S: Idiopathic osteosclerosis of the
jaws: panoramic radiographic and computed tomographic
ﬁndings, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
83:517-521, 1997.
Massive Osteolysis
Frederiksen NL, Wesley RK, Sciubba JJ et al: Massive osteolysis
of the maxillofacial skeleton: a clinical, radiographic, histo-
logic and ultrastructural study, Oral Surg Oral Med Oral Pathol
55:470-480, 1983.
Heffez L, Doku HC, Carter BL et al: Perspective of massive oste-
olysis: report of a case and review of the literature, Oral Surg
Oral Med Oral Pathol 55:331-343, 1983.
Holroyd I, Dillon M, Roberts GJ: Gorham’s disease: a case
(including dental presentation) of vanishing bone disease,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89:125-129,
2000.
Kayada Y, Yoshiga K, Takada K et al: Massive osteolysis of the
mandible with subsequent obstructive sleep apnea syndrome:
a case report, J Oral Maxillofac Surg 53:1463-1465, 1995.
Mignogna MD, Fedele S, Lo Russo L et al: Gorham’s disease of
the mandible mimicking periodontal disease on radiograph,
J Clin Periodontol 32:1022-1025, 2005.
Mignogna MD, Fedele S, Lo Russo L et al: Treatment of Gorham’s
disease with zoledronic acid, Oral Oncol 41:747-750,
2005.
Patel D: Gorham’s disease or massive osteolysis, Clin Med Res
3:65-74, 2005.
Ricalde P, Ord RA, Sun CCJ: Vanishing bone disease in a ﬁve
year old: report of a case and review of the literature, Int J
Oral Maxillofac Surg 32:222-226, 2003.
Tsang WM, Tong ACK, Chow LTC et al: Massive osteolysis
(Gorham disease) of the maxillofacial skeleton: report of 2
cases, J Oral Maxillofac Surg 62:225-230, 2004. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

672 ORAL AND MAXILLOFACIAL PATHOLOGY
Paget’s Disease
Ankrom MA, Shapiro JR: Paget’s disease of bone (osteitis defor-
mans), J Am Geriatr Soc 46:1025-1033, 1998.
Carrillo R, Morales A, Rodriguez-Peralto JL et al: Benign ﬁbro-
osseous lesions in Paget’s disease of the jaws, Oral Surg Oral
Med Oral Pathol 71:588-592, 1991.
Cheng YSL, Wright JM, Walstad WR et al: Osteosarcoma arising
in Paget’s disease of the mandible, Oral Oncol 38:785-792,
2002.
Daroszewska A, Ralston SH: Mechanisms of disease: genetics of
Paget’s disease of bone and related disorders, Nat Clin Pract
Rheumatol 2:270-277, 2006.
Drake WM, Kendler DL, Brown JP: Consensus statement on the
modern therapy of Paget’s disease of bone from a Western
Osteoporosis Alliance Symposium, Clin Ther 23:620-626,
2001.
Gleich LL, Eberle RC, Shaha AR et al: Paget’s sarcoma of the
mandible, Head Neck 17:425-430, 1995.
Mailander JC: The “black beard” sign of monostotic Paget’s
disease of the mandible, Clin Nucl Med 11:325-327, 1986.
Mankin HJ, Hornicek FJ: Paget’s sarcoma: a historical and
outcome review, Clin Orthop Relat Res 438:97-102, 2005.
Selby PL, Davie MW, Ralston SH et al: Guidelines on the man-
agement of Paget’s disease of bone, Bone 31:10-19, 2002.
Siris ES: Paget’s disease of bone, J Bone Miner Res 13:1061-1065,
1998.
Smith J, Eveson J: Paget’s disease of bone with particular refer-
ence to dentistry, J Oral Pathol 10:233-247, 1981.
Takata S, Yasui N, Nakatsuka K et al: Evolution of understanding
of genetics of Paget’s disease of bone and related diseases,
J Bone Miner Metab 22:519-523, 2004.
Tillman H: Paget’s disease of bone: a clinical, radiographic and
histopathologic study of 24 cases involving the jaws, Oral Surg
Oral Med Oral Pathol 15:1225-1234, 1962.
Whyte MP: Paget’s disease of bone, N Engl J Med 355:593-600,
2006.
Central Giant Cell Granuloma
Adornato MC, Paticoff KA: Intralesional corticosteroid injection
for treatment of central giant-cell granuloma, J Am Dent Assoc
132:186-190, 2001.
Auclair PL, Cuenin P, Kratochvil FJ et al: A clinical and histo-
morphologic comparison of the central giant cell granuloma
and the giant cell tumor, Oral Surg Oral Med Oral Pathol
66:197-208, 1988.
DeLange J, van den Akker HP: Clinical and radiological features
of central giant-cell lesions of the jaw, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 99:464-470, 2005.
DeLange J, van den Akker HP, Klip H: Incidence and disease-
free survival after surgical therapy of central giant cell granu-
lomas of the jaw in the Netherlands: 1990-1995, Head Neck
26:792-795, 2004.
DeLange J, van der Akker HP, van Zanten GOV et al: Calcitonin
therapy in central giant cell granuloma of the jaw: a random-
ized double-blind placebo-controlled study, Int J Oral Maxil-
lofac Surg 35:791-795, 2006.
DeLange J, Rosenberg AJWP, van den Akker HP et al: Treatment
of central giant cell granuloma of the jaw with calcitonin,
Int J Oral Maxillofac Surg 28:372-376, 1999.
Ficarra G, Kaban LB, Hansen LS: Giant cell lesions of the jaws:
a clinicopathologic and cytometric study, Oral Surg Oral Med
Oral Pathol 64:44-49, 1987.
Goldman KE, Marshall MK, Alessandrini E et al: Complications
of alpha-interferon therapy for aggressive central giant cell
lesion of the maxilla, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 100:285-291, 2005.
Itonaga I, Hussein I, Kudo O et al: Cellular mechanisms of
osteoclast formation and lacunar resorption in giant
cell granuloma of the jaw, J Oral Pathol Med 32:224-231,
2004.
Kaban LB, Mulliken JB, Ezekowitz RA et al: Antiangiogenic
therapy of a recurrent giant cell tumor of the mandible with
interferon alfa-2a, Pediatrics 103:1145-1149, 1999.
Kaban LB, Troulis MJ, Ebb D et al: Antiangiogenic therapy with
interferon alpha for giant cell lesions of the jaws, J Oral Maxil-
lofac Surg 60:1103-1111, 2002.
Kaffe I, Ardekian L, Taicher S et al: Radiologic features of central
giant cell granuloma of the jaws, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 81:720-726, 1996.
Kaplan I, Manor I, Yahalom R et al: Central giant cell granuloma
associated with central ossifying ﬁbroma of the jaws: a clini-
copathologic study, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 103(4):e35-e41, 2007.
Kruse-Lösler B, Diallo R, Gaertner C et al: Central giant cell
granuloma of the jaws: a clinical radiologic, and histopatho-
logic study of 26 cases, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 101:346-354, 2006.
Miloro M, Quinn PD: Synchronous central giant cell lesions of
the jaws: report of a case and review of the literature, J Oral
Maxillofac Surg 53:1350-1355, 1995.
Pogrel MA: Calcitonin treatment for central giant cell granu-
loma, J Oral Maxillofac Surg 61:649-653, 2003.
Pogrel MA, Regezi JA, Harris ST et al: Calcitonin treatment for
central giant cell granulomas of the mandible: report of two
cases, J Oral Maxillofac Surg 57:848-853, 1999.
Stavropoulos F, Katz J: Central giant cell granulomas: a system-
atic review of the radiographic characteristics with the addi-
tion of 20 new cases, Dentomaxillofac Radiol 31:213-217,
2002.
Whitaker SB, Waldron CA: Central giant cell lesions of the jaws:
a clinical, radiologic and histopathologic study, Oral Surg Oral
Med Oral Pathol 75:199-208, 1993.
Yamaguchi T, Dorfman HD: Giant cell reparative granuloma: a
comparative clinicopathologic study of lesions in gnathic and
extragnathic sites, Int J Surg Pathol 9:189-200, 2001.
Cherubism
Beaman FD, Bancroft LW, Peterson JJ: Imaging characteristics
of cherubism, AJR Am J Roentgenol 182:1051-1054, 2004.
Kaugars GE, Niamtu J III, Svirsky JA: Cherubism: diagnosis,
treatment, and comparison with central giant cell granulo-
mas and giant cell tumors, Oral Surg Oral Med Oral Pathol
73:369-374, 1992.
Mangion J, Rahman N, Edkins S et al: The gene for cherubism
maps to chromosome 4p16.3, Am J Hum Genet 65:151-157,
1999.
Meng XM, Yu SF, Yu GY: Clinicopathologic study of 24 cases of
cherubism, Int J Oral Maxillofac Surg 34:350-356, 2005.
Peñarrocha M, Bonet J, Minguez M: Cherubism: a clinical, radio-
graphic, and histopathologic comparison of 7 cases, J Oral
Maxillofac Surg 64:924-930, 2006.
Peters WJN: Cherubism: a study of twenty cases from one family,
Oral Surg Oral Med Oral Pathol 47:307-311, 1979.
Southgate J, Sarma U, Townend JV et al: Study of the cell biology
and biochemistry of cherubism, J Clin Pathol 51:831-837,
1998.
Tiziani V, Reichenberger E, Buzzo CL et al: The gene for
cherubism maps to chromosome 4p16, Am J Hum Genet
65:158-166, 1999.
Ueki Y, Tiziani V, Santanna C et al: Mutations in the gene
encoding c-Abl-binding protein SH3BP2 cause cherubism,
Nat Genet 125-126, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 673
Von Wowern N: Cherubism: a 36-year long-term follow-up of 2
generations in different families and review of the literature,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:765-772,
2000.
Simple Bone Cyst
Copete MA, Kawamata A, Langlais RP: Solitary bone cyst of the
jaws: radiographic review of 44 cases, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 85:221-225, 1998.
Kaugars GE, Cale AE: Traumatic bone cyst, Oral Surg Oral Med
Oral Pathol 63:318-324, 1987.
Matsumura S, Murakami S, Kakimoto N et al: Histopathologic
and radiographic ﬁndings of the simple bone cyst, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 85:619-625, 1998.
Peñarrocha-Diago M, Sanchis-Bielsa JM, Bonet-Marco J et al:
Surgical treatment and follow-up of solitary bone cyst of the
mandible: a report of seven cases, Br J Oral Maxillofac Surg
39:221-223, 2001.
Perdiagão PF, Silva EC, Sakurai E et al: Idiopathic bone cavity: a
clinical, radiographic, and histological study, Br J Oral Maxil-
lofac Surg 41:407-409, 2003.
Saito Y, Hoshino Y, Nagamine T et al: Simple bone cyst: a clinical
and histopathologic study of ﬁfteen cases, Oral Surg Oral Med
Oral Pathol 74:487-491, 1992.
Sapp JP, Stark ML: Self-healing traumatic bone cysts, Oral Surg
Oral Med Oral Pathol 69:597-602, 1990.
Shimoyama T, Horie N, Nasu D et al: So-called simple bone cyst
of the jaw: a family of pseudocysts of diverse nature and etiol-
ogy, J Oral Sci 41:93-98, 1999.
Tong AC, Ng IO, Yan BS: Variations in clinical presentations of
the simple bone cyst: report of cases, J Oral Maxillofac Surg
61:1487-1491, 2003.
Aneurysmal Bone Cyst
Althof PA, Ohmori K, Zhou M et al: Cytogenetic and molecular
cytogenetic ﬁndings in 43 aneurysmal bone cysts: aberrations
of 17p mapped to 17p13.2 by ﬂuorescence in situ hybridiza-
tion, Mod Pathol 17:518-525, 2004.
Bataineh AB: Aneurysmal bone cysts of the maxilla: a clinico-
pathologic review, J Oral Maxillofac Surg 55:1212-1216,
1997.
Kaffe I, Naor H, Calderon S et al: Radiological and clinical fea-
tures of aneurysmal bone cyst of the jaws, Dentomaxillofac
Radiol 28:167-172, 1999.
Kalantar Motamedi MH: Aneurysmal bone cysts of the jaws:
clinicopathological features, radiographic evaluation and
treatment analysis of 17 cases, J Craniomaxillofac Surg 26:56-
62, 1998.
Mankin HJ, Hornicek FJ, Ortiz-Cruz E et al: Aneurysmal bone
cyst: a review of 150 patients, J Clin Oncol 23:6756-6762,
2005.
Mendenhall WM, Zlotecki RA, Gibbs CP et al: Aneurysmal bone
cyst, Am J Clin Oncol 29:311-315, 2006.
Padwa BL, Denhart BC, Kaban LB: Aneurysmal bone cyst—“plus”:
a report of three cases, J Oral Maxillofac Surg 55:1144-1152,
1997.
Struthers PJ, Shear M: Aneurysmal bone cyst of the jaws. I. Clini-
copathologic features, Int J Oral Surg 13:85-91, 1984.
Struthers PJ, Shear M: Aneurysmal bone cyst of the jaws. II.
Pathogenesis, Int J Oral Surg 13:92-100, 1984.
Toljanic JS, Lechewski E, Huvos AG et al: Aneurysmal bone cyst
of the jaws: a case study and review of the literature, Oral Surg
Oral Med Oral Pathol 64:72-77, 1987.
Fibro-Osseous Lesions—General Aspects and Classiﬁcation
Brannon RB, Fowler CB: Benign ﬁbro-osseous lesions: a review
of current concepts, Adv Anat Pathol 8:126-143, 2001.
Koury ME, Regezi JA, Perrott DH et al: “Atypical” ﬁbro-osseous
lesions: diagnostic challenges and treatment concepts, Int J
Oral Maxillofac Surg 24:162-169, 1995.
MacDonald-Jankowski DS: Fibro-osseous lesions of the face and
jaws, Clin Radiol 59:11-25, 2004.
Slootweg PJ: Maxillofacial ﬁbro-osseous lesions: classiﬁcation
and differential diagnosis, Semin Diagn Pathol 13:104-112,
1996.
Waldron CA: Fibro-osseous lesions of the jaws, J Oral Maxillofac
Surg 51:828-835, 1993.
Wright JM: Reactive, dysplastic and neoplastic conditions of
periodontal ligament origin, Periodontol 2000 21:7-15,
1999.
Fibrous Dysplasia
Akintoye SO, Lee JS, Feimster T et al: Dental characteristics of
ﬁbrous dysplasia and McCune-Albright syndrome, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 96:275-282, 2003.
Akintoye SO, Otis LL, Atkinson JC et al: Analyses of vari-
able panoramic radiographic characteristics of maxillo-
mandibular ﬁbrous dysplasia in McCune-Albright syndrome,
Oral Dis 10:36-43, 2004.
Becelli R, Perugini M, Cerulli G et al: Surgical treatment of
ﬁbrous dysplasia of the cranio-maxillo-facial area. Review of
the literature and personal experience from 1984 to 1999,
Minerva Stomatol 51:293-300, 2002.
Cohen MM Jr, Howell RE: Etiology of ﬁbrous dysplasia and
McCune-Albright syndrome, Int J Oral Maxillofac Surg 28:366-
371, 1999.
DiCaprio MR, Enneking WF: Fibrous dysplasia. Pathophysiol-
ogy, evaluation, and treatment, J Bone Joint Surg Am 87:1848-
1864, 2005.
Frodel JL, Funk G, Boyle J et al: Management of aggressive
midface and orbital ﬁbrous dysplasia, Arch Facial Plast Surg
2:187-195, 2000.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: McCune-Albright
syndrome. In Syndromes of the head and neck, ed 4, pp 334-338,
New York, 2001, Oxford University Press.
MacDonald-Jankowski D: Fibrous dysplasia in the jaws of a
Hong Kong population: radiographic presentation and sys-
tematic review, Dentomaxillofac Radiol 28:195-202, 1999.
Petrikowski CG, Pharoah MJ, Lee L et al: Radiographic differen-
tiation of osteogenic sarcoma, osteomyelitis, and ﬁbrous dys-
plasia, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
80:744-750, 1995.
Waldron CA, Giansanti JS: Benign ﬁbro-osseous lesions of the
jaws. I. Fibrous dysplasia of the jaws, Oral Surg Oral Med Oral
Pathol 35:190-201, 1973.
Cemento-Osseous Dysplasias
Groot RH, van Merkesteyn JPR, Bras J: Diffuse sclerosing osteo-
myelitis and ﬂorid osseous dysplasia, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 81:333-342, 1996.
Higuchi Y, Nakamura N, Tashiro H: Clinicopathologic study of
cemento-osseous dysplasia producing cysts of the mandible,
Oral Surg Oral Med Oral Pathol 65:339-342, 1988.
Kawai T, Hiranuma H, Kishino M et al: Cemento-osseous
dysplasia of the jaws in 54 patients: a radiographic study, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 87:107-114,
1999.
MacDonald-Jankowski DS: Florid cemento-osseous dysplasia: a
systematic review, Dentomaxillofac Radiol 32:141-149, 2003.
Mahomed F, Altini M, Meer S et al: Cemento-osseous dysplasia
with associated simple bone cysts, J Oral Maxillofac Surg
63:1549-1554, 2005.
Melrose RJ: The clinico-pathologic spectrum of cemento-osseous
dysplasia, Oral Maxillofac Clin North Am 9:643-653, 1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

674 ORAL AND MAXILLOFACIAL PATHOLOGY
Melrose RJ, Abrams AM, Mills BG: Florid osseous dysplasia, a
clinico-pathologic study of thirty-four cases, Oral Surg Oral
Med Oral Pathol 41:62-82, 1976.
Schneider LC, Dolinsky HB, Grodjesk JE et al: Malignant spindle
cell tumor arising in the mandible of a patient with ﬂorid
osseous dysplasia, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 88:69-73, 1999.
Schneider LC, Mesa ML: Differences between ﬂorid osseous dys-
plasia and diffuse sclerosing osteomyelitis, Oral Surg Oral Med
Oral Pathol 70:308-312, 1990.
Su L, Weathers DR, Waldron CA: Distinguishing features of
focal cemento-osseous dysplasias and cemento-ossifying
ﬁbromas. I. A pathologic spectrum of 316 cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 84:301-309, 1997.
Summerlin DJ, Tomich CE: Focal cemento-osseous dysplasia: a
clinicopathologic study of 221 cases, Oral Surg Oral Med Oral
Pathol 78:611-620, 1994.
Waldron CA: Fibro-osseous lesions of the jaws, J Oral Maxillofac
Surg 43:249-262, 1985.
Familial Gigantiform Cementoma
Abdelsayed RA, Eversole LR, Singh BS et al: Gigantiform cemen-
toma: clinicopathologic presentation of 3 cases, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 91:438-444, 2001.
Cannon JS, Keller EE, Dahlin DC: Gigantiform cementoma:
report of two cases (mother and son), J Oral Surg 38:65-70,
1980.
Coleman H, Altini M, Kieser J et al: Familial ﬂorid cemento-
osseous dysplasia—a case report and review of the literature,
J Dent Assoc S Afr 51:766-770, 1996.
Finical SJ, Kane WJ, Clay RP et al: Familial gigantiform cemen-
toma, Plast Reconstr Surg 103:949-954, 1999.
Rossbach HC, Letson D, Lacson A et al: Familial gigantiform
cementoma with brittle bone disease, pathologic fractures,
and osteosarcoma: a possible explanation of an ancient
mystery, Pediatr Blood Cancer 44:390-396, 2005.
Toffanin A, Benetti R, Manconi R: Familial ﬂorid cemento-
osseous dysplasia: a case report, J Oral Maxillofac Surg 58:1440-
1446, 2000.
Young SK, Markowitz NR, Sullivan S et al: Familial gigantiform
cementoma: classiﬁcation and presentation of a large pedi-
gree, Oral Surg Oral Med Oral Pathol 68:740-747, 1989.
Ossifying Fibroma
Eversole LR, Leider AS, Nelson K: Ossifying ﬁbroma: a clinico-
pathologic study of 64 cases, Oral Surg Oral Med Oral Pathol
60:505-511, 1985.
MacDonald-Jankowski DS: Cemento-ossifying ﬁbromas in the
jaws of Hong Kong Chinese, Dentomaxillofac Radiol 27:298-
304, 1998.
Pimenta FJ, Silveira LFG, Tavares GC et al: HRPT2 gene altera-
tions in ossifying ﬁbroma of the jaws, Oral Oncol 42:735-739,
2006.
Slootweg PJ: Maxillofacial ﬁbro-osseous lesions: classiﬁcation
and differential diagnosis, Semin Diagn Pathol 13:104-112,
1996.
Su L, Weathers DR, Waldron CA: Distinguishing features of
focal cemento-osseous dysplasias and cemento-ossifying
ﬁbromas. I. A pathologic spectrum of 316 cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 84:301-309, 1997.
Waldron CA, Giansanti JS: Benign ﬁbro-osseous lesions of the
jaws. II. Benign ﬁbro-osseous lesions of periodontal ligament
origin, Oral Surg Oral Med Oral Pathol 35:340-350, 1973.
Juvenile Ossifying Fibroma
El-Mofty S: Psammomatoid and trabecular juvenile ossifying
ﬁbroma of the craniofacial skeleton: two distinct clinico-
pathologic entities, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 93:296-304, 2002.
Johnson LC, Youseﬁ M, Vinh TN et al: Juvenile active ossifying
ﬁbroma: its nature, dynamics and origin, Acta Otolaryngol
Suppl 488:1-40, 1991.
Makek MS: So-called “ﬁbroosseous lesions” of tumorous origin:
biology confronts terminology, J Craniomaxillofac Surg 15:154-
168, 1987.
Margo C, Ragsdale BD, Perman KI et al: Psammomatoid
(juvenile) ossifying ﬁbroma of the orbit, Ophthalmology
92:150-159, 1985.
Slootweg PJ, Panders AK, Koopmans R et al: Juvenile ossifying
ﬁbroma. An analysis of 33 cases with emphasis on histopatho-
logical aspects, J Oral Pathol Med 23:385-388, 1994.
Williams HK, Mangham C, Speight PM: Juvenile ossifying
ﬁbroma. An analysis of eight cases and a comparison with
other ﬁbro-osseous lesions, J Oral Pathol Med 29:13-18,
2000.
Osteoma
Cutilli BJ, Quinn PD: Traumatically induced peripheral osteoma:
report of case, Oral Surg Oral Med Oral Pathol 73:667-669,
1992.
Johann AC, de Freitas JB, de Aguiar MC et al: Peripheral osteoma
of the mandible: case report and review of the literature,
J Craniomaxillofac Surg 33:276-281, 2005.
Kondoh T, Seto K, Kobayashi K: Osteoma of the mandibular
condyle: report of a case with a review of the literature, J Oral
Maxillofac Surg 56:972-979, 1998.
Ortakoglu K, Gunaydin Y, Aydintug YS et al: Osteoma of the
mandibular condyle: report of a case with 5-year follow-up,
Mil Med 170:117-120, 2005.
Richards HE, Strider JW Jr, Short SG et al: Large peripheral
osteoma arising from the genial tubercle area, Oral Surg Oral
Med Oral Pathol 61:268-271, 1986.
Schneider LC, Dolinski HB, Grodjesk JE: Solitary peripheral
osteoma of the jaws: report of a case and review of the litera-
ture, Oral Surg Oral Med Oral Pathol 38:452-455, 1980.
Woldenberg Y, Nash M, Bodner L: Peripheral osteoma of the
maxillofacial region. Diagnosis and management: a study of
14 cases, Med Oral Patol Oral Cir Bucal 10(suppl 2):E139-
E142, 2005.
Yassin OM, Bataineh AB, Mansour MJ: An unusual osteoma of
the mandible, J Clin Pediatr Dent 21:337-340, 1997.
Gardner Syndrome
Baykul T, Heybeli N, Oyar O et al: Multiple huge osteomas of the
mandible causing disﬁgurement related with Gardner’s syn-
drome: case report, Auris Nasus Larynx 30:447-451, 2003.
Bilkay U, Erdem O, Ozek C et al: Benign osteoma with Gardner
syndrome: review of the literature and report of a case,
J Craniofac Surg 15:506-509, 2004.
Butler J, Healy C, Toner M et al: Gardner syndrome—review and
report of a case, Oral Oncol Extra 41:89-92, 2005.
Chimenos-Küstner E, Pascual M, Blanco I et al: Hereditary
familial polyposis and Gardner’s syndrome: contribution
of the odontostomatology examination in its diagnosis and
a case description, Med Oral Patol Oral Cir Bucal 10:402-409,
2005.
Fotiadis C, Tsekouras DK, Antonakis P et al: A case report and
review of the literature, World J Gastroenterol 11:5408-5411,
2005.
Galiatsatos P, Foulkes WD: Familial adenomatous polyposis,
Am J Gastroenterol 101:385-398, 2006.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Gardner syndrome.
In Syndromes of the head and neck, ed 4, pp 437-444, New York,
2001, Oxford University Press. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 14 BONE PATHOLOGY 675
Ida M, Nakamura T, Utsunomiya J: Osteomatous changes
and tooth abnormalities found in the jaws of patients with
adenomatosis coli, Oral Surg Oral Med Oral Pathol 52:2-11,
1981.
Lew D, DeWitt A, Hicks RJ et al: Osteomas of the condyle associ-
ated with Gardner’s syndrome causing limited mandibular
movement, J Oral Maxillofac Surg 57:1004-1009, 1999.
Sondergaard JO, Bulows S, Jarvinen H et al: Dental anomalies in
familial adenomatous polyposis, Acta Odontol Scand 45:61-63,
1987.
Thacker NS, Evans DGR, Horner K et al: Florid oral manifesta-
tions in an atypical familial adenomatous polyposis family
with late presentation of colorectal polyps, J Oral Pathol Med
25:459-462, 1996.
Osteoblastoma
Ahmed MS, Nwoku AL: Benign osteoblastoma of the mandibular
ramus: review of the literature and report of a case, J Oral
Maxillofac Surg 58:1310-1317, 2000.
Angiero F, Mellone P, Baldi A et al: Osteoblastoma of the jaws:
report of two cases and review of the literature, In Vivo
20:665-670, 2006.
Capodiferro S, Maiorano E, Giardina C et al: Osteoblastoma of
the mandible: clinicopathologic study of four cases and litera-
ture review, Head Neck 27:616-625, 2005.
Dorfman HD, Weiss SW: Borderline osteoblastic tumors: prob-
lems in differential diagnosis of aggressive osteoblastoma
and low grade osteosarcoma, Semin Diagn Pathol 1:215-245,
1984.
Eisenbud L, Kahn L, Friedman E: Benign osteoblastoma of
the mandible: ﬁfteen year follow-up showing spontaneous
regression after biopsy, J Oral Maxillofac Surg 45:53-57,
1987.
Jones AC, Prihoda TJ, Kacher JE et al: Osteoblastoma of the
maxilla and mandible: a report of 24 cases, review of the lit-
erature, and discussion of its relationship to osteoid osteoma
of the jaws, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
102:639-650, 2006.
O’Connell JX, Nanthakumar SS, Nielsen GP et al: Osteoid
osteoma: the uniquely innervated bone tumor, Mod Pathol
11:175-180, 1998.
Peters TED, Oliver DR, McDonald JS: Benign osteoblastoma of
the mandible: report of a case, J Oral Maxillofac Surg 53:1347-
1349, 1995.
Rawal YB, Angiero F, Allen CM et al: Gnathic osteoblastoma:
clinicopathologic review of seven cases with long-term follow-
up, Oral Oncol 42:123-130, 2006.
Unni KK: Dahlin’s bone tumors: general aspects and data on
11,087 cases, ed 5, pp 131-142, 1996, Philadelphia,
Lippincott-Raven.
Cementoblastoma
Biggs JT, Benenati FW: Surgically treating a benign cementoblas-
toma while retaining the involved tooth, J Am Dent Assoc
126:1288-1290, 1995.
Brannon RB, Fowler CB, Carpenter WM et al: Cementoblastoma:
an innocuous neoplasm? A clinicopathologic study of 44
cases and review of the literature with special emphasis on
recurrence, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
93:311-320, 2002.
Jelic JS, Loftus MJ, Miller AS et al: Benign cementoblastoma:
report of an unusual case and analysis of 14 additional cases,
J Oral Maxillofac Surg 51:1033-1037, 1993.
Ohki K, Kumamoto H, Nitta Y et al: Benign cementoblastoma
involving multiple maxillary teeth: report of a case with a
review of the literature, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 97:53-58, 2004.
Paciﬁci L, Tallarico M, Bartoli A et al: Benign cementoblastoma:
a clinical case of conservative surgical treatment of the
involved tooth, Minerva Stomatol 53:685-691, 2004.
Slootweg PJ: Cementoblastoma and osteoblastoma: a compari-
son of histologic features, J Oral Pathol Med 21:385-389,
1992.
Ulmansky M, Hjørting-Hansen E, Praetorius F et al: Benign
cementoblastoma. A review and ﬁve new cases, Oral Surg Oral
Med Oral Pathol 77:48-55, 1994.
Chondroma
Dorfman HD, Czerniak B: Bone tumors, pp 253-285, St Louis,
1998, Mosby.
Hyams VJ, Batsakis JG, Michaels L: Tumors of the upper respiratory
tract and ear, atlas of tumor pathology, series 2, fascicle 25,
pp 163-164, Washington, DC, 1988, Armed Forces Institute
of Pathology.
Lazow SK, Pihlstrom RT, Solomon MP: Condylar chondroma:
report of a case, J Oral Maxillofac Surg 56:373-378, 1998.
Unni KK: Dahlin’s bone tumors. General aspects and data on 11,087
cases, ed 5, pp 25-35, Philadelphia, 1996, Lippincott-Raven.
Chondromyxoid Fibroma
Chow LTC, Lin J, Yip KMH et al: Chondromyxoid ﬁbroma-like
osteosarcoma: a distinct variant of low-grade osteosarcoma,
Histopathology 29:429-436, 1996.
Damm DD, White DK, Geissler RH et al: Chondromyxoid
ﬁbroma of the maxilla: electron microscopic ﬁndings and
review of the literature, Oral Surg Oral Med Oral Pathol 59:176-
183, 1985.
Hammad HM, Hammond HL, Kurago ZB et al: Chondromyxoid
ﬁbroma of the jaws: case report and review of the literature,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85:293-300,
1998.
Macan D, Cabov T, Uglesic V et al: Chondromyxoid ﬁbroma of
the mandible, Br J Oral Maxillofac Surg 41:261-263, 2003.
Müller S, Whitaker SB, Weathers DR: Chondromyxoid ﬁbroma
of the mandible: diagnostic image cytometry ﬁndings and
review of the literature, Oral Surg Oral Med Oral Pathol 73:465-
468, 1992.
Smith CA, Magenis RE, Himoe E et al: Chondromyxoid ﬁbroma
of the nasal cavity with an interstitial insertion between
chromosomes 6 and 19, Cancer Genet Cytogenet 171:97-100,
2006.
Tallini G, Dorfman H, Brys P et al: Correlation between clinico-
pathological features and karyotype in 100 cartilaginous and
chordoid tumours. A report from the Chromosomes and
Morphology (CHAMP) Collaborative Study Group, J Pathol
196:194-203, 2002.
Wu CT, Inwards CY, O’Laughlin S et al: Chondromyxoid ﬁbroma
of bone: a clinicopathologic review of 278 cases, Hum Pathol
29:438-446, 1998.
Synovial Chondromatosis
Ardekian L, Faquin W, Troulis MJ et al: Synovial chondromatosis
of the temporomandibular joint: report and analysis of eleven
cases, J Oral Maxillofac Surg 63:941-947, 2005.
Deahl ST, Ruprecht A: Asymptomatic, radiographically detected
chondrometaplasia in the temporomandibular joint, Oral
Surg Oral Med Oral Pathol 72:371-374, 1991.
Holmlund AB, Eriksson L, Reinholt FP: Synovial chondromatosis
of the temporomandibular joint: clinical, surgical and histo-
logical aspects, Int J Oral Maxillofac Surg 32:143-147, 2003.
Karlis V, Glickman RS, Zaslow M: Synovial chondromatosis of
the temporomandibular joint with intracranial extension,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86:664-666,
1998. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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676 ORAL AND MAXILLOFACIAL PATHOLOGY
Lustman J, Zeltzer R: Synovial chondromatosis of the temporo-
mandibular joint: review of the literature and case report,
Int J Oral Maxillofac Surg 18:90-94, 1989.
Miyamoto H, Sakashita H, Wilson DF et al: Synovial chondroma-
tosis of the temporomandibular joint, Br J Oral Maxillofac Surg
38:205-208, 2000.
Petito AR, Bennett J, Assael LA et al: Synovial chondromatosis of
the temporomandibular joint: varying presentation in 4 cases,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:758-764,
2000.
Von Lindern JJ, Theuerkauf I, Niederhagen B et al: Synovial
chondromatosis of the temporomandibular joint: clinical,
diagnostic, and histomorphologic ﬁndings, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 94:31-38, 2002.
Yu Q, Yang Y, Wang P et al: CT features of synovial chondroma-
tosis in the temporomandibular joint, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 97:524-528, 2004.
Desmoplastic Fibroma
Bakaeen G, Rajab LD: Desmoplastic ﬁbroma of the mandible:
report of a case, Int J Paediatr Dent 9:117-121, 1999.
Bertoni F, Present D, Marchetti C et al: Desmoplastic ﬁbroma of
the jaw: the experience of the Istituto Beretta, Oral Surg Oral
Med Oral Pathol 61:179-184, 1986.
Fletcher CDM, Uni KK, Mertens F: WHO classiﬁcation of tumors:
pathology and genetics of tumors of soft tissue and bone, p 288,
Lyon, France, 2002, IARC Press.
Freedman PD, Cardo VA, Kerpel SM et al: Desmoplastic ﬁbroma
(ﬁbromatosis) of the jaw-bones: report of a case and review
of the literature, Oral Surg Oral Med Oral Pathol 46:386-395,
1978.
Said-Al-Naief N, Fernandes R, Louis P et al: Desmoplastic ﬁbroma
of the jaw: a case report and review of literature, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 101:82-94,
2006.
Templeton K, Glass N, Young SK: Desmoplastic ﬁbroma of the
mandible in a child: report of a case, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 84:620-623, 1997.
Vargas-Gonzalez R, San Martin-Brieke W, Gil-Orduna C et al:
Desmoplastic ﬁbroma-like tumor of maxillofacial region asso-
ciated with tuberous sclerosis, Pathol Oncol Res10:237-239,
2004.
Osteosarcoma
August M, Magennis P, Dewitt D: Osteogenic sarcoma of the
jaws: factors inﬂuencing prognosis, Int J Oral Maxillofac Surg
26:198-204, 1997.
Bennett JH, Thomas G, Evans AW et al: Osteosarcoma of the
jaws: a 30-year retrospective review, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 90:323-333, 2000.
Canadian Society of Otolaryngology-Head and Neck Surgery
Oncology Study Group: Osteogenic sarcoma of the mandible
and maxilla: a Canadian review (1980-2000), J Otolaryngol
33:139-144, 2004.
Fernandes R, Nikitakis NG, Pazoki A et al: Osteogenic sarcoma
of the jaw: a 10-year experience, J Oral Maxillofac Surg
65:1286-1291, 2007.
Garrington GE, Scoﬁeld HH, Cornyn J et al: Osteosarcoma of the
jaws: analysis of 56 cases, Cancer 20:377-391, 1967.
Givol N, Buchner A, Taicher S et al: Radiological features of
osteogenic sarcoma of the jaws. A comparative study of dif-
ferent radiographic modalities, Dentomaxillofac Radiol 27:313-
320, 1998.
Huvos AG, Woodard HQ, Cahan WG et al: Postradiation
sarcoma of bone and soft tissues: a clinicopathologic study of
66 patients, Cancer 55:1244-1255, 1985.
Lewis M, Perl A, Som PM et al: Osteogenic sarcoma of the jaw.
A clinicopathologic review of 12 patients, Arch Otolaryngol
Head Neck Surg 123:169-174, 1997.
Nakayama E, Sugiura K, Ishibashi H et al: The clinical and diag-
nostic imaging ﬁndings of osteosarcoma of the jaw, Dentomax-
illofac Radiol 34:182-188, 2005.
Nakayama E, Sugiura K, Kobayashi I et al: The association
between the computed tomography ﬁndings, histologic fea-
tures, and outcome of osteosarcoma of the jaw, J Oral Maxil-
lofac Surg 63:311-318, 2005.
Oda D, Bavisotto LM, Schmidt RA et al: Head and neck osteo-
sarcoma at the University of Washington, Head Neck 19:513-
523, 1997.
Ogunlewe MO, Ajayi OF, Adeyemo WL et al: Osteogenic sarcoma
of the jaw bones: a single institution experience over a 21-
year period, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
101:76-81, 2006.
Patel SG, Meyers P, Huvos AG et al: Improved outcomes in
patients with osteogenic sarcoma of the head and neck,
Cancer 95:1495-1503, 2002.
Patel SG, See ACH, Williamson PA et al: Radiation-induced
sarcoma of the head and neck, Head Neck 21:346-354,
1999.
Piattelli A, Favia GF: Periosteal osteosarcoma of the jaws: report
of 2 cases, J Periodontol 71:325-329, 2000.
Rosen G, Caparros B, Huvos AG: Preoperative chemotherapy
for osteogenic sarcoma: selection of postoperative chemo-
therapy based upon the response of the primary tumor
to preoperative chemotherapy, Cancer 49:1221-1230,
1982.
Slootweg PJ, Müller H: Osteosarcoma of the jawbones, J Maxillo-
fac Surg 13:158-166, 1985.
Smeele LE, Kostense PJ, van der Waal I et al: Effect of chemo-
therapy on survival of craniofacial osteosarcoma: a systematic
review of 201 patients, J Clin Oncol 15:363-367, 1997.
Tanzawa H, Uchiyama S, Sato K: Statistical observation of osteo-
sarcoma of the maxillofacial region in Japan, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2:444-448, 1991.
van Es RJJ, Keus RB, van der Waal I et al: Osteosarcoma of the
jaw bones. Long-term follow up of 48 cases, Int J Oral Maxil-
lofac Surg 26:191-197, 1997.
Chondrosarcoma
Aziz SR, Miremadi AR, McCabe JC: Mesenchymal chondrosar-
coma of the maxilla with diffuse metastasis: case report
and literature review, J Oral Maxillofac Surg 60:931-935,
2002.
Garrington GE, Collett WK: Chondrosarcoma. I. A selected lit-
erature review, J Oral Pathol 17:1-11, 1988.
Garrington GE, Collett WK: Chondrosarcoma. II. Chondrosar-
coma of the jaws: analysis of 37 cases, J Oral Pathol 17:12-20,
1988.
Koch BB, Karnell LH, Hoffman HT et al: National Cancer Data-
base report on chondrosarcoma of the head and neck, Head
Neck 22:408-425, 2000.
Lockhart R, Menard P, Martin JP et al: Mesenchymal chondro-
sarcoma of the jaws: report of four cases, Int J Oral Maxillofac
Surg 27:358-362, 1998.
Nakashima Y, Unni KK, Shives TC et al: Mesenchymal chondro-
sarcoma of bone and soft tissue: a review of 111 cases, Cancer
57:2444-2453, 1985.
Saito K, Unni KK, Wollan PC et al: Chondrosarcoma of the jaw
and facial bones, Cancer 76:1550-1558, 1995.
Vencio EF, Reeve CM, Unni KK et al: Mesenchymal chondrosar-
coma of the jaw bones. Clinicopathologic study of 19 cases,
Cancer 82:2350-2355, 1998. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 14 BONE PATHOLOGY 677
Ewing Sarcoma
Arafat A, Ellis G, Adrian JC: Ewing’s sarcoma of the jaws, Oral
Surg Oral Med Oral Pathol 55:589-596, 1983.
Berk R, Heller A, Heller D et al: Ewing’s sarcoma of the mandi-
ble: a case report, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 79:159-162, 1995.
Daw NC, Mahmoud HH, Meyer WH et al: Bone sarcomas of the
head and neck in children: the St. Jude Children’s Research
Hospital experience, Cancer 88:2172-2180, 2000.
de Alava E, Gerald WL: Molecular biology of the Ewing’s
sarcoma/primitive neuroectodermal tumor family, J Clin
Oncol 18:204-213, 2000.
Fiorillo A, Tranfa F, Canale G et al: Primary Ewing’s sarcoma of
the maxilla, a rare and curable localization: report of two new
cases, successfully treated by radiotherapy and systemic che-
motherapy, Cancer Lett 103:177-182, 1996.
Infante-Cassio P, Gutierrez-Perez JL, Garcia-Perla A et al:
Primary Ewing’s sarcoma of the maxilla and zygoma: report
of a case, J Oral Maxillofac Surg 63:1539-1542, 2005.
Kissane JM, Askin FB, Foulkes M et al: Ewing’s sarcoma of bone:
clinicopathologic aspects of 303 cases from the intergroup
Ewing’s sarcoma study, Hum Pathol 14:773-779, 1983.
La TH, Meyers PA, Wexler LH et al: Radiation therapy for
Ewing’s sarcoma: results from Memorial Sloan-Kettering in
the modern era, Int J Radiat Oncol Biol Phys 2:544-550,
2006.
Schultze-Mosgau S, Thorwarth M, Wehrhan F et al: Ewing
sarcoma of the mandible in a child: interdisciplinary treat-
ment concepts and surgical reconstruction, J Craniofac Surg
16:1140-1146, 2005.
Vaccani JP, Forte V, de Jong Al et al: Ewing’s sarcoma of the head
and neck in children, Int J Pediatr Otorhinolaryngol 48:209-
216, 1999.
Wexler LH, Kacker A, Piro JD et al: Combined modality treat-
ment of Ewing’s sarcoma of the maxilla, Head Neck 25:168-
172, 2003.
Metastatic Tumors to the Jaws
Bouquot JE, Weiland LH, Kurland LT: Metastasis to and from the
upper aero-digestive tract in the population of Rochester,
Minnesota, 1935-1984, Head Neck 11:212-218, 1989.
Clausen F, Poulson H: Metastatic carcinoma of the jaws, Acta
Pathol Microbiol Scand 57:361-374, 1963.
D’Silva NJ, Summerlin DJ, Cordell KG et al: Metastatic tumors
in the jaws: a retrospective study of 114 cases, J Am Dent Assoc
137:1667-1672, 2006.
Hashimoto N, Kurihara K, Yamasaki H et al: Pathologic charac-
teristics of metastatic carcinoma in the human mandible,
J Oral Pathol 16:362-367, 1987.
O’Carroll MK, Krolls SO, Mosca NG: Metastatic carcinoma to the
mandible: report of two cases, Oral Surg Oral Med Oral Pathol
76:368-374, 1993.
Zachariades N: Neoplasms metastatic to the mouth, jaws and
surrounding tissues, J Craniomaxillofac Surg 17:283-290,
1989. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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678
15
Odontogenic Cysts and Tumors
*
CHAPTER OUTLINE
ODONTOGENIC CYSTS
Dentigerous Cyst
Eruption Cyst
Primordial Cyst
Odontogenic Keratocyst
Orthokeratinized Odontogenic Cyst
Nevoid Basal Cell Carcinoma Syndrome
Gingival (Alveolar) Cyst of the Newborn
Gingival Cyst of the Adult
Lateral Periodontal Cyst
Calcifying Odontogenic Cyst
Glandular Odontogenic Cyst
Buccal Bifurcation Cyst
Carcinoma Arising in Odontogenic Cysts
ODONTOGENIC TUMORS
TUMORS OF ODONTOGENIC EPITHELIUM
Ameloblastoma
Malignant Ameloblastoma and Ameloblastic
Carcinoma
Clear Cell Odontogenic Carcinoma
Adenomatoid Odontogenic Tumor
Calcifying Epithelial Odontogenic Tumor
Squamous Odontogenic Tumor
MIXED ODONTOGENIC TUMORS
Ameloblastic Fibroma
Ameloblastic Fibro-Odontoma
Ameloblastic Fibrosarcoma
Odontoameloblastoma
Odontoma
TUMORS OF ODONTOGENIC ECTOMESENCHYME
Central Odontogenic Fibroma
Peripheral Odontogenic Fibroma
Granular Cell Odontogenic Tumor
Odontogenic Myxoma
Cementoblastoma
Odontogenic cysts and tumors constitute an important
aspect of oral and maxillofacial pathology. Odonto-
genic cysts are encountered relatively commonly in
dental practice. Odontogenic tumors, by contrast, are
uncommon lesions. Even in the specialized oral and
maxillofacial pathology laboratory, fewer than 1% of all
specimens received are odontogenic tumors.
Odontogenic Cysts
With rare exceptions, epithelium-lined cysts in bone
are seen only in the jaws. Other than a few cysts that
may result from the inclusion of epithelium along
embryonic lines of fusion, most jaw cysts are lined by
epithelium that is derived from odontogenic epithe-
lium. These are referred to as odontogenic cysts. (Non-
odontogenic jaw cysts are discussed in Chapter 1.)
Odontogenic cysts are subclassiﬁed as developmen-
tal or inﬂammatory in origin. The inciting factors that
initiate the formation of developmental cysts are
*Dr. Charles A. Waldron wrote the original version of this chapter in the
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Chapter 15 ODONTOGENIC CYSTS AND TUMORS 679
unknown, but these lesions do not appear to be the
result of an inﬂammatory reaction. Inﬂammatory
cysts are the result of inﬂammation. Box 15-1 presents
categories of odontogenic cysts modiﬁed from the
2005 World Health Organization (WHO) classiﬁca-
tion. (The periapical cyst is discussed in Chapter 3.)
DENTIGEROUS CYST
(FOLLICULAR CYST)
The dentigerous cyst is deﬁned as a cyst that origi-
nates by the separation of the follicle from around the
crown of an unerupted tooth. This is the most common
type of developmental odontogenic cyst, making up
about 20% of all epithelium-lined cysts of the jaws. The
dentigerous cyst encloses the crown of an unerupted
tooth and is attached to the tooth at the cemento-
enamel junction (Fig. 15-1). The pathogenesis of this
cyst is uncertain, but apparently it develops by accu-
mulation of ﬂuid between the reduced enamel epithe-
lium and the tooth crown.
Although most dentigerous cysts are considered to
be developmental in origin, there are some examples
that appear to have an inﬂammatory pathogenesis. For
example, it has been suggested that, on occasion, a
dentigerous cyst may develop around the crown of an
unerupted permanent tooth as a result of periapical
inﬂammation from an overlying primary tooth. Another
scenario involves a partially erupted mandibular third
molar that develops an inﬂamed cystlike lesion along
the distal or buccal aspect. Although many such lesions
probably are due to inﬂammation associated with
recurrent pericoronitis, these lesions are usually diag-
nosed as examples of dentigerous cyst, especially
because it is impossible to determine histopathologi-
cally whether the inﬂammatory component is primary
or secondary in nature. The term paradental cyst
sometimes has been applied to these lesions, but the
use of this term in the literature is confusing because
it also has been used to describe examples of what is
known as the buccal bifurcation cyst.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although dentigerous cysts may occur in association
with any unerupted tooth, most often they involve
mandibular third molars. Other relatively frequent
sites include maxillary canines, maxillary third molars,
and mandibular second premolars. Dentigerous cysts
rarely involve unerupted deciduous teeth. Occasion-
ally, they are associated with supernumerary teeth or
odontomas.
Although dentigerous cysts may be encountered in
patients across a wide age range, they are discovered
most frequently in patients between 10 and 30 years
of age. There is a slight male predilection, and the
prevalence is higher for whites than for blacks. Small
dentigerous cysts are usually completely asymptomatic
and are discovered only on a routine radiographic
examination or when ﬁlms are taken to determine the
reason for the failure of a tooth to erupt. Dentigerous
cysts can grow to a considerable size, and large cysts
may be associated with a painless expansion of the
bone in the involved area. Extensive lesions may result
Box 15-1
Classiﬁcation of Odontogenic Cysts
DEVELOPMENTAL
● Dentigerous cyst
● Eruption cyst
● Odontogenic keratocyst*
●Orthokeratinized odontogenic cyst
●Gingival (alveolar) cyst of the newborn
●Gingival cyst of the adult
●Lateral periodontal cyst
●Calcifying odontogenic cyst
†
●Glandular odontogenic cyst
INFLAMMATORY
●Periapical (radicular) cyst
●Residual periapical (radicular) cyst
●Buccal bifurcation cyst
*Although the odontogenic keratocyst is included with the odontogenic
tumors in the 2005 World Health Organization (WHO) classification
(“keratocystic odontogenic tumor”), the authors prefer to classify it as an
odontogenic cyst.
†
The term calcifying odontogenic cyst includes both nonneoplastic cysts
and true neoplasms. Although the calcifying odontogenic cyst is
included with odontogenic tumors in the 2005 WHO classiﬁcation, it is
discussed with the odontogenic cysts in this chapter.
Fig. 15-1 Dentigerous cyst. Gross specimen of a
dentigerous cyst involving a maxillary canine tooth. The cyst
has been cut open to show the cyst-to-crown relationship. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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680 ORAL AND MAXILLOFACIAL PATHOLOGY
in facial asymmetry. Large dentigerous cysts are uncom-
mon, and most lesions that are considered to be large
dentigerous cysts on radiographic examination will
prove to be odontogenic keratocysts or ameloblasto-
mas. Dentigerous cysts may become infected and be
associated with pain and swelling. Such infections may
arise in a dentigerous cyst that is associated with a
partially erupted tooth or by extension from a peri-
apical or periodontal lesion that affects an adjacent
tooth.
Radiographically, the dentigerous cyst typically
shows a unilocular radiolucent area that is associated
with the crown of an unerupted tooth. The radiolu-
cency usually has a well-deﬁned and often sclerotic
border, but an infected cyst may show ill-deﬁned
borders. A large dentigerous cyst may give the impres-
sion of a multilocular process because of the persis-
tence of bone trabeculae within the radiolucency.
Dentigerous cysts, however, are grossly and histopath-
ologically unilocular processes and probably never are
truly multilocular lesions.
The cyst-to-crown relationship shows several radio-
graphic variations. In the central variety, which is the
most common, the cyst surrounds the crown of the
tooth and the crown projects into the cyst (Fig. 15-2).
The lateral variety is usually associated with mesioan-
gular impacted mandibular third molars that are par-
tially erupted. The cyst grows laterally along the root
surface and partially surrounds the crown (Fig. 15-3).
In the circumferential variant, the cyst surrounds the
crown and extends for some distance along the root so
that a signiﬁcant portion of the root appears to lie
within the cyst (Fig. 15-4). Rarely, a third molar may
be displaced to the lower border of the mandible or
higher up into the ascending ramus. Maxillary anterior
teeth may be displaced into the ﬂoor of the nose, and
other maxillary teeth may be moved through the maxil-
lary sinus to the ﬂoor of the orbit. Dentigerous cysts
may displace the involved tooth for a considerable dis-
tance. Root resorption of adjacent erupted teeth can
occur.
Radiographic distinction between a small dentiger-
ous cyst and an enlarged follicle about the crown of an
unerupted tooth is difﬁcult and may be largely an aca-
demic exercise (Fig. 15-5). For the lesion to be consid-
ered a dentigerous cyst, some investigators believe that
the radiolucent space surrounding the tooth crown
should be at least 3 to 4 mm in diameter. Radiographic
ﬁndings are not diagnostic for a dentigerous cyst,
however, because odontogenic keratocysts, unilocular
ameloblastomas, and many other odontogenic and
nonodontogenic tumors may have radiographic fea-
tures that are essentially identical to those of a dentig-
erous cyst.
Fig. 15-2 Dentigerous cyst. Central type showing the
crown projecting into the cystic cavity. (Courtesy of Dr. Stephen E.
Irwin.)
Fig. 15-3 Dentigerous cyst. Lateral variety showing a large
cyst along the mesial root of the unerupted molar. This cyst
exhibited mucous cell prosoplasia. (Courtesy of Dr. John R. Cramer.)
Fig. 15-4 Dentigerous cyst. Circumferential variety
showing cyst extension along the mesial and distal roots of
the unerupted tooth. (Courtesy of Dr. Richard Marks.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 681
HISTOPATHOLOGIC FEATURES
The histopathologic features of dentigerous cysts vary,
depending on whether the cyst is inﬂamed or not
inﬂamed. In the noninﬂamed dentigerous cyst, the
ﬁbrous connective tissue wall is loosely arranged and
contains considerable glycosaminoglycan ground sub-
stance. Small islands or cords of inactive-appearing
odontogenic epithelial rests may be present in the
ﬁbrous wall. Occasionally these rests may be numer-
ous, and at times pathologists who are not familiar with
oral lesions have misinterpreted this ﬁnding as amelo-
blastoma. The epithelial lining consists of two to four
layers of ﬂattened nonkeratinizing cells, and the epi-
thelium and connective tissue interface is ﬂat (Fig.
15-6).
In the fairly common inﬂamed dentigerous cyst,
the ﬁbrous wall is more collagenized, with a variable
inﬁltration of chronic inﬂammatory cells. The epithe-
lial lining may show varying amounts of hyperplasia
with the development of rete ridges and more deﬁnite
squamous features (Fig. 15-7). A keratinized surface is
sometimes seen, but these changes must be differenti-
ated from those observed in the odontogenic kerato-
cyst. Focal areas of mucous cells may be found in the
epithelial lining of dentigerous cysts (Fig. 15-8). Rarely,
ciliated columnar cells are present. Small nests of seba-
ceous cells rarely may be noted within the ﬁbrous cyst
wall. These mucous, ciliated, and sebaceous elements
are believed to represent the multipotentiality of the
odontogenic epithelial lining in a dentigerous cyst.
Gross examination of the wall of a dentigerous cyst
may reveal one or several areas of nodular thickening
Fig. 15-5 Dentigerous cyst or enlarged follicle.
Radiolucent lesion involving the crown of an unerupted
mandibular premolar. Distinction between a dentigerous cyst
and an enlarged follicle for a lesion of this size by
radiographic and even histopathologic means is difﬁcult, if
not impossible. (Courtesy of Dr. Wally Austelle.)
Fig. 15-6 Dentigerous cyst. This noninﬂamed dentigerous
cyst shows a thin, nonkeratinized epithelial lining.
Fig. 15-7 Dentigerous cyst. This inﬂamed dentigerous cyst
shows a thicker epithelial lining with hyperplastic rete ridges.
The ﬁbrous cyst capsule shows a diffuse chronic
inﬂammatory inﬁltrate.
Fig. 15-8 Dentigerous cyst. Scattered mucous cells can be
seen within the epithelial lining. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

682 ORAL AND MAXILLOFACIAL PATHOLOGY
on the luminal surface. These areas must be examined
microscopically to rule out the presence of early neo-
plastic change.
Because a thin layer of reduced enamel epithelium
normally lines the dental follicle surrounding the
crown of an unerupted tooth, it can be difﬁcult to dis-
tinguish a small dentigerous cyst from simply a normal
or enlarged dental follicle based on microscopic fea-
tures alone. Again, this distinction often represents
largely an academic exercise; the most important con-
sideration is ensuring that the lesion does not represent
a more signiﬁcant pathologic process (e.g., odontogenic
keratocyst or ameloblastoma).
TREATMENT AND PROGNOSIS
The usual treatment for a dentigerous cyst is careful
enucleation of the cyst together with removal of the
unerupted tooth. If eruption of the involved tooth is
considered feasible, then the tooth may be left in place
after partial removal of the cyst wall. Patients may need
orthodontic treatment to assist eruption. Large dentig-
erous cysts also may be treated by marsupialization.
This permits decompression of the cyst, with a result-
ing reduction in the size of the bone defect. The cyst
can then be excised at a later date, with a less extensive
surgical procedure.
The prognosis for most dentigerous cysts is excel-
lent, and recurrence seldom is noted after complete
removal of the cyst. However, several potential compli-
cations must be considered. Much has been written
about the possibility that the lining of a dentigerous
cyst might undergo neoplastic transformation to an
ameloblastoma. Although undoubtedly this can occur,
the frequency of such neoplastic transformation is low.
Rarely, a squamous cell carcinoma may arise in the
lining of a dentigerous cyst (see page 700). It is likely
that some intraosseous mucoepidermoid carcino-
mas (see page 490) develop from mucous cells in the
lining of a dentigerous cyst.
ERUPTION CYST (ERUPTION
HEMATOMA)
The eruption cyst is the soft tissue analogue of the
dentigerous cyst. The cyst develops as a result of sepa-
ration of the dental follicle from around the crown of
an erupting tooth that is within the soft tissues overly-
ing the alveolar bone. One example of eruption cysts
developing in a child who was taking cyclosporin A has
been described. Presumably the cysts developed
because of collagen deposition in the gingival connec-
tive tissue that resulted in a thicker, less penetrable,
pericoronal roof.
CLINICAL FEATURES
The eruption cyst appears as a soft, often translucent
swelling in the gingival mucosa overlying the crown of
an erupting deciduous or permanent tooth. Most exam-
ples are seen in children younger than age 10. Although
the cyst may occur with any erupting tooth, the lesion
is most commonly associated with the deciduous man-
dibular central incisors, the ﬁrst permanent molars,
and the deciduous maxillary incisors. Surface trauma
may result in a considerable amount of blood in the
cystic ﬂuid, which imparts a blue to purple-brown
color. Such lesions sometimes are referred to as erup-
tion hematomas (Fig. 15-9).
HISTOPATHOLOGIC FEATURES
Intact eruption cysts seldom are submitted to the oral
and maxillofacial pathology laboratory, and most
examples consist of the excised roof of the cyst, which
has been removed to facilitate tooth eruption. These
show surface oral epithelium on the superior aspect.
The underlying lamina propria shows a variable inﬂam-
matory cell inﬁltrate. The deep portion of the speci-
men, which represents the roof of the cyst, shows a thin
layer of nonkeratinizing squamous epithelium (Fig.
15-10).
TREATMENT AND PROGNOSIS
Treatment may not be required because the cyst usually
ruptures spontaneously, permitting the tooth to erupt.
If this does not occur, then simple excision of the roof
of the cyst generally permits speedy eruption of the
tooth.
Fig. 15-9 Eruption cyst. This soft gingival swelling contains
considerable blood and can also be designated as an eruption
hematoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 683
PRIMORDIAL CYST
The concept and meaning of the term primordial cyst
often have been controversial and confusing. In the
older classiﬁcation of cysts widely used in the United
States, the primordial cyst was considered to originate
from cystic degeneration of the enamel organ epithe-
lium before the development of dental hard tissue.
Therefore, the primordial cyst occurs in place of a
tooth.
In the mid 1950s, oral pathologists in Europe
introduced the term odontogenic keratocyst to
denote a cyst with speciﬁc histopathologic features and
clinical behavior, which was believed to arise from the
dental lamina (i.e., the dental primordium). Subse-
quently, this concept was widely accepted, and the
terms odontogenic keratocyst and primordial cyst were
used synonymously. The 1972 WHO classiﬁcation
used the designation primordial cyst as the preferred
term for this lesion. The 1992 WHO classiﬁcation,
however, listed odontogenic keratocyst as the preferred
designation.
Whether there is a primordial cyst that is not micro-
scopically an odontogenic keratocyst is still unsettled.
Many believe that all primordial cysts are odontogenic
keratocysts, although some recognize the existence of
a primordial cyst that does not have the histopathologic
features of the odontogenic keratocyst. If such a lesion
exists, then it must be exceedingly rare. Reference to
this lesion is almost nonexistent in the current litera-
ture, and no reported series include a signiﬁcant
number of cases. In the authors’ experience, a cyst
clinically considered to represent a primordial cyst,
in the older meaning of the term, almost always is
an odontogenic keratocyst after microscopic study
(Fig. 15-11).
ODONTOGENIC KERATOCYST
The odontogenic keratocyst is a distinctive form of
developmental odontogenic cyst that deserves special
consideration because of its speciﬁc histopathologic
features and clinical behavior. There is general agree-
ment that the odontogenic keratocyst arises from cell
rests of the dental lamina. This cyst shows a different
growth mechanism and biologic behavior from the
more common dentigerous cyst and radicular cyst.
Most authors believe that dentigerous and radicular
cysts continue to enlarge as a result of increased osmotic
pressure within the lumen of the cyst. This mechanism
does not appear to hold true for odontogenic kerato-
cysts, and their growth may be related to unknown
factors inherent in the epithelium itself or enzymatic
activity in the ﬁbrous wall. Several investigators have
suggested that odontogenic keratocysts be regarded as
benign cystic neoplasms rather than cysts, and in the
latest WHO classiﬁcation of odontogenic tumors, these
lesions have been given the name “keratocystic odon-
togenic tumor.” The arguments to support this change
in nomenclature largely rely on a few studies that have
shown certain molecular genetic alterations that are
also present in some neoplasms. Unfortunately, these
studies have not examined other cystic lesions of the
jaws; therefore, it is currently unknown whether these
alterations are unique to the odontogenic keratocyst.
Most oral and maxillofacial pathologists do not feel
that sufﬁcient evidence exists to justify renaming this
widely recognized lesion, with the likely result of
causing widespread confusion among the professional
community.
Although there are wide variations in the reported
frequency of odontogenic keratocysts compared with
that of other types of odontogenic cysts, several studies
Fig. 15-10 Eruption cyst. A cystic epithelial cavity can be
seen below the mucosal surface.
Fig. 15-11 Primordial cyst. This patient gave no history of
extraction of the third molar. A cyst is located in the third
molar area. The cyst was excised, and histopathologic
examination revealed an odontogenic keratocyst. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

684 ORAL AND MAXILLOFACIAL PATHOLOGY
that include large series of cysts indicate that odonto-
genic keratocysts make up 3% to 11% of all odontogenic
cysts.
CLINICAL AND RADIOGRAPHIC
FEATURES
Odontogenic keratocysts may be found in patients who
range in age from infancy to old age, but about 60% of
all cases are diagnosed in people between 10 and 40
years of age. There is a slight male predilection. The
mandible is involved in 60% to 80% of cases, with a
marked tendency to involve the posterior body and
ascending ramus (Fig. 15-12).
Small odontogenic keratocysts are usually asymp-
tomatic and discovered only during the course of a
radiographic examination. Larger odontogenic kerato-
cysts may be associated with pain, swelling, or drain-
age. Some extremely large cysts, however, may cause
no symptoms.
Odontogenic keratocysts tend to grow in an antero-
posterior direction within the medullary cavity of the
bone without causing obvious bone expansion. This
feature may be useful in differential clinical and radio-
graphic diagnosis because dentigerous and radicular
cysts of comparable size are usually associated with
bony expansion. Multiple odontogenic keratocysts may
be present, and such patients should be evaluated for
other manifestations of the nevoid basal cell carci-
noma (Gorlin) syndrome (see page 688).
Odontogenic keratocysts demonstrate a well-
deﬁned radiolucent area with smooth and often corti-
cated margins. Large lesions, particularly in the
posterior body and ascending ramus of the mandible,
may appear multilocular (Fig. 15-13). An unerupted
tooth is involved in the lesion in 25% to 40% of cases;
in such instances, the radiographic features suggest
the diagnosis of dentigerous cyst (Figs. 15-14 and
15-15). In these cases, the cyst has presumably arisen
from dental lamina rests near an unerupted tooth and
has grown to envelop the unerupted tooth. Resorption
of the roots of erupted teeth adjacent to odontogenic
keratocysts is less common than that noted with den-
tigerous and radicular cysts.
The diagnosis of odontogenic keratocyst is based
on the histopathologic features. The radiographic ﬁnd-
ings, although often highly suggestive, are not diagnos-
tic. The radiographic ﬁndings in an odontogenic
keratocyst may simulate those of a dentigerous cyst, a
radicular cyst, a residual cyst, a lateral periodontal cyst
(Fig. 15-16), or the so-called globulomaxillary cyst
(which is no longer considered to be a true entity).
Odontogenic keratocysts of the anterior midline maxil-
lary region can mimic nasopalatine duct cysts. For
unknown reasons, this particular subset of keratocyst
usually occurs in older individuals with a mean age of
20% 2%13%
49% 7% 9%
Fig. 15-12 Odontogenic keratocyst. Relative distribution
of odontogenic keratocysts in the jaws.
Fig. 15-13 Odontogenic keratocyst. Large, multilocular
cyst involving most of the ascending ramus. (Courtesy of Dr. S.C.
Roddy.)
Fig. 15-14 Odontogenic keratocyst. This cyst involves the
crown of an unerupted premolar. Radiographically, this lesion
cannot be differentiated from a dentigerous cyst. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 685
nearly 70 years. Rare examples of peripheral odonto-
genic keratocysts within the gingival soft tissues have
been reported.
HISTOPATHOLOGIC FEATURES
The odontogenic keratocyst typically shows a thin,
friable wall, which is often difﬁcult to enucleate from
the bone in one piece. The cystic lumen may contain a
clear liquid that is similar to a transudate of serum, or
it may be ﬁlled with a cheesy material that, on micro-
scopic examination, consists of keratinaceous debris.
Microscopically, the thin ﬁbrous wall is essentially
devoid of any inﬂammatory inﬁltrate. The epithelial
lining is composed of a uniform layer of stratiﬁed squa-
mous epithelium, usually six to eight cells in thickness.
The epithelium and connective tissue interface is
usually ﬂat, and rete ridge formation is inconspicuous.
Detachment of portions of the cyst-lining epithelium
from the ﬁbrous wall is commonly observed. The
luminal surface shows ﬂattened parakeratotic epithe-
lial cells, which exhibit a wavy or corrugated appear-
ance (Fig. 15-17). The basal epithelial layer is composed
of a palisaded layer of cuboidal or columnar epithelial
cells, which are often hyperchromatic. Small satellite
cysts, cords, or islands of odontogenic epithelium may
be seen within the ﬁbrous wall. These structures have
been present in 7% to 26% of cases in various reported
series. In rare instances, cartilage has been observed in
the wall of an odontogenic keratocyst.
In the presence of inﬂammatory changes, the typical
features of the odontogenic keratocyst may be altered.
The parakeratinized luminal surface may disappear,
and the epithelium may proliferate to form rete ridges
with the loss of the characteristic palisaded basal layer
(Fig. 15-18). When these changes involve most of the
cyst lining, the diagnosis of odontogenic keratocyst
Fig. 15-15 Odontogenic keratocyst. Computed
tomography (CT) scan showing a large cyst involving the
crown of an unerupted maxillary third molar. The cyst largely
ﬁlls the maxillary sinus. (Courtesy of Dr. E.B. Bass.)
Fig. 15-16 Odontogenic keratocyst. This cyst cannot be
radiographically differentiated from a lateral periodontal cyst.
(Courtesy of Dr. Keith Lemmerman.)
Fig. 15-17 Odontogenic keratocyst. The epithelial lining is
6 to 8 cells thick, with a hyperchromatic and palisaded basal
cell layer. Note the corrugated parakeratotic surface. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

686 ORAL AND MAXILLOFACIAL PATHOLOGY
cannot be conﬁrmed unless other sections show the
typical features described earlier.
Some investigators recognize a microscopic ortho-
keratotic variant and include this lesion as a subtype of
the odontogenic keratocyst. However, these cysts do
not demonstrate a hyperchromatic and palisaded basal
cell layer, which is so characteristic of true odontogenic
keratocysts. In addition, the clinical behavior of these
orthokeratinized cysts differs markedly from that of the
typical parakeratinized cysts described in this section.
The authors believe that it is more logical to discuss
these orthokeratinizing cysts separately (see following
section).
TREATMENT AND PROGNOSIS
Although the presence of an odontogenic keratocyst
may be suspected on clinical or radiographic grounds,
histopathologic conﬁrmation is required for the diag-
nosis. Consequently, most odontogenic keratocysts are
treated similarly to other odontogenic cysts, that is, by
enucleation and curettage. Complete removal of the
cyst in one piece is often difﬁcult because of the thin,
friable nature of the cyst wall. In contrast to other odon-
togenic cysts, odontogenic keratocysts often tend to
recur after treatment. Whether this is due to fragments
of the original cyst that were not removed at the time
of the operation or a “new” cyst that has developed
from dental lamina rests in the general area of the
original cyst cannot be determined with certainty.
The reported frequency of recurrence in various
studies ranges from 5% to 62%. This wide variation may
be related to the total number of cases studied, the
length of follow-up periods, and the inclusion or exclu-
sion of orthokeratinized cysts in the study group.
Several reports that include large numbers of cases
indicate a recurrence rate of approximately 30%.
Recurrence is encountered more often in mandibular
odontogenic keratocysts, particularly those in the pos-
terior body and ascending ramus. Multiple recurrences
are not unusual. Although many odontogenic kerato-
cysts recur within 5 years of the original surgery, a sig-
niﬁcant number of recurrences may not be manifested
until 10 or more years after the original surgical pro-
cedure. Long-term clinical and radiographic follow-up,
therefore, is necessary.
Many surgeons recommend peripheral ostectomy
of the bony cavity with a bone bur to reduce the fre-
quency of recurrence. Others advocate chemical cau-
terization of the bony cavity with Carnoy’s solution
after cyst removal. Intraluminal injection of Carnoy’s
solution also has been used to free the cyst from the
bony wall, thereby allowing easier removal with a
lower recurrence rate. After cystotomy and incisional
biopsy, some surgeons have treated large odontogenic
keratocysts by insertion of a polyethylene drainage
tube to allow decompression and subsequent re-
duction in size of the cystic cavity (Fig. 15-19). Such
Fig. 15-18 Odontogenic keratocyst. The characteristic
microscopic features have been lost in the central area of this
portion of the cystic lining because of the heavy chronic
inﬂammatory cell inﬁltrate.
B
A
Fig. 15-19 Decompression of an odontogenic keratocyst.
A, Large unilocular radiolucency associated with the right
mandibular third molar. B, Six months after insertion of a
polyethylene drainage tube to allow decompression, the cyst
has shrunk and the third molar has migrated downward and
forward. (Courtesy of Dr. Tom Szakal.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 687
decompression treatment results in thickening of the
cyst lining, allowing easier removal with an apparently
lower recurrence rate.
Other than the tendency for recurrences, the overall
prognosis for most odontogenic keratocysts is good.
Occasionally, a locally aggressive odontogenic kerato-
cyst cannot be controlled without local resection and
bone grafting. In extremely rare instances, keratocysts
have been seen to extend up into the skull base region.
A few examples of carcinoma arising in an odontogenic
keratocyst have been reported, but the propensity for
an odontogenic keratocyst to undergo malignant alter-
ation is no greater and is possibly less than that for
other types of odontogenic cysts. Patients with odonto-
genic keratocysts should be evaluated for manifesta-
tions of the nevoid basal cell carcinoma syndrome (see
page 688), particularly if the patient is in the ﬁrst or
second decade of life or if multiple keratocysts are
identiﬁed.
ORTHOKERATINIZED
ODONTOGENIC CYST
The designation orthokeratinized odontogenic cyst
does not denote a speciﬁc clinical type of odontogenic
cyst but refers only to an odontogenic cyst that micro-
scopically has an orthokeratinized epithelial lining.
Although such lesions were originally called the ortho-
keratinized variant of odontogenic keratocyst, it is generally
accepted that they are clinicopathologically different
from the more common parakeratinized odontogenic
keratocyst and should be placed into a different cate-
gory. Orthokeratinized odontogenic cysts represent 7%
to 17% of all keratinizing jaw cysts.
CLINICAL AND RADIOGRAPHIC
FEATURES
Orthokeratinized odontogenic cysts occur predomi-
nantly in young adults and show a 2:1 male-to-female
ratio. The lesion occurs twice as frequently in the
mandible than the maxilla, with a tendency to involve
the posterior areas of the jaws. They have no clinical
or radiographic features that differentiate them from
other inﬂammatory or developmental odontogenic
cysts. The lesion usually appears as a unilocular radio-
lucency, but occasional examples have been multilocu-
lar. About two thirds of orthokeratinized odontogenic
cysts are encountered in a lesion that appears clinically
and radiographically to represent a dentigerous cyst;
they most often involve an unerupted mandibular third
molar tooth (Figs. 15-20 and 15-21). The size can vary
from less than 1 cm to large lesions greater than 7 cm
in diameter.
HISTOPATHOLOGIC FEATURES
The cyst lining is composed of stratiﬁed squamous
epithelium, which shows an orthokeratotic surface
of varying thickness. Keratohyaline granules may be
prominent in the superﬁcial epithelial layer subjacent
to the orthokeratin. The epithelial lining may be rela-
tively thin, and a prominent palisaded basal layer, char-
acteristic of the odontogenic keratocyst, is not present
(Fig. 15-22).
TREATMENT AND PROGNOSIS
Enucleation with curettage is the usual treatment for
orthokeratinized odontogenic cysts. Recurrence has
rarely been noted, and the reported frequency is
around 2%, which is in marked contrast with the 30%
or higher recurrence rate associated with odontogenic
keratocysts. It has been suggested that cysts with an
orthokeratinized surface may be at slightly greater risk
Fig. 15-20 Orthokeratinized odontogenic cyst. Small
unilocular radiolucency associated with the impacted
mandibular left third molar. (Courtesy of Dr. Tom McDonald.)
Fig. 15-21 Orthokeratinized odontogenic cyst. A large
cyst involving a horizontally impacted lower third molar.
(Courtesy of Dr. Carroll Gallagher.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

688 ORAL AND MAXILLOFACIAL PATHOLOGY
for malignant transformation, but evidence for this
is scant. Orthokeratinized odontogenic cysts have not
been associated with nevoid basal cell carcinoma
syndrome.
NEVOID BASAL CELL CARCINOMA
SYNDROME (GORLIN SYNDROME)
Nevoid basal cell carcinoma syndrome (Gorlin
syndrome) is an autosomal dominant inherited condi-
tion that exhibits high penetrance and variable expres-
sivity. The syndrome is caused by mutations in patched
(PTCH), a tumor suppressor gene that has been mapped
to chromosome 9q22.3-q31. Approximately 35% to
50% of affected patients represent new mutations. The
chief components are multiple basal cell carcinomas of
the skin, odontogenic keratocysts, intracranial calciﬁ-
cation, and rib and vertebral anomalies. Many other
anomalies have been reported in these patients and
probably also represent manifestations of the syn-
drome. The prevalence of Gorlin syndrome is esti-
mated to be about 1 in 60,000.
CLINICAL AND RADIOGRAPHIC
FEATURES
There is great variability in the expressivity of nevoid
basal cell carcinoma syndrome, and no single compo-
nent is present in all patients. The most common and
signiﬁcant features are summarized in Box 15-2. The
patient often has a characteristic facies, with frontal
and temporoparietal bossing, which results in an
increased cranial circumference (>60 cm in adults).
The eyes may appear widely separated, and many
patients have true mild ocular hypertelorism. Mild
mandibular prognathism is also commonly present
(Fig. 15-23).
Basal cell carcinomas of the skin are a major com-
ponent of the syndrome. Even though the microscopic
appearance of the syndromic basal cell carcinomas is
identical to that of nonsyndromic basal cell carcinoma,
the syndromic lesions generally have a much less
aggressive biologic behavior. The basal cell carcinomas
usually begin to appear at puberty or in the second and
third decades of life, although they can develop in
young children. The tumors may vary from ﬂesh-
colored papules to ulcerating plaques. They often
appear on skin that is not exposed to sunlight, but they
are most commonly located in the midface area (Fig.
15-24). The number of skin tumors may vary from only
a few to many hundreds. Blacks with the syndrome
tend to develop basal cell carcinomas less frequently
than whites (40% versus 90%), and they have fewer of
these lesions, probably because of protective skin
pigmentation.
Fig. 15-22 Orthokeratinized odontogenic cyst.
Microscopic features showing a thin epithelial lining. The
basal epithelial layer does not demonstrate palisading.
Keratohyaline granules are present, and a thick layer of
orthokeratin is seen on the luminal surface.
Box 15-2
Major Clinical Features of the Nevoid
Basal Cell Carcinoma Syndrome
50% OR GREATER FREQUENCY
●Multiple basal cell carcinomas
● Odontogenic keratocysts
●Epidermal cysts of the skin
● Palmar/plantar pits
● Calciﬁed falx cerebri
●Enlarged head circumference
●Rib anomalies (splayed, fused, partially missing, biﬁd)
●Mild ocular hypertelorism
● Spina biﬁda occulta of cervical or thoracic vertebrae
15% TO 49% FREQUENCY
● Calciﬁed ovarian ﬁbromas
●Short fourth metacarpals
●Kyphoscoliosis or other vertebral anomalies
●Pectus excavatum or carinatum
● Strabismus (exotropia)
LESS THAN 15% FREQUENCY (BUT NOT RANDOM)
● Medulloblastoma
● Meningioma
● Lymphomesenteric cysts
● Cardiac ﬁbroma
● Fetal rhabdomyoma
● Marfanoid build
●Cleft lip and/or palate
●Hypogonadism in males
● Mental retardation
From Gorlin RJ: Nevoid basal-cell carcinoma syndrome, Medicine 66:98-
113, 1987. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 689
Palmar and plantar pits are present in about 65% to
80% of patients (Fig. 15-25). These punctate lesions
represent a localized retardation of the maturation of
basal epithelial cells, resulting in a focally depressed
area as the result of a markedly thinned keratin layer.
Basal cell carcinomas rarely may develop at the base
of the pits.
Ovarian ﬁbromas have been reported in 15% to 25%
of women with this syndrome. A number of other
tumors also have been reported to occur with lesser
frequency. These include medulloblastoma within the
ﬁrst 2 years of life, meningioma, cardiac ﬁbroma, and
fetal rhabdomyoma.
Skeletal anomalies are present in 60% to 75% of
patients with this syndrome. The most common
anomaly is a biﬁd rib or splayed ribs (Fig. 15-26). This
anomaly may involve several ribs and may be bilateral.
Kyphoscoliosis has been observed in about 30% to 40%
of patients, and a number of other anomalies, such as
spina biﬁda occulta and shortened metacarpals, seem
to occur with unusual frequency. A distinctive lamellar
calciﬁcation of the falx cerebri, noted on an anteropos-
terior skull radiograph or computed tomography (CT)
image, is a common ﬁnding and is present in most
affected patients (Fig. 15-27).
Fig. 15-23 Nevoid basal cell carcinoma syndrome. This
11-year-old girl shows hypertelorism and mandibular
swelling. (Courtesy of Dr. Richard DeChamplain.)
Fig. 15-24 Nevoid basal call carcinoma syndrome. An
ulcerating basal cell carcinoma is present on the upper face.
Fig. 15-25 Nevoid basal cell carcinoma syndrome.
Plantar pits.
Fig. 15-26 Nevoid basal cell carcinoma syndrome. Chest
ﬁlm showing presence of biﬁd ribs (arrows). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

690 ORAL AND MAXILLOFACIAL PATHOLOGY
Fig. 15-27 Nevoid basal cell carcinoma syndrome.
Anteroposterior skull ﬁlm showing calciﬁcation of the falx
cerebri. (Courtesy of Dr. Ramesh Narang.)
Fig. 15-28 Nevoid basal cell carcinoma syndrome. Large cysts are present in the right and
left mandibular molar regions, together with a smaller cyst involving the right maxillary canine
in the same patient shown in Fig. 15-23. (Courtesy of Dr. Richard DeChamplain.)
Jaw cysts are one of the most constant features of the
syndrome and are present in at least 75% of the patients.
The cysts are odontogenic keratocysts, although there
are some differences between the cysts in patients with
nevoid basal cell carcinoma syndrome and in those
with isolated keratocysts. The cysts are frequently mul-
tiple; some patients have had as many as ten separate
cysts. The patient’s age when the ﬁrst keratocyst is
removed is signiﬁcantly younger in those affected by
this syndrome than in those with isolated keratocysts.
For most patients with this syndrome, their ﬁrst kera-
tocyst is removed before age 19. About one third of
patients with nevoid basal cell carcinoma syndrome
have only a solitary cyst at the time of the initial pre-
sentation, but in most cases additional cysts will develop
over periods ranging from 1 to 20 years.
Radiographically, the cysts in patients with nevoid
basal cell carcinoma syndrome do not differ signiﬁ-
cantly from isolated keratocysts. The cysts in patients
with this syndrome are often associated with the crowns
of unerupted teeth; on radiographs they may mimic
dentigerous cysts (Fig. 15-28).
HISTOPATHOLOGIC FEATURES
The cysts in the nevoid basal cell carcinoma syndrome
histopathologically are invariably odontogenic kerato-
cysts. The keratocysts in patients with this syndrome
tend to have more satellite cysts, solid islands of epithe-
lial proliferation, and odontogenic epithelial rests
within the ﬁbrous capsule than do isolated keratocysts
(Fig. 15-29). Foci of calciﬁcation also appear to be
more common. These features, however, are not diag-
nostic for nevoid basal cell carcinoma syndrome
because they may be seen in isolated keratocysts.
Odontogenic keratocysts associated with this syndrome
have been shown to demonstrate overexpression of
p53 and cyclin D1 (bcl-1) oncoproteins when com-
pared with nonsyndrome keratocysts.
The basal cell tumors of the skin cannot be distin-
guished from ordinary basal cell carcinomas. They
exhibit a wide spectrum of histopathologic ﬁndings,
from superﬁcial basal cell lesions to aggressive, nodu-
loulcerative basal cell carcinomas. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 691
TREATMENT AND PROGNOSIS
Most of the anomalies in nevoid basal cell carcinoma
syndrome are minor and usually not life threatening.
The prognosis generally depends on the behavior of
the skin tumors. In a few cases, aggressive basal cell
carcinomas have caused the death of the patient as a
result of tumor invasion of the brain or other vital struc-
tures (Figs. 15-30 and 15-31). Because the develop-
ment of the basal cell carcinomas seems to be triggered
by ultraviolet (UV) light exposure, patients should take
appropriate precautions to avoid sunlight. For the same
reason, radiation therapy should be avoided if at all
possible. The jaw cysts are treated by enucleation, but
in many patients additional cysts will continue to
develop. Varying degrees of jaw deformity may result
from the operations for multiple cysts. Infection of the
cysts in patients with this syndrome is also relatively
common. Some investigators have suggested that
affected children should have magnetic resonance
imaging (MRI) studies every 6 months until 7 years of
age to monitor for the development of medulloblas-
toma. Genetic counseling is appropriate for affected
individuals.
GINGIVAL (ALVEOLAR) CYST OF
THE NEWBORN
Gingival cysts of the newborn are small, superﬁcial,
keratin-ﬁlled cysts that are found on the alveolar
mucosa of infants. These cysts arise from remnants of
the dental lamina. They are common lesions, having
been reported in up to half of all newborns. However,
because they disappear spontaneously by rupture into
the oral cavity, the lesions seldom are noticed or
sampled for biopsy. Similar inclusion cysts (e.g.,
Epstein’s pearls and Bohn’s nodules) are also found
in the midline of the palate or laterally on the hard and
soft palate (see page 26).
CLINICAL FEATURES
Gingival cysts of the newborn appear as small, usually
multiple whitish papules on the mucosa overlying the
alveolar processes of neonates (Fig. 15-32). The indi-
vidual cysts are usually no more than 2 to 3 mm in
Fig. 15-29 Nevoid basal cell carcinoma syndrome.
Odontogenic keratocyst showing numerous odontogenic
epithelial rests in the cyst wall.
Fig. 15-30 Nevoid basal cell carcinoma syndrome. This
52-year-old man had more than 100 basal cell carcinomas
removed from his face over a 30-year period. Several basal
cell carcinomas are present in this photograph. The lesion at
the inner canthus of the left eye was deeply invasive and was
eventually fatal as a result of brain invasion.
Fig. 15-31 Nevoid basal cell carcinoma syndrome. Facial
deformity secondary to multiple surgical procedures to
remove basal cell carcinomas. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

692 ORAL AND MAXILLOFACIAL PATHOLOGY
diameter. The maxillary alveolus is more commonly
involved than the mandibular.
HISTOPATHOLOGIC FEATURES
Examination of an intact gingival cyst of the newborn
shows a thin, ﬂattened epithelial lining with a para-
keratotic luminal surface. The lumen contains keratin-
aceous debris.
TREATMENT AND PROGNOSIS
No treatment is indicated for gingival cysts of the
newborn because the lesions spontaneously involute as
a result of the rupture of the cysts and resultant contact
with the oral mucosal surface. The lesions are rarely
seen after 3 months of age.
GINGIVAL CYST OF THE ADULT
The gingival cyst of the adult is an uncommon lesion.
It is considered to represent the soft tissue counterpart
of the lateral periodontal cyst (see next topic), being
derived from rests of the dental lamina (rests of Serres).
The diagnosis of gingival cyst of the adult should be
restricted to lesions with the same histopathologic fea-
tures as those of the lateral periodontal cyst. On rare
occasions, a cyst may develop in the gingiva at the site
of a gingival graft; however, such lesions probably rep-
resent epithelial inclusion cysts that are a result of the
surgical procedure.
CLINICAL FEATURES
Like the lateral periodontal cyst, the gingival cyst of the
adult shows a striking predilection to occur in the man-
dibular canine and premolar area (60% to 75% of cases).
Gingival cysts of the adult are most commonly found
in patients in the ﬁfth and sixth decades of life. They
are almost invariably located on the facial gingiva or
alveolar mucosa. Maxillary gingival cysts are usually
found in the incisor, canine, and premolar areas.
Clinically, the cysts appear as painless, domelike
swellings, usually less than 0.5 cm in diameter, although
rarely they may be somewhat larger (Fig. 15-33). They
are often bluish or blue-gray. In some instances, the cyst
may cause a superﬁcial “cupping out” of the alveolar
bone, which is usually not detected on a radiograph but
is apparent when the cyst is excised. If more bone is
missing, one could argue that the lesion may be a lateral
periodontal cyst that has eroded the cortical bone rather
than a gingival cyst that originated in the mucosa.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the gingival cyst of the
adult are similar to those of the lateral periodontal cyst,
consisting of a thin, ﬂattened epithelial lining with or
without focal plaques that contain clear cells (Figs. 15-
34 and 15-35). Small nests of these glycogen-rich clear
cells, which represent rests of the dental lamina, also
may be seen in the surrounding connective tissue. Some-
times the cystic lining is so thin that it is easily mistaken
for the endothelial lining of a dilated blood vessel.
TREATMENT AND PROGNOSIS
The gingival cyst of the adult responds well to simple
surgical excision. The prognosis is excellent.
LATERAL PERIODONTAL CYST
(BOTRYOID ODONTOGENIC CYST)
The lateral periodontal cyst is an uncommon type of
developmental odontogenic cyst that typically occurs
along the lateral root surface of a tooth. It is believed
Fig. 15-32 Gingival cyst of the newborn. Multiple whitish
papules on the alveolar ridge of a newborn infant.
Fig. 15-33 Gingival cyst of the adult. Tense, ﬂuid-ﬁlled
swelling on the facial gingiva. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 693
to arise from rests of the dental lamina, and it repre-
sents the intrabony counterpart of the gingival cyst of
the adult. The lateral periodontal cyst accounts for less
than 2% of all epithelium-lined jaw cysts.
In the past, the term lateral periodontal cyst was used
to describe any cyst that developed along the lateral
root surface, including lateral radicular cysts (see page
131) and odontogenic keratocysts (see page 683).
However, the lateral periodontal cyst has distinctive
clinical and microscopic features that distinguish it
from other lesions that sometimes develop in the same
location.
CLINICAL AND RADIOGRAPHIC
FEATURES
The lateral periodontal cyst is most often an asymptom-
atic lesion that is detected only during a radiographic
examination. It most frequently occurs in patients in
the ﬁfth through the seventh decades of life; rarely does
it occur in someone younger than age 30. Around 75%
to 80% of cases occur in the mandibular premolar-
canine-lateral incisor area. Maxillary examples also
usually involve this same tooth region (Fig. 15-36).
Radiographically, the cyst appears as a well-circum-
scribed radiolucent area located laterally to the root or
roots of vital teeth. Most such cysts are less than 1.0 cm
in greatest diameter (Figs. 15-37 and 15-38).
Occasionally, the lesion may have a polycystic
appearance; such examples have been termed botry-
oid odontogenic cysts. Grossly and microscopically,
they show a grapelike cluster of small individual cysts
(Fig. 15-39). These lesions are generally considered to
Fig. 15-34 Gingival cyst of the adult. Low-power
photomicrograph showing a thin-walled cyst in the gingival
soft tissue.
Fig. 15-35 Gingival cyst of the adult. High-power
photomicrograph showing a plaquelike thickening of the
epithelial lining.
1% 15%4%
1% 66%14%
Fig. 15-36 Lateral periodontal cyst. Relative distribution
of lateral periodontal cysts in the jaws.
Fig. 15-37 Lateral periodontal cyst. Radiolucent lesion
between the roots of a vital mandibular canine and ﬁrst
premolar. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

694 ORAL AND MAXILLOFACIAL PATHOLOGY
represent a variant of the lateral periodontal cyst, pos-
sibly the result of cystic degeneration and subsequent
fusion of adjacent foci of dental lamina rests. The bot-
ryoid variant often shows a multilocular radiographic
appearance, but it also may appear unilocular.
The radiographic features of the lateral periodontal
cyst are not diagnostic; an odontogenic keratocyst that
develops between the roots of adjacent teeth may show
identical radiographic ﬁndings. An inﬂammatory
radicular cyst that occurs laterally to a root in relation
to an accessory foramen or a cyst that arises from
periodontal inﬂammation also may simulate a lateral
periodontal cyst radiographically (see page 132). In
one study of 46 cases of cystic lesions in the lateral
periodontal region, only 13 met the histopathologic
criteria for the lateral periodontal cyst; 8 were odonto-
genic keratocysts, 20 were inﬂammatory cysts, and 5
were of undetermined origin.
HISTOPATHOLOGIC FEATURES
The lateral periodontal cyst has a thin, generally non-
inﬂamed, ﬁbrous wall, with an epithelial lining that is
only one to three cells thick in most areas. This epithe-
lium usually consists of ﬂattened squamous cells,
but sometimes the cells are cuboidal in shape. Foci of
glycogen-rich clear cells may be interspersed among
the lining epithelial cells. Some cysts show focal nodular
thickenings of the lining epithelium, which are com-
posed chieﬂy of clear cells (Fig. 15-40). Clear cell epi-
thelial rests sometimes are seen within the ﬁbrous wall.
Rarely, botryoid odontogenic cysts exhibit focal areas
that histopathologically are suggestive of the glandular
odontogenic cyst (see page 697).
Fig. 15-38 Lateral periodontal cyst. A larger lesion
causing root divergence.
Fig. 15-39 Lateral periodontal cyst. Gross specimen of a
botryoid variant. Microscopically, this grapelike cluster
revealed three separate cavities.
B
A
Fig. 15-40 Lateral periodontal cyst. A, This
photomicrograph shows a thin epithelial lining with focal
nodular thickenings. B, These thickenings often show a
swirling appearance of the cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 695
TREATMENT AND PROGNOSIS
Conservative enucleation of the lateral periodontal
cyst is the treatment of choice. Usually, this can be
accomplished without damage to the adjacent teeth.
Recurrence is unusual, although it has been reported
with the botryoid variant, presumably because of its
polycystic nature. An exceedingly rare case of squa-
mous cell carcinoma, which apparently originated in a
lateral periodontal cyst, also has been reported.
CALCIFYING ODONTOGENIC CYST
(GORLIN CYST; DENTINOGENIC
GHOST CELL TUMOR; CALCIFYING
CYSTIC ODONTOGENIC TUMOR;
CALCIFYING GHOST CELL
ODONTOGENIC CYST)
The calcifying odontogenic cyst is an uncommon
lesion that demonstrates considerable histopathologic
diversity and variable clinical behavior. Although it is
widely considered to represent a cyst, some investiga-
tors prefer to classify it as a neoplasm. Some calcifying
odontogenic cysts appear to represent nonneoplastic
cysts; other members of this group, variously desig-
nated as dentinogenic ghost cell tumors or epithe-
lial odontogenic ghost cell tumors, have no cystic
features, may be inﬁltrative or even malignant, and are
regarded as neoplasms.
In addition, the calcifying odontogenic cyst may be
associated with other recognized odontogenic tumors,
most commonly odontomas. However, adenomatoid
odontogenic tumors and ameloblastomas have also
been associated with calcifying odontogenic cysts. The
WHO classiﬁcation of odontogenic tumors groups
the calcifying odontogenic cyst with all its variants as
an odontogenic tumor rather than an odontogenic cyst.
Given the innocuous clinical behavior of this lesion,
the widely recognized historic categorization of the
lesion as a cyst, and the cystic nature of the majority of
these lesions, the change in terminology does not seem
practical.
CLINICAL AND RADIOGRAPHIC
FEATURES
The calcifying odontogenic cyst is predominantly an
intraosseous lesion, although 13% to 30% of cases in
reported series have appeared as peripheral (extraos-
seous) lesions. Both the intraosseous and extraosseous
forms occur with about equal frequency in the maxilla
and mandible. About 65% of cases are found in the
incisor and canine areas (Fig. 15-41). Patients may
range in age from infant to elder. The mean age is 33
years, and most cases are diagnosed in the second and
third decades of life. Calcifying odontogenic cysts that
are associated with odontomas tend to occur in younger
patients, with a mean age of 17 years. The rare neoplas-
tic variants of the calcifying odontogenic cyst appear to
occur in older patients; because of the paucity of
reported cases, however, this may not be signiﬁcant.
The central calcifying odontogenic cyst is usually a
unilocular, well-deﬁned radiolucency, although the
lesion may occasionally appear multilocular. Radi-
opaque structures within the lesion, either irregular
calciﬁcations or toothlike densities, are present in
about one third to one half of cases (Fig. 15-42). In
approximately one third of cases, the radiolucent lesion
is associated with an unerupted tooth, most often a
canine. Most calcifying odontogenic cysts are between
2% 12%38%
11% 10%27%
Fig. 15-41 Calcifying odontogenic cyst. Relative
distribution of calcifying odontogenic cysts in the jaws.
Fig. 15-42 Calcifying odontogenic cyst. Maxillary
radiolucent lesion containing calciﬁed structures. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

696 ORAL AND MAXILLOFACIAL PATHOLOGY
2.0 and 4.0 cm in greatest diameter, but lesions as large
as 12.0 cm have been noted. Root resorption or diver-
gence of adjacent teeth is seen with some frequency
(Fig. 15-43).
Extraosseous calcifying odontogenic cysts are local-
ized sessile or pedunculated gingival masses with no
distinctive clinical features (Fig. 15-44). They can
resemble common gingival ﬁbromas, gingival cysts, or
peripheral giant cell granulomas.
HISTOPATHOLOGIC FEATURES
The cystic (nonneoplastic) forms comprise 86% to 98%
of all calcifying odontogenic cysts in various reported
series. These may occur both intraosseously and
extraosseously. Most commonly, a well-deﬁned cystic
lesion is found with a ﬁbrous capsule and a lining of
odontogenic epithelium of 4 to 10 cells in thickness.
The basal cells of the epithelial lining may be cuboidal
or columnar and are similar to ameloblasts. The overly-
ing layer of loosely arranged epithelium may resemble
the stellate reticulum of an ameloblastoma.
The most characteristic histopathologic feature
of the calcifying odontogenic cyst is the presence of
variable numbers of “ghost cells” within the epithelial
component. These eosinophilic ghost cells are altered
epithelial cells that are characterized by the loss
of nuclei with preservation of the basic cell outline
(Fig. 15-45).
The nature of the ghost cell change is controversial.
Some believe that this change represents coagulative
necrosis or accumulation of enamel protein; others
contend it is a form of normal or aberrant keratiniza-
tion of odontogenic epithelium. Masses of ghost cells
BA
Fig. 15-43 Calcifying odontogenic cyst. A, Expansion of the posterior maxillary alveolus
caused by a large calcifying odontogenic cyst. B, Panoramic radiograph of the same patient
showing a large radiolucency in the posterior maxilla. A small calciﬁed structure is seen in the
lower portion of the cyst. (Courtesy of Dr. Tom Brock.)
Fig. 15-44 Peripheral calcifying odontogenic cyst.
Nodular mass of the mandibular facial gingiva.
Fig. 15-45 Calcifying odontogenic cyst. The cyst lining
shows ameloblastoma-like epithelial cells, with a columnar
basal layer. Large eosinophilic ghost cells are present within
the epithelial lining. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 697
may fuse to form large sheets of amorphous, acellular
material. Calciﬁcation within the ghost cells is common.
This ﬁrst appears as ﬁne basophilic granules that may
increase in size and number to form extensive masses
of calciﬁed material. Areas of an eosinophilic matrix
material that are considered by some authors to repre-
sent dysplastic dentin (dentinoid) also may be present
adjacent to the epithelial component. This is believed
to be the result of an inductive effect by the odonto-
genic epithelium on the adjacent mesenchymal tissue
(Fig. 15-46).
Several variants of the cystic type of calcifying odon-
togenic cyst are seen. In some cases, the epithelial
lining proliferates into the lumen so that the lumen is
largely ﬁlled with masses of ghost cells and dystrophic
calciﬁcations. Multiple daughter cysts may be present
within the ﬁbrous wall, and a foreign body reaction to
herniated ghost cells may be conspicuous.
In another variant, unifocal or multifocal epithelial
proliferation of the cyst lining into the lumen may
resemble ameloblastoma. These proliferations are
intermixed with varying numbers of ghost cells. These
epithelial proliferations superﬁcially resemble, but
do not meet, the strict histopathologic criteria for
ameloblastoma.
About 20% of cystic calcifying odontogenic cysts are
associated with odontomas. This variant is usually a
unicystic lesion that shows the features of a calcifying
odontogenic cyst together with those of a small complex
or compound odontoma.
Neoplastic (solid) calcifying odontogenic cysts are
uncommon, accounting for 2% to 16% of all calcifying
odontogenic cysts in reported series. These may occur
intraosseously or extraosseously.
The extraosseous forms of the solid variant appear
to be more common. These show varying-sized islands
of odontogenic epithelium in a ﬁbrous stroma. The
epithelial islands show peripheral palisaded columnar
cells and central stellate reticulum, which resemble
ameloblastoma. Nests of ghost cells, however, are
present within the epithelium, and juxtaepithelial den-
tinoid is commonly present. These features differenti-
ate this lesion from the peripheral ameloblastoma.
The rare intraosseous variant is a solid tumor that
consists of ameloblastoma-like strands and islands of
odontogenic epithelium in a mature ﬁbrous connective
tissue stroma. Variable numbers of ghost cells and jux-
taepithelial dentinoid are present.
A small number of aggressive or malignant epithe-
lial odontogenic ghost cell tumors (odontogenic ghost
cell carcinoma) have been reported. These lesions
have cellular pleomorphism and mitotic activity with
invasion of the surrounding tissues.
TREATMENT AND PROGNOSIS
The prognosis for a patient with a calcifying odonto-
genic cyst is good; only a few recurrences after simple
enucleation have been reported. The peripheral neo-
plastic calcifying odontogenic cyst appears to have the
same prognosis as a peripheral ameloblastoma, with a
minimal chance of recurrence after simple surgical
excision.
When a calcifying odontogenic cyst is associated
with some other recognized odontogenic tumor, such
as an ameloblastoma, the treatment and prognosis are
likely to be the same as for the associated tumor.
Although few cases have been reported, odontogenic
ghost cell carcinomas appear to have an unpredictable
behavior. Recurrences are common, and a few patients
have died from either uncontrolled local disease or
metastases. An overall 5-year survival rate of 73% has
been calculated for reported cases.
GLANDULAR ODONTOGENIC CYST
(SIALO-ODONTOGENIC CYST)
The glandular odontogenic cyst is a rare type of
developmental odontogenic cyst that can show aggres-
sive behavior. Although it is generally accepted as
being of odontogenic origin, it also shows glandular or
salivary features that presumably are an indication of
the pluripotentiality of odontogenic epithelium.
CLINICAL AND RADIOGRAPHIC
FEATURES
The glandular odontogenic cyst occurs most commonly
in middle-aged adults, with a mean age of 48 years at
the time of diagnosis; rarely does it occur before the
age of 20. Nearly 75% of reported cases have occurred
in the mandible. The cyst has a strong predilection for
Fig. 15-46 Calcifying odontogenic cyst. Eosinophilic
dentinoid material is present adjacent to a sheet of ghost
cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

698 ORAL AND MAXILLOFACIAL PATHOLOGY
the anterior region of the jaws, and many mandibular
lesions will cross the midline.
The size of the cyst can vary from small lesions less
than 1 cm in diameter to large destructive lesions that
may involve most of the jaw. Small cysts may be asymp-
tomatic; however, large cysts often produce clinical
expansion, which sometimes can be associated with
pain or paresthesia (Fig. 15-47).
Radiographically, the lesion presents as either a uni-
locular or multilocular radiolucency. The margins of
the radiolucency are usually well deﬁned with a scle-
rotic rim.
HISTOPATHOLOGIC FEATURES
The glandular odontogenic cyst is lined by squamous
epithelium of varying thickness. The interface between
the epithelium and the ﬁbrous connective tissue wall
is generally ﬂat. The ﬁbrous cyst wall is usually devoid
of any inﬂammatory cell inﬁltrate. The superﬁcial epi-
thelial cells that line the cyst cavity tend to be cuboidal
to columnar, resulting in an uneven hobnail and some-
times papillary surface (Fig. 15-48). Occasionally, cilia
may be noted. Pools of mucicarminophilic material are
often present within the epithelium. Cuboidal cells
usually line these pools. Mucous cells may or may not
be present within the epithelium. In focal areas, the
epithelial lining cells may form spherical nodules,
similar to those seen in lateral periodontal cysts.
There is some histopathologic overlap between the
features of the glandular odontogenic cyst and those
of some intraosseous, low-grade, predominantly cystic
mucoepidermoid carcinomas (see page 490). In
selected microscopic ﬁelds, the microscopic features
may be identical. Examination of multiple sections,
however, usually permits the differentiation of these
lesions.
TREATMENT AND PROGNOSIS
Most cases of glandular odontogenic cyst have been
treated by enucleation or curettage. However, this cyst
shows a propensity for recurrence, which is observed
in approximately 30% of all cases. Recurrence appears
to be more common among the lesions that present in
a multilocular fashion. Because of its potentially aggres-
sive nature and tendency for recurrence, some authors
have advocated en bloc resection, particularly for mul-
tilocular lesions.
BUCCAL BIFURCATION CYST
The buccal bifurcation cyst is an uncommon
in ﬂammatory odontogenic cyst that characteristically
develops on the buccal aspect of the mandibular ﬁrst
BA
Fig. 15-47 Glandular odontogenic cyst. A, Expansile lesion of the anterior mandible. B, The
panoramic radiograph shows a large multilocular radiolucency. (Courtesy of Dr. Cheng-Chung Lin.)
Fig. 15-48 Glandular odontogenic cyst. The cyst is lined
by stratiﬁed squamous epithelium that exhibits surface
columnar cells with cilia. Small microcysts and clusters of
mucous cells are present. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 699
permanent molar. The pathogenesis of this cyst is
uncertain. Some of these lesions have been associated
with teeth that demonstrate buccal enamel extensions
into the bifurcation area (see page 93). Such extensions
may predispose these teeth to buccal pocket formation,
which could then enlarge to form a cyst in response to
pericoronitis. It has been speculated that when the
tooth erupts, an inﬂammatory response may occur in
the surrounding follicular tissues that stimulates cyst
formation.
The term paradental cyst sometimes has been used
synonymously for the buccal bifurcation cyst. Such
lesions typically occur distal or buccal of partially
erupted mandibular third molars with a history of peri-
coronitis. The pathogenesis of the so-called paradental
cyst also is uncertain. However, the distinction of para-
dental cysts from secondarily inﬂamed dentigerous
cysts is difﬁcult, if not impossible, in many instances
(see page 679).
CLINICAL AND RADIOGRAPHIC
FEATURES
The buccal bifurcation cyst typically occurs in children
from 5 to 13 years of age. The patient has slight-to-
moderate tenderness on the buccal aspect of the man-
dibular ﬁrst molar, which may be in the process of
erupting. The patient often notes associated clinical
swelling and a foul-tasting discharge. Periodontal
probing usually reveals pocket formation on the buccal
aspect of the involved tooth. Around one third of
patients have been reported to have bilateral involve-
ment of the ﬁrst molars.
Radiographs typically show a well-circumscribed
unilocular radiolucency involving the buccal bifurca-
tion and root area of the involved tooth (Fig. 15-49).
The average size of the lucent defect is 1.2 cm, but the
lesion may be as large as 2.5 cm in diameter. An
occlusal radiograph is most helpful in demonstrating
the buccal location of the lesion. The root apices of
the molar are characteristically tipped toward the
lingual mandibular cortex (Fig. 15-50). Many cases
are associated with proliferative periostitis (see page
148) of the overlying buccal cortex, which is character-
ized by a single or multiple layers of reactive bone
formation.
HISTOPATHOLOGIC FEATURES
The microscopic features are nonspeciﬁc and show a
cyst that is lined by nonkeratinizing stratiﬁed squa-
mous epithelium with areas of hyperplasia. A promi-
nent chronic inﬂammatory cell inﬁltrate is present in
the surrounding connective tissue wall.
Fig. 15-49 Buccal bifurcation cyst. Well-circumscribed
unilocular radiolucency superimposed on the roots of the
mandibular ﬁrst permanent molar. (Courtesy of Dr. Michael
Pharoah.)
Fig. 15-50 Buccal bifurcation cyst. Occlusal radiograph of
the lesion shown in Fig. 15-49. Note the lingual displacement
of the roots of the ﬁrst permanent molar. (Courtesy of Dr. Michael
Pharoah.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

700 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The buccal bifurcation cyst is usually treated by enucle-
ation; extraction of the associated tooth is unnecessary.
Within 1 year of surgery, there is usually complete
healing with normalization of periodontal probing
depths and radiographic evidence of bone ﬁll. One
report described three cases that resolved without
surgery—either with no treatment at all or by daily irri-
gation of the buccal pocket with saline and hydrogen
peroxide.
CARCINOMA ARISING IN
ODONTOGENIC CYSTS
Carcinoma arising within bone is a rare lesion that is
essentially limited to the jaws. Because the putative
source of the epithelium giving rise to the carcinoma is
odontogenic, these intraosseous jaw carcinomas are
collectively known as odontogenic carcinomas.
Odontogenic carcinomas may arise in an ameloblas-
toma, rarely from other odontogenic tumors, de novo
(without evidence of a preexisting lesion), or from the
epithelial lining of odontogenic cysts. Some intraosse-
ous mucoepidermoid carcinomas (see page 490) also
may arise from mucous cells lining a dentigerous cyst.
Most intraosseous carcinomas apparently arise in
odontogenic cysts. Although infrequently documented
in the literature, carcinomatous transformation of the
lining of an odontogenic cyst may be more common
than is generally appreciated. Several studies have
shown that 1% to 2% of all oral cavity carcinomas seen
in some oral and maxillofacial pathology services may
originate from odontogenic cysts. The pathogenesis of
carcinomas arising in odontogenic cysts is unknown.
Occasionally, areas within the lining of odontogenic
cysts histopathologically demonstrate varying degrees
of epithelial dysplasia, and such changes likely give rise
to the carcinoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although carcinomas arising in cysts may be seen in
patients across a wide age range, they are encountered
most often in older patients. The mean reported age is
57 to 61 years. This lesion is about twice as common
in men as in women. Pain and swelling are the most
common complaints. However, many patients have no
symptoms, and the diagnosis of carcinoma is made
only after microscopic examination of a presumed
odontogenic cyst.
Radiographic ﬁndings may mimic those of any
odontogenic cyst, although the margins of the radiolu-
cent defect are usually irregular and ragged. Computed
tomography of the lesion may demonstrate a destruc-
tive pattern that is not appreciated on viewing plain
radiographs. A lesion considered to be a residual peri-
apical cyst is apparently the most common type asso-
ciated with carcinomatous transformation, although
routine periapical cysts can also exhibit malignant
change. In about 25% of reported cases, the carcinoma
appeared to have arisen in a dentigerous cyst (Fig.
15-51). In one patient, the carcinoma appeared to
originate in a lateral periodontal cyst.
A few examples of carcinoma arising in an odonto-
genic keratocyst also have been documented (Fig.
15-52). However, some reported examples do not
appear to have arisen in true parakeratinized odonto-
genic keratocysts, but rather in orthokeratinized
odontogenic cysts.
HISTOPATHOLOGIC FEATURES
Most carcinomas arising in cysts have histopathologi-
cally been well-differentiated squamous cell carci-
nomas. It is sometimes possible to identify a transition
from a normal-appearing cyst lining to invasive squa-
mous cell carcinoma (Figs. 15-53 and 15-54).
TREATMENT AND PROGNOSIS
The treatment of patients with carcinomas arising in
cysts has varied from local block excision to radical
resection, with or without radiation or adjunctive
chemotherapy. The prognosis is difﬁcult to evaluate
because most reports consist of isolated cases; often
the follow-up is inadequate. Several larger studies
indicate an approximate 50% 5-year survival rate after
Fig. 15-51 Carcinoma arising in a dentigerous cyst.
Radiolucent lesion surrounding the crown of an impacted
third molar in a 56-year-old woman. This was clinically
considered to be a dentigerous cyst. (Courtesy of Dr. Richard
Ziegler.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 701
treatment. Metastases to regional lymph nodes have
been demonstrated in a few cases.
Before a given lesion can be accepted as an example
of primary intraosseous carcinoma, the possibility that
the tumor represents metastatic spread from an intra-
oral or extraoral site must be ruled out by appropriate
studies.
Odontogenic Tumors
Odontogenic tumors comprise a complex group of
lesions of diverse histopathologic types and clinical
behavior. Some of these lesions are true neoplasms and
may rarely exhibit malignant behavior. Others may
represent tumorlike malformations (hamartomas).
Odontogenic tumors, like normal odontogenesis,
demonstrate varying inductive interactions between
odontogenic epithelium and odontogenic ectomesen-
chyme. This ectomesenchyme was formerly referred to
as mesenchyme because it was thought to be derived
from the mesodermal layer of the embryo. It is now
accepted that this tissue differentiates from the ecto-
dermal layer in the cephalic portion of the embryo.
Tumors of odontogenic epithelium are composed
only of odontogenic epithelium without any participa-
tion of odontogenic ectomesenchyme.
Other odontogenic neoplasms, sometimes referred
to as mixed odontogenic tumors, are composed of
odontogenic epithelium and ectomesenchymal ele-
ments. Dental hard tissue may or may not be formed
in these lesions.
A third group, tumors of odontogenic ectomesen-
chyme, is composed principally of ectomesenchymal
elements. Although odontogenic epithelium may be
Fig. 15-52 Carcinoma arising in a cyst. There is a massive
carcinoma of the mandible, with extension into the parotid
gland, the face, and the base of the brain. Nineteen years
previously, a large odontogenic keratocyst with areas of
epithelial dysplasia had been removed from the ascending
ramus. The patient had suffered multiple recurrences, with
eventual change into invasive carcinoma.
Fig. 15-53 Carcinoma arising in a cyst. High-power view
of a dentigerous cyst from a 53-year-old man. The lining
demonstrates full-thickness epithelial dysplasia.
Fig. 15-54 Carcinoma arising in a cyst. Same case as
Fig. 15-53 showing islands of invasive epithelial cells in the
cyst wall. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

702 ORAL AND MAXILLOFACIAL PATHOLOGY
included within these lesions, it does not appear to play
any essential role in their pathogenesis.
Box 15-3 presents categories of odontogenic tumors
modiﬁed from the 2005 WHO classiﬁcation.
Tumors of Odontogenic
Epithelium
Epithelial odontogenic tumors are composed of odon-
togenic epithelium without participation of odonto-
genic ectomesenchyme. Several distinctly different
tumors are included in the group; ameloblastoma is the
most important and common of them.
AMELOBLASTOMA
The ameloblastoma is the most common clinically
signiﬁcant odontogenic tumor. Its relative frequency
equals the combined frequency of all other odonto-
genic tumors, excluding odontomas. Ameloblastomas
are tumors of odontogenic epithelial origin. Theoreti-
cally, they may arise from rests of dental lamina, from
a developing enamel organ, from the epithelial lining
of an odontogenic cyst, or from the basal cells of the
oral mucosa. Ameloblastomas are slow-growing, locally
invasive tumors that run a benign course in most cases.
They occur in three different clinicoradiographic situ-
ations, which deserve separate consideration because
of differing therapeutic considerations and prognosis:
1.Conventional solid or multicystic (about 86% of
all cases)
2.Unicystic (about 13% of all cases)
3.Peripheral (extraosseous) (about 1% of all cases)
CONVENTIONAL SOLID OR MULTICYSTIC
INTRAOSSEOUS AMELOBLASTOMA
CLINICAL AND RADIOGRAPHIC
FEATURES
Conventional solid or multicystic intraosseous
ameloblastoma is encountered in patients across a
wide age range. It is rare in children younger than age
10 and relatively uncommon in the 10- to 19-year-old
group. The tumor shows an approximately equal preva-
lence in the third to seventh decades of life. There is
no signiﬁcant sex predilection. Some studies indicate
a greater frequency in blacks; others show no racial
predilection. About 80% to 85% of conventional amelo-
blastomas occur in the mandible, most often in the
molar-ascending ramus area. About 15% to 20% of
ameloblastomas occur in the maxilla, usually in the
posterior regions (Fig. 15-55). The tumor is often
asymptomatic, and smaller lesions are detected only
during a radiographic examination. A painless swelling
or expansion of the jaw is the usual clinical presenta-
tion (Figs. 15-56 and 15-57). If untreated, then the
lesion may grow slowly to massive or grotesque propor-
tions (Fig. 15-58). Pain and paresthesia are uncom-
mon, even with large tumors.
The most typical radiographic feature is that of a
multilocular radiolucent lesion. The lesion is often
described as having a “soap bubble” appearance (when
Box 15-3
Classiﬁcation of Odontogenic Tumors
I.Tumors of odontogenic epithelium
A.Ameloblastoma
1. Malignant ameloblastoma
2. Ameloblastic carcinoma
B.Clear cell odontogenic carcinoma
C.Adenomatoid odontogenic tumor
D.Calcifying epithelial odontogenic tumor
E.Squamous odontogenic tumor
II.Mixed odontogenic tumors
A.Ameloblastic ﬁbroma
B.Ameloblastic ﬁbro-odontoma
C.Ameloblastic ﬁbrosarcoma
D.Odontoameloblastoma
E.Compound odontoma
F.Complex odontoma
III.Tumors of odontogenic ectomesenchyme
A.Odontogenic ﬁbroma
B.Granular cell odontogenic tumor
C.Odontogenic myxoma
D.Cementoblastoma
6% 1%6%
66% 11%10%
Fig. 15-55 Ameloblastoma. Relative distribution of
ameloblastomas in the jaws. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 703
the radiolucent loculations are large) or as being “hon-
eycombed” (when the loculations are small) (Figs.
15-59 to 15-61). Buccal and lingual cortical expansion
is frequently present. Resorption of the roots of teeth
adjacent to the tumor is common. In many cases an
unerupted tooth, most often a mandibular third molar,
is associated with the radiolucent defect. Solid amelo-
blastomas may radiographically appear as unilocular
radiolucent defects, which may resemble almost any
type of cystic lesion (Fig. 15-62). The margins of these
radiolucent lesions, however, often show irregular scal-
loping. Although the radiographic features, particularly
of the typical multilocular defect, may be highly sug-
gestive of ameloblastoma, a variety of odontogenic and
Fig. 15-56 Ameloblastoma. Large expansile mass of the
anterior mandible. (Courtesy of Dr. Michael Tabor.)
Fig. 15-57 Ameloblastoma. Prominent expansion of the
lingual alveolus caused by a large ameloblastoma of the
mandibular symphysis. The radiograph of the patient is
shown in Fig. 15-61.
Fig. 15-58 Ameloblastoma. Massive tumor of the anterior
mandible. (Courtesy of Dr. Ronald Baughman.)
Fig. 15-59 Ameloblastoma. Large multilocular lesion
involving the mandibular angle and ascending ramus. The
large loculations show the “soap bubble” appearance. An
unerupted third molar has been displaced high into the
ramus. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

704 ORAL AND MAXILLOFACIAL PATHOLOGY
nonodontogenic lesions may show similar radiographic
features (see Appendix).
One form of ameloblastoma that does not have
these characteristic features is the desmoplastic amelo-
blastoma, a variant that Eversole and colleagues
documented initially in the literature in 1984. The
desmoplastic ameloblastoma has a marked predi-
lection to occur in the anterior regions of the jaws,
particularly the maxilla. Radiographically, this type
seldom suggests the diagnosis of ameloblastoma and
usually resembles a ﬁbro-osseous lesion because of its
mixed radiolucent and radiopaque appearance (Fig.
15-63). This mixed radiographic appearance is due to
osseous metaplasia within the dense ﬁbrous septa that
characterize the lesion, not because the tumor itself is
producing a mineralized product.
Fig. 15-60 Ameloblastoma. Periapical ﬁlms showing the “honeycombed” appearance.
(Courtesy of Dr. John Hann.)
Fig. 15-61 Ameloblastoma. Destructive radiolucent lesion
associated with root resorption of the anterior teeth. (Courtesy
of Dr. Richard Brock.)
Fig. 15-62 Ameloblastoma. This small unilocular
radiolucency lesion could easily be mistaken for a lateral
periodontal cyst. (Courtesy of Dr. Tony Traynham.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 705
HISTOPATHOLOGIC FEATURES
Conventional solid or multicystic intraosseous amelo-
blastomas show a remarkable tendency to undergo
cystic change; grossly, most tumors have varying com-
binations of cystic and solid features. The cysts may be
seen only at the microscopic level or may be present
as multiple large cysts that include most of the tumor.
Several microscopic subtypes of conventional amelo-
blastoma are recognized, but these microscopic pat-
terns generally have little bearing on the behavior of
the tumor. Large tumors often show a combination of
microscopic patterns.
The follicular and plexiform patterns are the
most common. Less common histopathologic patterns
include the acanthomatous, granular cell, desmo-
plastic, and basal cell types.
FOLLICULAR PATTERN
The follicular histopathologic pattern is the most
common and recognizable. Islands of epithelium
resemble enamel organ epithelium in a mature ﬁbrous
connective tissue stroma. The epithelial nests consist of
a core of loosely arranged angular cells resembling the
stellate reticulum of an enamel organ. A single layer
of tall columnar ameloblast-like cells surrounds this
central core. The nuclei of these cells are located at the
opposite pole to the basement membrane (reversed
polarity). In other areas, the peripheral cells may be
more cuboidal and resemble basal cells. Cyst forma-
tion is common and may vary from microcysts, which
form within the epithelial islands, to large macroscopic
cysts, which may be several centimeters in diameter
(Figs. 15-64 and 15-65).
PLEXIFORM PATTERN
The plexiform type of ameloblastoma consists of
long, anastomosing cords or larger sheets of odonto-
genic epithelium. The cords or sheets of epithelium are
bounded by columnar or cuboidal ameloblast-like cells
surrounding more loosely arranged epithelial cells.
The supporting stroma tends to be loosely arranged
and vascular. Cyst formation is relatively uncommon
in this variety. When it occurs, it is more often associ-
ated with stromal degeneration rather than cystic
change within the epithelium (Fig. 15-66).
ACANTHOMATOUS PATTERN
When extensive squamous metaplasia, often associ-
ated with keratin formation, occurs in the central
portions of the epithelial islands of a follicular
ameloblastoma, the term acanthomatous ameloblas-
Fig. 15-63 Desmoplastic ameloblastoma. Large mixed
radiolucent and radiopaque lesion of the anterior and right
body of the mandible. (Courtesy of Dr. Román Carlos.)
Fig. 15-64 Ameloblastoma (follicular pattern). Multiple
islands of odontogenic epithelium demonstrating peripheral
columnar differentiation with reverse polarization. The
central zones resemble stellate reticulum and exhibit foci of
cystic degeneration.
Fig. 15-65 Ameloblastoma (follicular pattern). This high-
power photomicrograph highlights the peripheral columnar
cells exhibiting reverse polarization. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

706 ORAL AND MAXILLOFACIAL PATHOLOGY
toma is sometimes applied. This change does not
indicate a more aggressive course for the lesion; histo-
pathologically, however, such a lesion may be confused
with squamous cell carcinoma or squamous odonto-
genic tumor (Fig. 15-67).
GRANULAR CELL PATTERN
Ameloblastomas may sometimes show transformation
of groups of lesional epithelial cells to granular cells.
These cells have abundant cytoplasm ﬁlled with eosin-
ophilic granules that resemble lysosomes ultrastructur-
ally and histochemically. Although originally considered
to represent an aging or degenerative change in long-
standing lesions, this variant has been seen in young
patients and in clinically aggressive tumors. When this
granular cell change is extensive in an ameloblastoma,
the designation of granular cell ameloblastoma is
appropriate (Fig. 15-68).
DESMOPLASTIC PATTERN
This type of ameloblastoma contains small islands and
cords of odontogenic epithelium in a densely collage-
nized stroma. Immunohistochemical studies have
shown increased production of the cytokine known as
transforming growth factor-b (TGF-β) in association with
this lesion, suggesting that this may be responsible for
the desmoplasia. Peripheral columnar ameloblast-like
cells are inconspicuous about the epithelial islands
(Fig. 15-69).
BASAL CELL PATTERN
The basal cell variant of ameloblastoma is the least
common type. These lesions are composed of nests of
uniform basaloid cells, and they histopathologically are
very similar to basal cell carcinoma of the skin. No stel-
late reticulum is present in the central portions of the
Fig. 15-66 Ameloblastoma (plexiform pattern).
Anastomosing cords of odontogenic epithelium.
Fig. 15-67 Ameloblastoma (acanthomatous pattern).
Islands of ameloblastoma demonstrating central squamous
differentiation.
Fig. 15-68 Ameloblastoma (granular cell variant). Tumor
island exhibiting central cells with prominent granular
cytoplasm.
Fig. 15-69 Ameloblastoma (desmoplastic variant). Thin
cords of ameloblastic epithelium within a dense ﬁbrous
connective tissue stroma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 707
nests. The peripheral cells about the nests tend to be
cuboidal rather than columnar (Fig. 15-70).
TREATMENT AND PROGNOSIS
Patients with conventional solid or multicystic intraos-
seous ameloblastomas have been treated by a variety
of means. These range from simple enucleation and
curettage to en bloc resection (Fig. 15-71). The optimal
method of treatment has been the subject of contro-
versy for many years. The conventional ameloblastoma
tends to inﬁltrate between intact cancellous bone tra-
beculae at the periphery of the lesion before bone
resorption becomes radiographically evident. There-
fore, the actual margin of the tumor often extends
beyond its apparent radiographic or clinical margin.
Attempts to remove the tumor by curettage often leave
small islands of tumor within the bone, which later
manifest as recurrences. Recurrence rates of 50% to
90% have been reported in various studies after curet-
tage. Recurrence often takes many years to become
clinically manifest, and 5-year disease-free periods do
not indicate a cure.
Marginal resection is the most widely used treat-
ment, but recurrence rates of up to 15% have been
reported after marginal or block resection. Some
surgeons advocate a more conservative approach to
treatment by planning surgery after careful evaluation
of computed tomography (CT) scans of the tumor.
Removal of the tumor, followed by peripheral ostec-
tomy, often reduces the need for extensive reconstruc-
tive surgery. Some tumors may not be amenable to this
approach because of their size or growth pattern.
Other surgeons advocate that the margin of the
resection should be at least 1.0 to 1.5 cm past the
radiographic limits of the tumor. Ameloblastomas
of the posterior maxilla are particularly dangerous
because of the difﬁculty of obtaining an adequate surgi-
cal margin around the tumor. Orbital invasion by max-
illary ameloblastomas occasionally has been described.
Although some studies suggest that the ameloblastoma
may be radiosensitive, radiation therapy has seldom
been used as a treatment modality because of the
intraosseous location of the tumor and the potential for
secondary radiation-induced malignancy developing
in a relatively young patient population.
The conventional ameloblastoma is a persistent,
inﬁltrative neoplasm that may kill the patient by pro-
gressive spread to involve vital structures. Most of these
tumors, however, are not life-threatening lesions.
Rarely, an ameloblastoma exhibits frank malignant
behavior. These are discussed separately.
Fig. 15-70 Ameloblastoma (basal cell variant). Islands of
hyperchromatic basaloid cells with peripheral palisading.
BA
Fig. 15-71 Ameloblastoma. A, Gross photograph of a mandibular resection specimen.
B, The radiograph of the specimen shows a large radiolucent defect associated with an
inferiorly displaced third molar. (Courtesy of Dr. Mary Richardson.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

708 ORAL AND MAXILLOFACIAL PATHOLOGY
UNICYSTIC AMELOBLASTOMA
The unicystic ameloblastoma has for several decades
been given separate consideration based on its clinical,
radiographic, and pathologic features. Although its
response to treatment in reports from the 1970s and
1980s suggested that this lesion might behave in a less
aggressive fashion, recent reports have disputed this
concept. Unicystic ameloblastomas account for 10% to
46% of all intraosseous ameloblastomas in various
studies. Whether the unicystic ameloblastoma origi-
nates de novo as a neoplasm or whether it is the result
of neoplastic transformation of nonneoplastic cyst epi-
thelium has been long debated. Both mechanisms
probably occur, but proof of which is involved in an
individual patient is virtually impossible to obtain.
CLINICAL AND RADIOGRAPHIC
FEATURES
Unicystic ameloblastomas are most often seen in
younger patients, with about 50% of all such tumors
diagnosed during the second decade of life. The average
age in one large series was 23 years. More than 90% of
unicystic ameloblastomas are found in the mandible,
usually in the posterior regions. The lesion is often
asymptomatic, although large lesions may cause a pain-
less swelling of the jaws.
In many patients, this lesion typically appears as
a circumscribed radiolucency that surrounds the
crown of an unerupted mandibular third molar (Figs.
15-72 and 15-73), clinically resembling a dentigerous
cyst. Other tumors simply appear as sharply deﬁned
radiolucent areas and are usually considered to be a
primordial, radicular, or residual cyst, depending on
the relationship of the lesion to teeth in the area. In
some instances, the radiolucent area may have scal-
loped margins but is still a unicystic ameloblastoma.
Whether a unicystic ameloblastoma can have a truly
multilocular radiographic presentation is arguable.
The surgical ﬁndings may also suggest that the lesion
in question is a cyst, and the diagnosis of ameloblas-
toma is made only after microscopic study of the
specimen.
HISTOPATHOLOGIC FEATURES
Three histopathologic variants of unicystic ameloblas-
toma have been described. In the ﬁrst type (luminal
unicystic ameloblastoma), the tumor is conﬁned to
the luminal surface of the cyst. The lesion consists of a
ﬁbrous cyst wall with a lining that consists totally or
partially of ameloblastic epithelium. This demonstrates
a basal layer of columnar or cuboidal cells with hyper-
chromatic nuclei that show reverse polarity and basilar
cytoplasmic vacuolization (Fig. 15-74). The overlying
epithelial cells are loosely cohesive and resemble stel-
late reticulum. This ﬁnding does not seem to be related
to inﬂammatory edema.
In the second microscopic variant, one or more
nodules of ameloblastoma project from the cystic lining
into the lumen of the cyst. This type is called an intra-
luminal unicystic ameloblastoma. These nodules
may be relatively small or largely ﬁll the cystic lumen.
In some cases, the nodule of tumor that projects into
the lumen demonstrates an edematous, plexiform
pattern that resembles the plexiform pattern seen
in conventional ameloblastomas (Fig. 15-75). These
Fig. 15-72 Unicystic ameloblastoma. A large radiolucency
in a 7-year-old boy with displacement of the developing
second molar to the inferior border of the mandible. This was
believed to be a large dentigerous cyst. (Courtesy of Dr. Larry
Chewning.)
Fig. 15-73 Unicystic ameloblastoma (intraluminal
plexiform type). Coronal computed tomography (CT) image
that shows a large cystic lesion with an intraluminal mass
arising from the cyst wall (arrow). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 709
lesions are sometimes referred to as plexiform uni-
cystic ameloblastomas. The intraluminal cellular
proliferation does not always meet the strict histopath-
ologic criteria for ameloblastoma, and this may be sec-
ondary to inﬂammation that nearly always accompanies
this pattern. Typical ameloblastoma, however, may be
found in other, less inﬂamed parts of the specimen.
In the third variant, known as mural unicystic
ameloblastoma, the ﬁbrous wall of the cyst is inﬁl-
trated by typical follicular or plexiform ameloblastoma.
The extent and depth of the ameloblastic inﬁltration
may vary considerably. With any presumed unicystic
ameloblastoma, multiple sections through many levels
of the specimen are necessary to rule out the possibility
of mural invasion of tumor cells (Fig. 15-76).
TREATMENT AND PROGNOSIS
The clinical and radiographic ﬁndings in most cases of
unicystic ameloblastoma suggest that the lesion is an
odontogenic cyst. These tumors are usually treated as
cysts by enucleation. The diagnosis of ameloblastoma
is made only after microscopic examination of the pre-
sumed cyst. If the ameloblastic elements are conﬁned
to the lumen of the cyst with or without intraluminal
tumor extension, then the cyst enucleation has proba-
bly been adequate treatment. The patient, however,
should be kept under long-term follow-up. If the speci-
men shows extension of the tumor into the ﬁbrous cyst
wall for any appreciable distance, then subsequent
management of the patient is more controversial. Some
surgeons believe that local resection of the area is
indicated as a prophylactic measure; others prefer to
keep the patient under close radiographic observation
and delay further treatment until there is evidence of
recurrence.
Recurrence rates of 10% to 20% were described after
enucleation and curettage of unicystic ameloblastomas
in many of the earlier series of cases. This range is
considerably less than the 50% to 90% recurrence rates
noted after curettage of conventional solid and multi-
cystic intraosseous ameloblastomas. One recent series
of unicystic ameloblastomas reported recurrence rates
after conservative excision of 50% at one institution and
80% at another. A systematic review of the literature
before 2005 determined that 30% of these lesions
recurred after enucleation. These ﬁndings suggest that
Fig. 15-74 Unicystic ameloblastoma (luminal type). The
cyst is lined by ameloblastic epithelium showing a
hyperchromatic, polarized basal layer. The overlying epithelial
cells are loosely cohesive and resemble stellate reticulum.
Fig. 15-75 Unicystic ameloblastoma (intraluminal
plexiform type). Photomicrograph of the intraluminal mass
arising from the cyst wall in the same patient shown in
Fig. 15-72. The inset shows the intraluminal mass at higher
magniﬁcation.
Fig. 15-76 Unicystic ameloblastoma (mural type). The
epithelial lining of the cystic component can be seen on the
left edge of the photomicrograph. Islands of follicular
ameloblastoma are inﬁltrating into the ﬁbrous connective
tissue wall on the right. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

710 ORAL AND MAXILLOFACIAL PATHOLOGY
this lesion may not be as innocuous as previously
thought. Alternatively, it is possible that some of those
tumors that are designated as “unicystic” may, in fact,
have a more characteristic invasive component that
has not been detected histopathologically because it is
essentially impossible to examine these lesions in every
360-degree plane of section.
PERIPHERAL (EXTRAOSSEOUS)
AMELOBLASTOMA
The peripheral ameloblastoma is uncommon and
accounts for about 1% to 10% of all ameloblastomas.
This tumor probably arises from rests of dental lamina
beneath the oral mucosa or from the basal epithelial
cells of the surface epithelium. Histopathologically,
these lesions have the same features as the intraosseous
form of the tumor.
CLINICAL FEATURES
The peripheral ameloblastoma is usually a painless,
nonulcerated sessile or pedunculated gingival or alveo-
lar mucosal lesion. The clinical features are non-
speciﬁc, and most lesions are clinically considered
to represent a ﬁbroma or pyogenic granuloma. Most
examples are smaller than 1.5 cm, but larger lesions
have been reported (Fig. 15-77). The tumor has been
found in patients across a wide age range, but most are
seen in middle-aged persons, with an average reported
age of 52 years.
Peripheral ameloblastomas are most commonly
found on the posterior gingival and alveolar mucosa,
and they are somewhat more common in mandibular
than in maxillary areas. In some cases, the superﬁcial
alveolar bone becomes slightly eroded, but signiﬁcant
bone involvement does not occur. A few examples of a
microscopically identical lesion have been reported in
the buccal mucosa at some distance from the alveolar
or gingival soft tissues.
HISTOPATHOLOGIC FEATURES
Peripheral ameloblastomas have islands of amelo-
blastic epithelium that occupy the lamina propria
underneath the surface epithelium (Fig. 15-78). The
proliferating epithelium may show any of the features
described for the intraosseous ameloblastoma; plexi-
form or follicular patterns are the most common. Con-
nection of the tumor with the basal layer of the surface
epithelium is seen in about 50% of cases. Whether this
represents origin of the tumor from the basal layer of
the epithelium or merging of the tumor with the surface
epithelium has not been ascertained.
Basal cell carcinomas of the oral mucosa have
been reported, but most of these would be designated
best as peripheral ameloblastomas. A peripheral
odontogenic ﬁbroma may be confused microscopi-
cally with a peripheral ameloblastoma, particularly if a
prominent epithelial component is present in the
former. The presence of dysplastic dentin or cemen-
tum-like elements in the peripheral odontogenic
ﬁbroma and the lack of peripheral columnar epithelial
cells showing reverse polarity of their nuclei should
serve to distinguish the two lesions.
TREATMENT AND PROGNOSIS
Unlike the intraosseous ameloblastoma, the peripheral
ameloblastoma shows an innocuous clinical behavior.
Patients respond well to local surgical excision.
Although local recurrence has been noted in 15% to
20% of cases, further local excision almost always
results in a cure. Several examples of malignant change
Fig. 15-77 Peripheral ameloblastoma. Sessile gingival
mass. (Courtesy of Dr. Dean K. White.)
Fig. 15-78 Peripheral ameloblastoma. Interconnecting
cords of ameloblastic epithelium ﬁlling the lamina propria. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 711
in a peripheral ameloblastoma have been reported, but
this is rare.
MALIGNANT AMELOBLASTOMA AND
AMELOBLASTIC CARCINOMA
Rarely, an ameloblastoma exhibits frank malignant
behavior with development of metastases. The fre-
quency of malignant behavior in ameloblastomas is
difﬁcult to determine but probably occurs in far less
than 1% of all ameloblastomas.
The terminology for these lesions is somewhat con-
troversial. The term malignant ameloblastoma should be
used for a tumor that shows the histopathologic fea-
tures of ameloblastoma, both in the primary tumor and
in the metastatic deposits. The term ameloblastic carci-
noma should be reserved for an ameloblastoma that has
cytologic features of malignancy in the primary tumor,
in a recurrence, or in any metastatic deposit. These
lesions may follow a markedly aggressive local course,
but metastases do not necessarily occur.
CLINICAL AND RADIOGRAPHIC
FEATURES
Malignant ameloblastomas have been observed in
patients who range in age from 4 to 75 years (mean
age, 30 years). For patients with documented meta s-
tases, the interval between the initial treatment of the
ameloblastoma and ﬁrst evidence of metastasis varies
from 1 to 30 years. In nearly one third of cases, metas-
tases do not become apparent until 10 years after treat-
ment of the primary tumor. Ameloblastic carcinomas,
in contrast, tend to develop later in life, with the mean
age at diagnosis typically being in the sixth decade of
life.
Metastases from ameloblastomas are most often
found in the lungs. These have sometimes been
regarded as aspiration or implant metastases. However,
the peripheral location of some of these lung meta s-
tases suggests that they must have occurred by blood
or lymphatic routes rather than aspiration.
Cervical lymph nodes are the second most common
site for metastasis of an ameloblastoma. Spread to ver-
tebrae, other bones, and viscera has also occasionally
been conﬁrmed.
The radiographic ﬁndings of malignant amelo-
blastomas may be essentially the same as those in
typical nonmetastasizing ameloblastomas. Amelo-
blastic carcinomas are often more aggressive lesions,
with ill-deﬁned margins and cortical destruction
(Fig. 15-79).
HISTOPATHOLOGIC FEATURES
With malignant ameloblastomas, the primary jaw
tumor and the metastatic deposits show no microscopic
features that differ from those of ameloblastomas with
a completely benign local course. With ameloblastic
carcinomas, the metastatic deposits or primary tumor
shows the microscopic pattern of ameloblastoma in
addition to cytologic features of malignancy. These
include an increased nuclear-to-cytoplasmic ratio,
nuclear hyperchromatism, and the presence of mitoses
(Fig. 15-80). Necrosis in tumor islands and areas of
dystrophic calciﬁcation may also be present.
BA
Fig. 15-79 Ameloblastic carcinoma. A, Rapidly growing tumor showing prominent labial
expansion of the mandible in the incisor and premolar area. B, The panoramic radiograph
shows irregular destruction of the mandible. (From Neville BW, Damm DD, White DK: Color atlas of
clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

712 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The prognosis of patients with malignant ameloblasto-
mas appears to be poor, but the paucity of documented
cases with long-term follow-up does not permit accu-
rate assumptions to be made. About 50% of the patients
with documented metastases and long-term follow-up
have died of their disease. Lesions designated as amelo-
blastic carcinoma have demonstrated a uniformly aggres-
sive clinical course, with perforation of the cortical
plates of the jaw and extension of the tumor into adja-
cent soft tissues.
CLEAR CELL ODONTOGENIC
CARCINOMA (CLEAR CELL
ODONTOGENIC TUMOR)
Clear cell odontogenic carcinoma is a rare jaw
tumor that was ﬁrst described in 1985. To date, approx-
imately 50 examples have been documented. The
tumor appears to be of odontogenic origin, but its his-
togenesis is uncertain. Histochemical and ultrastruc-
tural studies show that the clear cells, which are the
prominent feature of this neoplasm, have similarities
to glycogen-rich presecretory ameloblasts.
CLINICAL AND RADIOGRAPHIC
FEATURES
The clear cell odontogenic carcinoma exhibits a vari-
able clinical pattern. A wide age range (from 14 to 89
years of age) has been described, but most cases are
diagnosed in patients older than age 50. More than
80% of the lesions develop in the mandible. Some
patients complain of pain and bony swelling; others are
relatively symptom free. Approximately 60% of patients
will have evidence of soft tissue involvement by the
tumor at the time of diagnosis because the lesion per-
forates bone.
Radiographically, the lesions appear as unilocular or
multilocular radiolucencies. The margins of the radio-
lucency are often somewhat ill deﬁned or irregular
(Fig. 15-81).
HISTOPATHOLOGIC FEATURES
Three histopathologic patterns have been described for
clear cell odontogenic carcinoma. The biphasic pattern
consists of varying-sized nests of epithelial cells, with a
clear or faintly eosinophilic cytoplasm admixed with
more eosinophilic polygonal epithelial cells (Fig.
15-82). The second pattern is more monophasic, char-
acterized by only clear cells that are arranged in nests
Fig. 15-80 Ameloblastic carcinoma. Ameloblastic
epithelium demonstrating hyperchromatism, pleomorphism,
and numerous mitotic ﬁgures.
Fig. 15-81 Clear cell odontogenic carcinoma. Unilocular
radiolucent defect.
Fig. 15-82 Clear cell odontogenic carcinoma.
Hyperchromatic epithelial nests including clusters of cells
with abundant clear cytoplasm. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 713
and cords. Thin strands of hyalinized connective tissue
often separate the clear cell nests. The third pattern has
a resemblance to ameloblastoma in that the peripheral
cells of the clear cell islands may infrequently demon-
strate palisading (Fig. 15-83). Often the lesional cells
do not exhibit a signiﬁcant degree of nuclear or cyto-
logic pleomorphism. Furthermore, mitoses are gener-
ally sparse and necrosis is not a prominent feature. The
clear cells contain small amounts of glycogen, but
mucin stains are negative. In some cases, islands more
typical of ameloblastoma are interspersed among the
other tumor elements.
Clear cell odontogenic carcinoma may be difﬁcult
to distinguish from intraosseous mucoepidermoid car-
cinoma with a prominent clear cell component,
although the negative mucin stains are consistent with
the former. A clear cell variant of the calcifying epithe-
lial odontogenic tumor may also present problems in
the differential diagnosis, but amyloid stains should be
negative in the case of clear cell odontogenic tumor.
A metastatic clear cell neoplasm, such as a renal cell
carcinoma, clear cell breast carcinoma, or clear cell
melanoma, may also need to be ruled out before the
diagnosis of clear cell odontogenic carcinoma can be
established.
TREATMENT AND PROGNOSIS
Clear cell odontogenic carcinomas largely demonstrate
an aggressive clinical course, with invasion of contigu-
ous structures and a tendency to recur. Most patients
require fairly radical surgery. Metastatic involvement
of regional lymph nodes has been documented in 25%
of these patients, and pulmonary metastases have been
described as well.
ADENOMATOID ODONTOGENIC
TUMOR
The adenomatoid odontogenic tumor represents 3%
to 7% of all odontogenic tumors, and more than 750
examples have been reported in the literature. Although
this lesion was formerly considered to be a variant of
the ameloblastoma and was designated as “adenoame-
loblastoma,” its clinical features and biologic behavior
indicate that it is a separate entity. Although there
is evidence that the tumor cells are derived from
enamel organ epithelium, investigators have also sug-
gested that the lesion arises from remnants of dental
lamina.
CLINICAL AND RADIOGRAPHIC
FEATURES
Adenomatoid odontogenic tumors are largely limited
to younger patients, and two thirds of all cases are
diagnosed when patients are 10 to 19 years of age. This
tumor is deﬁnitely uncommon in a patient older than
age 30. It has a striking tendency to occur in the ante-
rior portions of the jaws and is found twice as often in
the maxilla as in the mandible (Fig. 15-84). Females
are affected about twice as often as males.
Most adenomatoid odontogenic tumors are rela-
tively small. They seldom exceed 3 cm in greatest
diameter, although a few large lesions have been
reported. Peripheral (extraosseous) forms of the tumor
are also encountered but are rare. These usually appear
as small, sessile masses on the facial gingiva of the
maxilla. Clinically, these lesions cannot be differenti-
ated from the common gingival ﬁbrous lesions.
Fig. 15-83 Clear cell odontogenic carcinoma. Tumor
island demonstrating cells with a clear cytoplasm. Note the
peripheral columnar differentiation.
2% 9%53%
2% 7%27%
Fig. 15-84 Adenomatoid odontogenic tumor. Relative
distribution of adenomatoid odontogenic tumor in the jaws. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

714 ORAL AND MAXILLOFACIAL PATHOLOGY
Adenomatoid odontogenic tumors are frequently
asymptomatic and are discovered during the course of
a routine radiographic examination or when ﬁlms are
made to determine why a tooth has not erupted. Larger
lesions cause a painless expansion of the bone.
In about 75% of cases, the tumor appears as a cir-
cumscribed, unilocular radiolucency that involves the
crown of an unerupted tooth, most often a canine. This
follicular type of adenomatoid odontogenic tumor may
be impossible to differentiate radiographically from
the more common dentigerous cyst. The radiolucency
associated with the follicular type of adenomatoid
odontogenic tumor sometimes extends apically along
the root past the cementoenamel junction. This feature
may help to distinguish an adenomatoid odontogenic
tumor from a dentigerous cyst (Fig. 15-85).
Less often the adenomatoid odontogenic tumor is a
well-delineated unilocular radiolucency that is not
related to an unerupted tooth, but rather is located
between the roots of erupted teeth (extrafollicular
type) (Fig. 15-86).
The lesion may appear completely radiolucent;
often, however, it contains ﬁne (snowﬂake) calciﬁca-
tions (Fig. 15-87). This feature may be helpful in dif-
ferentiating the adenomatoid odontogenic tumor from
a dentigerous cyst.
HISTOPATHOLOGIC FEATURES
The adenomatoid odontogenic tumor is a well-deﬁned
lesion that is usually surrounded by a thick, ﬁbrous
capsule. When the lesion is bisected, the central portion
of the tumor may be essentially solid or may show
varying degrees of cystic change (Fig. 15-88).
Microscopically, the tumor is composed of spindle-
shaped epithelial cells that form sheets, strands, or
whorled masses of cells in a scant ﬁbrous stroma. The
epithelial cells may form rosettelike structures about a
central space, which may be empty or contain small
Fig. 15-85 Adenomatoid odontogenic tumor. Radiolucent
lesion involving an unerupted mandibular ﬁrst premolar. In
contrast to the usual dentigerous cyst, the radiolucency
extends almost to the apex of the tooth. (Courtesy of Dr. Tony
Traynham.)
Fig. 15-86 Adenomatoid odontogenic tumor. A small
radiolucency is present between the roots of the lateral
incisor and canine. (Courtesy of Dr. Ramesh Narang.)
Fig. 15-87 Adenomatoid odontogenic tumor. Well-
deﬁned pericoronal radiolucency enveloping the maxillary
right ﬁrst bicuspid. Note the prominent snowﬂake
calciﬁcations. (Courtesy of Dr. William Dobbins.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 715
amounts of eosinophilic material. This material may
stain for amyloid.
The tubular or ductlike structures, which are the
characteristic feature of the adenomatoid odontogenic
tumor, may be prominent, scanty, or even absent in a
given lesion. These consist of a central space sur-
rounded by a layer of columnar or cuboidal epithelial
cells. The nuclei of these cells tend to be polarized
away from the central space. The mechanism of forma-
tion of these tubular structures is not entirely clear but
is likely the result of the secretory activity of the tumor
cells, which appear to be preameloblasts. In any event,
these structures are not true ducts, and no glandular
elements are present in the tumor (Fig. 15-89).
Small foci of calciﬁcation may also be scattered
throughout the tumor. These have been interpreted as
abortive enamel formation. Some adenomatoid odon-
togenic tumors contain larger areas of matrix material
or calciﬁcation. This material has been interpreted as
dentinoid or cementum.
Some lesions also have another pattern, particularly
at the periphery of the tumor adjacent to the capsule.
This consists of narrow, often anastomosing cords
of epithelium in an eosinophilic, loosely arranged
matrix.
The histopathologic features of this lesion are
distinctive and should not be confused with any
other odontogenic tumor. Interestingly, some adeno-
matoid odontogenic tumors have been described
with focal areas that resemble calcifying epithelial
odontogenic tumor, odontoma, or calcifying odonto-
genic cyst. These lesions appear to behave as a routine
adenomatoid odontogenic tumor, however. The chief
problem relates to mistaking this tumor for an amelo-
blastoma by a pathologist who is not familiar with this
lesion. This error can lead to unnecessary radical
surgery.
TREATMENT AND PROGNOSIS
The adenomatoid odontogenic tumor is completely
benign; because of its capsule, it enucleates easily from
the bone. Aggressive behavior has not been docu-
mented, and recurrence after enucleation seldom, if
ever, occurs.
Fig. 15-88 Adenomatoid odontogenic tumor. A well-
circumscribed cystlike mass can be seen enveloping the
crown of a maxillary cuspid. Note the intraluminal
vegetations, which represent nodular tumor growth.
B
A
Fig. 15-89 Adenomatoid odontogenic tumor. A, Low-
power view demonstrating a thick capsule surrounding the
tumor. B, Higher magniﬁcation showing the ductlike
epithelial structures. The nuclei of the columnar calls are
polarized away from the central spaces. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

716 ORAL AND MAXILLOFACIAL PATHOLOGY
radiolucent, but the defect usually contains calciﬁed
structures of varying size and density. The tumor is
frequently associated with an impacted tooth, most
often a mandibular molar. Calciﬁcations are usually
scattered within the tumor. Although some authors
have suggested that these are often most prominent
around the crown of the impacted tooth (Fig. 15-92), a
recent review identiﬁed this feature in only 12% of
published cases with adequate radiographic documen-
tation. Similarly, the description of a “driven-snow”
pattern of the calciﬁcations appears to be much less
common than previously believed.
A few cases of peripheral (extraosseous) calcifying
epithelial odontogenic tumor have been reported.
These appear as nonspeciﬁc, sessile gingival masses,
most often on the anterior gingiva. Some of these have
CALCIFYING EPITHELIAL
ODONTOGENIC TUMOR
(PINDBORG TUMOR)
The calcifying epithelial odontogenic tumor, also
widely known as the Pindborg tumor, is an uncom-
mon lesion that accounts for less than 1% of all odon-
togenic tumors. Approximately 200 cases have been
reported to date. Although the tumor is clearly of odon-
togenic origin, its histogenesis is uncertain. The tumor
cells bear a close morphologic resemblance to the cells
of the stratum intermedium of the enamel organ;
however, some investigators have recently suggested
that the tumor arises from dental lamina remnants
based on its anatomic distribution in the jaws.
CLINICAL AND RADIOGRAPHIC
FEATURES
Although the calcifying epithelial odontogenic tumor
has been found in patients across a wide age range and
in many parts of the jaw, it is most often encountered
in patients between 30 and 50 years of age. There is
no sex predilection. About two thirds of all reported
cases have been found in the mandible, most often
in the posterior areas (Fig. 15-90). A painless, slow-
growing swelling is the most common presenting
sign.
Radiographically, the tumor exhibits either a uni-
locular or a multilocular radiolucent defect (Fig.
15-91), with the unilocular pattern encountered more
commonly in the maxilla. The margins of the lytic
defect are often scalloped and usually relatively well
deﬁned. However, approximately 20% of cases have
an ill-deﬁned periphery, and an additional 20%
exhibit a corticated border. The lesion may be entirely
21% 8%
57% 14%
Fig. 15-90 Calcifying epithelial odontogenic tumor.
Relative distribution of calcifying epithelial odontogenic
tumor in the jaws.
Fig. 15-91 Calcifying epithelial odontogenic tumor.
Honeycombed multilocular radiolucency containing ﬁne
calciﬁcations.
Fig. 15-92 Calcifying epithelial odontogenic tumor.
Prominent calciﬁcation around the crown of an impacted
second molar that is involved in the tumor. (Courtesy of Dr.
Harold Peacock.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 717
been associated with cupped-out erosion of the under-
lying bone.
HISTOPATHOLOGIC FEATURES
The calcifying epithelial odontogenic tumor has dis-
crete islands, strands, or sheets of polyhedral epithelial
cells in a ﬁbrous stroma (Fig. 15-93). The cellular
outlines of the epithelial cells are distinct, and intercel-
lular bridges may be noted. The nuclei show consider-
able variation, and giant nuclei may be seen. Some
tumors show considerable nuclear pleomorphism, but
this feature is not considered to indicate malignancy.
Large areas of amorphous, eosinophilic, hyalinized
(amyloid-like) extracellular material are also often
present. The tumor islands frequently enclose masses
of this hyaline material; this results in a cribriform
appearance. Calciﬁcations, which are a distinctive
feature of the tumor, develop within the amyloid-like
material and form concentric rings (Liesegang ring
calciﬁcations) (Fig. 15-94). These tend to fuse and
form large, complex masses.
Several microscopic variations may be encountered.
Some tumors consist of large sheets of epithelial cells
with minimal production of amyloid-like material and
calciﬁcations. Others show large diffuse masses of
amyloid-like material that contain only small nests or
islands of epithelium. A clear cell variant has been
described, in which clear cells constitute a signiﬁcant
portion of the epithelial component, and this tumor also
has been reported to have a cystic growth pattern.
The amyloid-like material in the Pindborg tumor
has been extensively investigated by histochemical,
immunohistochemical, and biochemical methods, as
well as by electron microscopy. The material generally
stains as amyloid (i.e., positive staining results with
Congo red or thioﬂavine T). After Congo red staining,
the amyloid will exhibit apple-green birefringence
when viewed with polarized light (Fig. 15-95). A recent
report has identiﬁed this material as a unique protein
that is produced by this tumor, and both the protein
structure and the DNA sequence of the responsible
gene have been described.
TREATMENT AND PROGNOSIS
Although it was originally believed that the calcifying
epithelial odontogenic tumor had about the same bio-
logic behavior as the ameloblastoma, accumulating
experience indicates that it tends to be less aggressive.
Conservative local resection to include a narrow rim
of surrounding bone appears to be the treatment of
choice, although lesions in the posterior maxilla should
probably be treated more aggressively. A recurrence
rate of about 15% has been reported; tumors treated
Fig. 15-93 Calcifying epithelial odontogenic tumor.
Sheets of polyhedral tumor cells with prominent eosinophilic
cytoplasm and intercellular bridging. Pools of amorphous
eosinophilic amyloid are present.
Fig. 15-94 Calcifying epithelial odontogenic tumor.
Multiple concentric Liesegang ring calciﬁcations.
Fig. 15-95 Calcifying epithelial odontogenic tumor. With
Congo red staining, the pools of amyloid exhibit an apple-
green birefringence when viewed with polarized light. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

718 ORAL AND MAXILLOFACIAL PATHOLOGY
by curettage have the highest frequency of recurrence.
The overall prognosis appears good, although rare
examples of malignant or borderline malignant calcify-
ing epithelial odontogenic tumor have been reported,
with documented metastasis to regional lymph nodes
and lung.
SQUAMOUS ODONTOGENIC TUMOR
Squamous odontogenic tumor is a rare benign odon-
togenic neoplasm that was ﬁrst described in 1975 and
is now recognized as a distinct entity. Fewer than 50
examples have been reported to date. Most of these
have been located within bone, although a few periph-
eral examples have been described. Before 1975, this
lesion was probably believed to represent an atypical
acanthomatous ameloblastoma or even a squamous
cell carcinoma. The squamous odontogenic tumor may
arise from neoplastic transformation of dental lamina
rests or perhaps the epithelial rests of Malassez. The
tumor appears to originate within the periodontal liga-
ment that is associated with the lateral root surface of
an erupted tooth.
CLINICAL AND RADIOGRAPHIC
FEATURES
Squamous odontogenic tumors have been found in
patients whose ages ranged from 8 to 74 years (average
age, 38). They are randomly distributed throughout
the alveolar processes of the maxilla and mandible,
with no site of predilection. A few patients have had
multiple squamous odontogenic tumors that involved
several quadrants of the mouth; one family with three
affected siblings who each had multiple lesions has
been reported. There is no apparent sex predilection.
A painless or mildly painful gingival swelling, often
associated with mobility of the associated teeth, is the
most common complaint. About 25% of reported
patients have had no symptoms, and their lesions were
detected during a radiographic examination.
The radiographic ﬁndings are not speciﬁc or diag-
nostic and consist of a triangular radiolucent defect
lateral to the root or roots of the teeth (Fig. 15-96).
In some instances, this suggests vertical periodontal
bone loss. The radiolucent area may be somewhat ill
deﬁned or may show a well-deﬁned, sclerotic margin.
Most examples are relatively small lesions that seldom
exceed 1.5 cm in greatest diameter.
HISTOPATHOLOGIC FEATURES
The microscopic ﬁndings of squamous odontogenic
tumor are distinctive and consist of varying-shaped
islands of bland-appearing squamous epithelium in a
mature ﬁbrous connective tissue stroma. The periph-
eral cells of the epithelial islands do not show the char-
acteristic polarization seen in ameloblastomas (Fig.
15-97). Microcystic vacuolization and individual cell
keratinization within the epithelial islands are common
Fig. 15-96 Squamous odontogenic tumor. Lucent defect
extending along the roots of the lateral incisor and ﬁrst
premolar teeth. (Courtesy of Dr. Ed McGaha.)
B
A
Fig. 15-97 Squamous odontogenic tumor. A, Low-power
photomicrograph showing islands of bland-appearing
squamous epithelium in a ﬁbrous stroma. B, Higher-power
photomicrograph showing bland appearance of the
epithelium with microcyst formation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 719
features. Small microcysts are sometimes observed
within the epithelial islands. Laminated calciﬁed bodies
and globular eosinophilic structures, which do not
stain for amyloid, are present within the epithelium in
some cases. The former probably represents dystrophic
calciﬁcations; the nature of the latter is unknown.
Islands of epithelium that closely resemble those of
the squamous odontogenic tumor have been observed
within the ﬁbrous walls of dentigerous and radicular
cysts. These have been designated as squamous odonto-
genic tumorlike proliferations in odontogenic cysts. These
islands do not appear to have any signiﬁcance relative
to the behavior of the cyst, and evaluation of the clini-
cal, radiographic, and histopathologic features should
permit differentiation from a squamous odontogenic
tumor.
In published reports, some squamous odontogenic
tumors have been misdiagnosed initially as ameloblas-
tomas, resulting in unnecessary radical surgery.
TREATMENT AND PROGNOSIS
Conservative local excision or curettage appears to
be effective for patients with squamous odontogenic
tumors, and most reported cases have not recurred
after local excision. A few instances of recurrence have
been reported, but these have responded well to further
local excision. Maxillary squamous odontogenic tumors
may be somewhat more aggressive than mandibular
lesions, with a greater tendency to invade adjacent
structures. This may be because of the porous, spongy
nature of the maxillary bone. The multicentric lesions
have typically exhibited a less aggressive, almost ham-
artomatous behavior when compared with solitary
lesions. A well-documented example of apparent
malignant transformation of squamous odontogenic
tumor has been reported.
Mixed Odontogenic Tumors
The group of mixed odontogenic tumors, composed
of proliferating odontogenic epithelium in a cellular
ectomesenchyme resembling the dental papilla, poses
problems in classiﬁcation. Some of these lesions show
varying degrees of inductive effect by the epithelium
on the mesenchyme, leading to the formation of varying
amounts of enamel and dentin. Some of these lesions
(the common odontomas) are clearly nonneoplastic
developmental anomalies; others appear to be true
neoplasms. The nature of others is uncertain.
In some instances, the histopathologic ﬁndings alone
cannot distinguish between the neoplastic lesions
and the developmental anomalies. Clinical and radio-
graphic features often are of considerable assistance in
making this distinction.
AMELOBLASTIC FIBROMA
The ameloblastic ﬁbroma is considered to be a true
mixed tumor in which the epithelial and mesenchymal
tissues are both neoplastic. It is an uncommon tumor,
but the data regarding its frequency are difﬁcult to
evaluate because (particularly in earlier reports) some
lesions that were diagnosed as ameloblastic ﬁbroma
may actually have represented the early developing
stage of an odontoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Ameloblastic ﬁbromas tend to occur in younger
patients; most lesions are diagnosed in the ﬁrst two
decades of life. This lesion, however, is occasionally
encountered in middle-aged patients. The tumor is
slightly more common in males than in females. Small
ameloblastic ﬁbromas are asymptomatic; larger tumors
are associated with swelling of the jaws. The posterior
mandible is the most common site; about 70% of all
cases are located in this area (Fig. 15-98). Convincing
examples of this tumor arising within the gingival soft
tissue have only recently been described, but this
appears to represent a rare phenomenon.
Radiographically, either a unilocular or multilocular
radiolucent lesion is seen, with the smaller lesions
tending to be unilocular. The radiographic margins
tend to be well deﬁned, and they may be sclerotic. An
unerupted tooth is associated with the lesion in about
75% of cases (Fig. 15-99). The ameloblastic ﬁbroma
may grow to a large size, and cases that involve a
23% 4%
69% 4%
Fig. 15-98 Ameloblastic ﬁbroma. Relative distribution of
ameloblastic ﬁbroma in the jaws. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

720 ORAL AND MAXILLOFACIAL PATHOLOGY
considerable portion of the body and ascending ramus
of the mandible have been reported.
HISTOPATHOLOGIC FEATURES
The ameloblastic ﬁbroma appears as a solid, soft tissue
mass with a smooth outer surface. A deﬁnite capsule
may or may not be present. Microscopically, the tumor
is composed of a cell-rich mesenchymal tissue resem-
bling the primitive dental papilla admixed with prolif-
erating odontogenic epithelium. The latter may have
one of two patterns, both of which are usually present
in any given case. The most common epithelial pattern
consists of long, narrow cords of odontogenic epithe-
lium, often in an anastomosing arrangement. These
cords are usually only two cells in thickness and are
composed of cuboidal or columnar cells (Fig. 15-100).
In the other pattern, the epithelial cells form small,
discrete islands that resemble the follicular stage of
the developing enamel organ. These show peripheral
columnar cells, which surround a mass of loosely
arranged epithelial cells that resemble stellate reticu-
lum. In contrast to the follicular type of ameloblastoma,
these follicular islands in the ameloblastic ﬁbroma
seldom demonstrate microcyst formation.
The mesenchymal portion of the ameloblastic
ﬁbroma consists of plump stellate and ovoid cells in a
loose matrix, which closely resembles the developing
dental papilla. Collagen formation is generally incon-
spicuous. Juxtaepithelial hyalinization of the mes-
enchymal portion of the tumor is sometimes seen,
and occasionally diffuse areas of hyalinized acellular
lesional tissue are evident.
In recent years, a few examples of ameloblastic
ﬁbroma occurring in conjunction with calcifying odon-
togenic cyst have been reported.
TREATMENT AND PROGNOSIS
The proper management of ameloblastic ﬁbroma has
been an ongoing topic of debate. Although initially it
was believed that the ameloblastic ﬁbroma was an
innocuous lesion that seldom recurred after simple
local excision or curettage, subsequent reports seemed
to indicate a substantial risk of recurrence after conser-
vative therapy. The highest recurrence rate (43.5%)
was recorded in a series of cases from the Armed
Forces Institute of Pathology, and it could be argued
that this was a biased sample of larger lesions that were
inherently more difﬁcult to manage. In other series of
cases, from 0% to 18% of ameloblastic ﬁbromas were
reported to recur after conservative removal and an
adequate follow-up period. Based on these data, recent
recommendations have emphasized conservative
initial therapy for ameloblastic ﬁbroma. More aggres-
sive surgical excision should probably be reserved for
recurrent lesions. Approximately 45% of the cases of
the rare ameloblastic ﬁbrosarcoma develop in the
setting of a recurrent ameloblastic ﬁbroma.
Fig. 15-99 Ameloblastic ﬁbroma. Well-deﬁned
radiolucent defect associated with an unerupted second
molar. (Courtesy of Dr. Robert Lauer.)
B
A
Fig. 15-100 Ameloblastic ﬁbroma. A, Long, narrow cords
of odontogenic epithelium supported by richly cellular,
primitive connective tissue. B, Basophilic epithelial islands
with peripheral nuclear palisading. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 721
AMELOBLASTIC FIBRO-ODONTOMA
The ameloblastic ﬁbro-odontoma is deﬁned as a
tumor with the general features of an ameloblastic
ﬁbroma but that also contains enamel and dentin.
Some investigators believe that the ameloblastic ﬁbro-
odontoma is only a stage in the development of an
odontoma and do not consider it to be a separate entity.
Certainly the histopathologic features of a developing
odontoma may overlap somewhat with ameloblastic
ﬁbro-odontoma. There are well-documented examples,
however, of this tumor exhibiting progressive growth
and causing considerable deformity and bone destruc-
tion. Such lesions appear to be true neoplasms.
However, distinguishing between a developing odon-
toma and an ameloblastic ﬁbro-odontoma may be dif-
ﬁcult based on histopathologic grounds alone.
CLINICAL AND RADIOGRAPHIC
FEATURES
The ameloblastic ﬁbro-odontoma is usually encoun-
tered in children with an average age of 10 years. It is
rarely encountered in adults. Like the ameloblastic
ﬁbroma, ameloblastic ﬁbro-odontomas occur more
frequently in the posterior regions of the jaws (Fig.
15-101). There is no signiﬁcant sex predilection. The
lesion is commonly asymptomatic and is discovered
when radiographs are taken to determine the reason
for failure of a tooth to erupt. Large examples may be
associated with a painless swelling of the affected
bone.
Radiographically, the tumor shows a well-circum-
scribed unilocular or, rarely, multilocular radiolucent
21% 14%
54% 11%
Fig. 15-101 Ameloblastic ﬁbro-odontoma. Relative
distribution of ameloblastic ﬁbro-odontoma in the jaws.
Fig. 15-102 Ameloblastic ﬁbro-odontoma. Radiolucent defect in the ramus containing
small calciﬁcations having the radiodensity of tooth structure.
defect that contains a variable amount of calciﬁed
material with the radiodensity of tooth structure. The
calciﬁed material within the lesion may appear as mul-
tiple, small radiopacities or as a solid conglomerate
mass (Fig. 15-102). In most instances, an unerupted
tooth is present at the margin of the lesion, or the crown
of the unerupted tooth may be included within the
defect. Some ameloblastic ﬁbro-odontomas contain
only a minimal amount of calcifying enamel and
dentin matrix and appear radiographically as radiolu-
cent lesions (Fig. 15-103). These cannot be differenti-
ated from the wide variety of unilocular radiolucencies
that may involve the jaws. At the other extreme, some
ameloblastic ﬁbro-odontomas appear as largely calci-
ﬁed masses with only a narrow rim of radiolucency
about the periphery of the lesion. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

722 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
The soft tissue component of the ameloblastic ﬁbro-
odontoma is microscopically identical to the amelo-
blastic ﬁbroma and has narrow cords and small
islands of odontogenic epithelium in a loose primitive-
appearing connective tissue that resembles the dental
papilla. The calcifying element consists of foci of
enamel and dentin matrix formation in close relation-
ship to the epithelial structures (Fig. 15-104). The more
calciﬁed lesions show mature dental structures in the
form of rudimentary small teeth or conglomerate
masses of enamel and dentin. Some researchers have
designated a similar tumor in which the calcifying
component consists only of dentin matrix and denti-
noid material as ameloblastic ﬁbro-dentinoma. It is
questionable whether this lesion represents a separate
entity, and it is probably best considered as only a
variant of the ameloblastic ﬁbro-odontoma.
TREATMENT AND PROGNOSIS
A patient with an ameloblastic ﬁbro-odontoma is gen-
erally treated by conservative curettage, and the lesion
usually separates easily from its bony bed. The tumor
is well circumscribed and does not invade the sur-
rounding bone.
The prognosis is excellent, and recurrence after
conservative removal is unusual. Development of an
ameloblastic ﬁbrosarcoma after curettage of an amelo-
blastic ﬁbro-odontoma has been reported, but this is
exceedingly rare.
AMELOBLASTIC FIBROSARCOMA
(AMELOBLASTIC SARCOMA)
The rare ameloblastic ﬁbrosarcoma is considered
to be the malignant counterpart of the ameloblastic
ﬁbroma, and slightly more than 60 cases have been
documented in the literature. Interestingly, in most
cases, only the mesenchymal portion of the lesion
shows features of malignancy; the epithelial compo-
nent remains rather bland. These tumors may appar-
ently arise de novo, although in approximately half of
known cases, the malignant lesion represents a recur-
rence of a tumor previously diagnosed as an ameloblas-
tic ﬁbroma or an ameloblastic ﬁbro-odontoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Ameloblastic ﬁbrosarcomas occur about 1.5 times as
often in males as in females. The lesion tends to occur
in younger patients (mean reported age, 27.5 years).
Although either the maxilla or the mandible may be
involved, about 80% of cases have occurred in the man-
dible. Pain and swelling associated with rapid clinical
growth are the common complaints.
Fig. 15-103 Ameloblastic ﬁbro-odontoma. Radiolucent
defect involving several unerupted teeth. Little calciﬁed
material is present in the radiolucent defect.
B
A
Fig. 15-104 Ameloblastic ﬁbro-odontoma. A, The soft
tissue component of the tumor is indistinguishable from an
ameloblastic ﬁbroma. B, Formation of disorganized tooth
structure can be seen. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 723
Radiographically, the ameloblastic ﬁbrosarcoma
shows an ill-deﬁned destructive radiolucent lesion that
suggests a malignant process (Fig. 15-105).
HISTOPATHOLOGIC FEATURES
Ameloblastic ﬁbrosarcomas contain an epithelial com-
ponent similar to that seen in the ameloblastic ﬁbroma,
although it is frequently less prominent than that
present in the typical ameloblastic ﬁbroma. The epithe-
lial component appears histopathologically benign and
does not demonstrate any cytologic atypia. The mesen-
chymal portion of the tumor, however, is highly cellu-
lar and shows hyperchromatic and often-bizarre
pleomorphic cells (Fig. 15-106). Mitoses are usually
prominent. In some cases with multiple recurrences,
the epithelial component becomes progressively less
conspicuous so that the tumor eventually shows only a
poorly differentiated ﬁbrosarcoma.
In a few instances, dysplastic dentin or small
amounts of enamel may be formed. Some have called
such lesions ameloblastic dentinosarcomas or ame-
loblastic ﬁbro-odontosarcomas. This additional sub-
classiﬁcation, however, appears unnecessary. Another
rare event that actually may be overrepresented in the
literature is concurrent malignant transformation of
both the epithelial and mesenchymal elements of an
ameloblastic ﬁbroma, resulting in an ameloblastic
carcinosarcoma.
TREATMENT AND PROGNOSIS
Once the diagnosis of ameloblastic ﬁbrosarcoma has
been conﬁrmed, radical surgical excision appears to be
the treatment of choice. Curettage or local excision is
usually followed by rapid local recurrence. The tumor
is locally aggressive and inﬁltrates adjacent bone and
soft tissues.
The long-term prognosis is difﬁcult to ascertain
because of the few reported cases with adequate follow-
up, with the best estimates suggesting that 20% of these
patients will succumb to their tumor. Most deaths have
resulted from uncontrolled local disease, and meta-
static tumor has been documented in only 3 of 53
evaluable cases.
ODONTOAMELOBLASTOMA
The odontoameloblastoma is an extremely rare
odontogenic tumor that contains an ameloblastoma-
tous component and odontoma-like elements. Fewer
BA
Fig. 15-105 Ameloblastic ﬁbrosarcoma. A, A 21-year-old woman complained of facial
asymmetry and recent increase in size of a mandibular mass that had been present for some
years. B, Radiograph of the same patient. Note the lytic destruction of the posterior mandible.
(Courtesy of Dr. Sam McKenna.)
Fig. 15-106 Ameloblastic ﬁbrosarcoma. The cellular
mesenchymal tissue shows hyperchromatism and atypical
cells. A small island of ameloblastic epithelium is present. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

724 ORAL AND MAXILLOFACIAL PATHOLOGY
than 20 cases have been reported with sufﬁcient docu-
mentation to support this diagnosis. This tumor was
formerly called ameloblastic odontoma and was confused
with the more common (though still relatively rare)
lesion currently designated as ameloblastic ﬁbro-
odontoma. Because the clinical behavior of these two
tumors is quite different, they should be distinguished
from one another. This neoplasm is also frequently
confused with an odontoma that is in its early stages of
development.
CLINICAL AND RADIOGRAPHIC
FEATURES
Because of the rarity of odontoameloblastomas, little
reliable information is available. The lesion appears to
occur more often in younger patients, and either jaw
can be affected. Pain, delayed eruption of teeth, and
expansion of the affected bone may be noted.
Radiographically, the tumor shows a radiolucent,
destructive process that contains calciﬁed structures.
These have the radiodensity of tooth structure and may
resemble miniature teeth or occur as larger masses of
calciﬁed material similar to a complex odontoma.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the odontoameloblas-
toma are complex. The proliferating epithelial portion
of the tumor has features of an ameloblastoma, most
often of the plexiform or follicular pattern. The amelo-
blastic component is intermingled with immature or
more mature dental tissue in the form of developing
rudimentary teeth, which is similar to the appearance
of a compound odontoma, or conglomerate masses
of enamel, dentin, and cementum, as seen in a complex
odontoma.
TREATMENT AND PROGNOSIS
Multiple recurrences of odontoameloblastomas have
been reported after local curettage, and it appears that
this tumor has the same biologic potential as the ame-
loblastoma. It is probably wise to treat a patient with
this lesion in the same manner as one with an amelo-
blastoma. However, there are no valid data on the long-
term prognosis.
ODONTOMA
Odontomas are the most common types of odonto-
genic tumors. Their prevalence exceeds that of all other
odontogenic tumors combined. Odontomas are consid-
ered to be developmental anomalies (hamartomas),
rather than true neoplasms. When fully developed,
odontomas consist chieﬂy of enamel and dentin, with
variable amounts of pulp and cementum. In their
earlier developmental stages, varying amounts of pro-
liferating odontogenic epithelium and mesenchyme
are present.
Odontomas are further subdivided into compound
and complex types. The compound odontoma is
composed of multiple, small toothlike structures. The
complex odontoma consists of a conglomerate mass
of enamel and dentin, which bears no anatomic resem-
blance to a tooth. In most series, compound odontomas
are more frequently diagnosed than complex, and it is
possible that some compound odontomas are not sub-
mitted for microscopic examination because the clini-
cian is comfortable with the clinical and radiographic
diagnosis. Occasionally, these lesions may show fea-
tures of both compound and complex odontoma.
CLINICAL AND RADIOGRAPHIC
FEATURES
Most odontomas are detected during the ﬁrst two
decades of life, and the mean age at the time of diag-
nosis is 14 years. The majority of these lesions are com-
pletely asymptomatic, being discovered on a routine
radiographic examination or when ﬁlms are taken to
determine the reason for failure of a tooth to erupt.
Odontomas are typically relatively small and seldom
exceed the size of a tooth in the area where they are
located. However, large odontomas up to 6 cm or more
in diameter are occasionally seen. These large odonto-
mas can cause expansion of the jaw.
Odontomas occur somewhat more frequently in the
maxilla than in the mandible. Although compound and
complex odontomas may be found in any site, the com-
pound type is more often seen in the anterior maxilla;
complex odontomas occur more often in the molar
regions of either jaw. Occasionally, an odontoma will
develop completely within the gingival soft tissues.
Radiographically, the compound odontoma
appears as a collection of toothlike structures of
varying size and shape surrounded by a narrow radio-
lucent zone (Figs. 15-107 and 15-108). The complex
odontoma appears as a calciﬁed mass with the
radiodensity of tooth structure, which is also sur-
rounded by a narrow radiolucent rim. An unerupted
tooth is frequently associated with the odontoma, and
the odontoma prevents eruption of the tooth (Fig.
15-109). Some small odontomas are present between
the roots of erupted teeth and are not associated
with disturbance in eruption. The radiographic ﬁnd-
ings are usually diagnostic, and the compound odon-
toma is seldom confused with any other lesion. A
developing odontoma may show little evidence of cal-
ciﬁcation and appear as a circumscribed radiolucent `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 725
Fig. 15-107 Compound odontoma. A small cluster of
toothlike structures is preventing the eruption of the
maxillary canine. (Courtesy of Dr. Robert J. Powers.)
Fig. 15-108 Compound odontoma. Multiple toothlets
preventing the eruption of the mandibular cuspid. (Courtesy of
Dr. Brent Bernard.)
Fig. 15-109 Complex odontoma. A large radiopaque mass is overlying the crown of the
mandibular right second molar, which has been displaced to the inferior border of the
mandible.
lesion. A complex odontoma, however, may be radio-
graphically confused with an osteoma or some other
highly calciﬁed bone lesion.
HISTOPATHOLOGIC FEATURES
The compound odontoma consists of multiple struc-
tures resembling small, single-rooted teeth, contained
in a loose ﬁbrous matrix (Fig. 15-110). The mature
enamel caps of the toothlike structures are lost during
decalciﬁcation for preparation of the microscopic
section, but varying amounts of enamel matrix are
often present. Pulp tissue may be seen in the coronal
and root portions of the toothlike structures. In patients
with developing odontomas, structures that resemble
tooth germs are present.
Complex odontomas consist largely of mature
tubular dentin. This dentin encloses clefts or hollow
circular structures that contained the mature enamel
that was removed during decalciﬁcation. The spaces
may contain small amounts of enamel matrix or imma-
ture enamel (Fig. 15-111). Small islands of eosino-
philic-staining epithelial ghost cells are present in
about 20% of complex odontomas. These may repre-
sent remnants of odontogenic epithelium that have
undergone keratinization and cell death from the local
anoxia. A thin layer of cementum is often present about
the periphery of the mass. Occasionally, a dentigerous
cyst may arise from the epithelial lining of the ﬁbrous
capsule of a complex odontoma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

726 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
Odontomas are treated by simple local excision, and
the prognosis is excellent.
Tumors of Odontogenic
Ectomesenchyme
CENTRAL ODONTOGENIC FIBROMA
The central odontogenic ﬁbroma is an uncommon
and somewhat controversial lesion. Approximately
70 examples have been reported. Formerly, some oral
and maxillofacial pathologists designated solid ﬁbrous
masses that were almost always associated with the
crown of an unerupted tooth as odontogenic ﬁbromas.
Most oral and maxillofacial pathologists today consider
such lesions to represent only hyperplastic dental
follicles, and these should not be considered to be
neoplasms.
CLINICAL AND RADIOGRAPHIC
FEATURES
Odontogenic ﬁbromas have been reported in patients
whose ages ranged from 4 to 80 years (mean age, 40
years). Of those cases reported in the literature, a
2.2:1.0 female-to-male ratio has been noted, indicating
a strong female predilection. About 45% of reported
cases have occurred in the maxilla; most maxillary
lesions are located anterior to the ﬁrst molar tooth (Fig.
15-112). In the mandible, however, about half of the
tumors are located posterior to the ﬁrst molar. One
third of odontogenic ﬁbromas are associated with an
unerupted tooth. Smaller odontogenic ﬁbromas are
usually completely asymptomatic; larger lesions may
be associated with localized bony expansion or loosen-
ing of teeth.
Radiographically, smaller odontogenic ﬁbromas
tend to be well-deﬁned, unilocular, radiolucent lesions
often associated with the periradicular area of erupted
teeth (Fig. 15-113). Larger lesions tend to be multi-
locular radiolucencies. Many lesions have a sclerotic
border. Root resorption of associated teeth is common,
and lesions located between the teeth often cause root
divergence. Approximately 12% of central odontogenic
ﬁbromas will exhibit radiopaque ﬂecks within the
lesion.
HISTOPATHOLOGIC FEATURES
Lesions reported as central odontogenic ﬁbroma have
shown considerable histopathologic diversity; this
has led some authors to describe two separate types,
Fig. 15-110 Compound odontoma. Surgical specimen
consisting of more than 20 malformed toothlike structures.
Fig. 15-111 Complex odontoma. This decalciﬁed section
shows a disorganized mass of dentin intermixed with small
pools of enamel matrix.
10% 6%29%
29% 18%8%
Fig. 15-112 Odontogenic ﬁbroma. Relative distribution of
odontogenic ﬁbroma in the jaws. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 727
although this concept has been questioned. The so-
called simple odontogenic ﬁbroma is composed of
stellate ﬁbroblasts, often arranged in a whorled pattern
with ﬁne collagen ﬁbrils and considerable ground sub-
stance (Fig. 15-114). Small foci of odontogenic epithe-
lial rests may or may not be present. Occasional foci of
dystrophic calciﬁcation may be seen. Some investiga-
tors have suggested that this lesion actually belongs
with the spectrum of odontogenic myxoma and should
be designated as a myxoﬁbroma. A more collagenized
odontogenic ﬁbroma needs to be differentiated from a
desmoplastic ﬁbroma, which is a more aggressive
lesion. The desmoplastic ﬁbroma, however, does not
have an epithelial component.
The central odontogenic ﬁbroma, World Health
Organization (WHO) type, has a more complex
pattern, which often consists of a fairly cellular ﬁbrous
connective tissue with collagen ﬁbers arranged in
interlacing bundles. Odontogenic epithelium in the
form of long strands or isolated nests is present through-
out the lesion and may be a prominent component
(Fig. 15-115). The ﬁbrous component may vary from
myxoid to densely hyalinized. Calciﬁcations composed
of cementum-like material or dentinoid are present in
some cases.
Twelve examples of central odontogenic ﬁbroma
associated with a giant cell granuloma–like compo-
nent have been reported since 1992 (Fig. 15-116).
It seems unlikely that this process represents a “colli-
sion” tumor with synchronous occurrence of an odon-
togenic ﬁbroma and a giant cell granuloma. Several of
these lesions have recurred, and the recurrences typi-
cally exhibit both components. Whether the odonto-
genic ﬁbroma somehow induced a giant cell response
in these patients or whether this is a distinct biphasic
lesion remains to be clariﬁed.
TREATMENT AND PROGNOSIS
Odontogenic ﬁbromas are usually treated by enucle-
ation and vigorous curettage. Although the tumor does
not have a deﬁnite capsule, it appears to have a limited
growth potential, particularly in the anterior regions of
the jaws. A few recurrences have been documented,
but the prognosis is very good.
PERIPHERAL ODONTOGENIC FIBROMA
The relatively uncommon peripheral odontogenic
ﬁbroma is considered to represent the soft tissue coun-
terpart of the central (intraosseous) odontogenic
ﬁbroma. In the past, some authors have designated
clinically and histopathologically similar lesions as
odontogenic epithelial hamartoma or as peripheral
Fig. 15-113 Odontogenic ﬁbroma. Apical radiolucent
lesion in the incisor and premolar area. (Courtesy of Dr. Robert
Provencher, Jr.)
Fig. 15-114 Odontogenic ﬁbroma (simple type).
Scattered ﬁbroblasts within a collagenous background. No
epithelial rests were found on multiple sections from this
tumor.
Fig. 15-115 Odontogenic ﬁbroma (World Health
Organization [WHO] type). A cellular ﬁbroblastic lesion
containing narrow cords of odontogenic epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

728 ORAL AND MAXILLOFACIAL PATHOLOGY
ﬁbroameloblastic dentinoma. It is likely that all of
these terms refer to the same lesion, and peripheral
odontogenic ﬁbroma seems to be the most appropriate
designation. A few series of this lesion have been
reported in the past 2 decades, bringing the total num-
ber of cases in the literature to approximately 175.
CLINICAL AND RADIOGRAPHIC
FEATURES
The peripheral odontogenic ﬁbroma appears as a ﬁrm,
slow-growing, and usually sessile gingival mass covered
by normal-appearing mucosa (Fig. 15-117). Rarely,
multifocal or diffuse lesions have been described. Clin-
ically, the peripheral odontogenic ﬁbroma cannot be
distinguished from the much more common ﬁbrous
gingival lesions (see Chapter 12). The lesion is most
often encountered on the facial gingiva of the mandi-
ble. Most lesions are between 0.5 and 1.5 cm in diam-
eter, and they infrequently cause displacement of the
teeth. Peripheral odontogenic ﬁbromas have been
recorded in patients across a wide age range, with most
identiﬁed from the second to the seventh decades of
life.
Radiographic studies demonstrate a soft tissue mass,
which in some cases has shown areas of calciﬁcation.
The lesion, however, does not involve the underlying
bone.
HISTOPATHOLOGIC FEATURES
The peripheral odontogenic ﬁbroma shows similar
histopathologic features to the central odontogenic
ﬁbroma (WHO type). The tumor consists of interwo-
ven fascicles of cellular ﬁbrous connective tissue, which
may be interspersed with areas of less cellular, myxoid
connective tissue. A granular cell change has been
rarely identiﬁed in the connective tissue component,
and giant cell granuloma–like areas have been described
in a few lesions. Islands or strands of odontogenic epi-
thelium are scattered throughout the connective tissue.
These may be prominent or scarce. The epithelial cells
may show vacuolization. Dysplastic dentin, amorphous
ovoid cementum-like calciﬁcations, and trabeculae of
osteoid may also be present.
TREATMENT AND PROGNOSIS
The peripheral odontogenic ﬁbroma is treated by local
surgical excision, and the prognosis is excellent. Recur-
rence of this lesion has been documented, however,
A
B
Fig. 15-116 Odontogenic ﬁbroma (WHO type) with
associated giant cell granuloma. A, Unilocular radiolucency
between the left mandibular bicuspids. B, Microscopic
examination reveals two distinct patterns. On the left, one
can see cords of odontogenic epithelium within a ﬁbrous
background, consistent with odontogenic ﬁbroma (WHO
type). Typical features of central giant cell granuloma are
present on the right side of the ﬁeld.
Fig. 15-117 Peripheral odontogenic ﬁbroma. This sessile
gingival mass cannot be clinically distinguished from the
common peripheral ossifying ﬁbroma. (Courtesy of Dr. Jerry
Stovall.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 729
so the patient and clinician should be aware of this
possibility.
GRANULAR CELL ODONTOGENIC
TUMOR (GRANULAR CELL
ODONTOGENIC FIBROMA)
The rare granular cell odontogenic tumor was ini-
tially reported as “granular cell ameloblastic ﬁbroma.”
Subsequently, it was designated as granular cell odon-
togenic ﬁbroma, but the noncommittal term granu-
lar cell odontogenic tumor is probably more
appropriate, given the controversial nature of the
lesion. Approximately 30 cases of this unusual tumor
have been reported.
CLINICAL AND RADIOGRAPHIC
FEATURES
Patients with granular cell odontogenic tumors have all
been adults at the time of diagnosis, with more than
half being older than 40 years of age. More than 70%
of the cases have developed in women. The tumor
occurs primarily in the mandible and most often in the
premolar and molar region. Some lesions are com-
pletely asymptomatic; others present as a painless,
localized expansion of the affected area. A few cases of
granular cell odontogenic tumor have been described
in the gingival soft tissues as well.
Radiographically, the lesion appears as a well-
demarcated radiolucency, which may be unilocular or
multilocular and occasionally shows small calciﬁca-
tions (Fig. 15-118).
HISTOPATHOLOGIC FEATURES
The granular cell odontogenic tumor is composed of
large eosinophilic granular cells, which closely resem-
ble the granular cells seen in the soft tissue granular
cell tumor (see page 536) or the granular cells seen in
the granular cell variant of the ameloblastoma (see
page 709). Narrow cords or small islands of odonto-
genic epithelium are scattered among the granular
cells (Fig. 15-119). Small cementum-like or dystrophic
calciﬁcations associated with the granular cells have
been seen in some lesions.
The nature of the granular cells is controversial.
Ultrastructural studies reveal the features of mesen-
chymal cells, and bodies consistent with lysosomal
structures have been identiﬁed within the lesional cell
cytoplasm. Immunohistochemically, the granular cells
in the granular cell odontogenic tumor do not react
with antibodies directed against S-100 protein, in con-
trast to the positive S-100 reactivity of the granular cell
tumor.
TREATMENT AND PROGNOSIS
The granular cell odontogenic ﬁbroma appears to be
completely benign in the overwhelming majority of
instances and responds well to curettage. Only one
recurrence has been documented, and a solitary
example of a malignant central granular cell odonto-
genic ﬁbroma has been reported.
ODONTOGENIC MYXOMA
Myxomas of the jaws are believed to arise from odon-
togenic ectomesenchyme. They bear a close micro-
scopic resemblance to the mesenchymal portion of a
developing tooth. Formerly, some investigators made a
distinction between odontogenic myxomas (derived
from odontogenic mesenchyme) and osteogenic
Fig. 15-118 Granular cell odontogenic tumor.
Radiolucent lesion involving the apical area of endodontically
treated maxillary teeth. (Courtesy of Dr. Steve Ferry.)
Fig. 15-119 Granular cell odontogenic tumor. Sheet of
large granular mesenchymal cells with small nests of
odontogenic epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

730 ORAL AND MAXILLOFACIAL PATHOLOGY
myxomas (presumably derived from primitive bone
tissue). However, most authorities in orthopedic patho-
logic practice do not accept that myxomas occur in the
extragnathic skeleton, and all myxomas of the jaws are
currently considered to be of odontogenic origin.
CLINICAL AND RADIOGRAPHIC
FEATURES
Myxomas are predominantly found in young adults but
may occur across a wide age group. The average age for
patients with myxomas is 25 to 30 years. There is no sex
predilection. The tumor may be found in almost any
area of the jaws, and the mandible is involved more
commonly than the maxilla (Fig. 15-120). Smaller
lesions may be asymptomatic and are discovered only
during a radiographic examination. Larger lesions are
often associated with a painless expansion of the
involved bone. In some instances, clinical growth of the
tumor may be rapid; this is probably related to the accu-
mulation of myxoid ground substance in the tumor.
Radiographically, the myxoma appears as a unilocu-
lar or multilocular radiolucency that may displace or
cause resorption of teeth in the area of the tumor (Fig.
15-121). The margins of the radiolucency are often
irregular or scalloped. The radiolucent defect may
contain thin, wispy trabeculae of residual bone, which
are often arranged at right angles to one another (Fig.
15-122). Large myxomas of the mandible may show a
“soap bubble” radiolucent pattern, which is indistin-
guishable from that seen in ameloblastomas (Fig.
15-123).
HISTOPATHOLOGIC FEATURES
At the time of surgery or gross examination of the spec-
imen, the gelatinous, loose structure of the myxoma is
obvious (Fig. 15-124). Microscopically, the tumor is
composed of haphazardly arranged stellate, spindle-
shaped, and round cells in an abundant, loose myxoid
stroma that contains only a few collagen ﬁbrils (Fig.
15-125). Histochemical study shows that the ground
substance is composed of glycosaminoglycans, chieﬂy
hyaluronic acid and chondroitin sulfate. Immunohisto-
chemically, the myxoma cells show diffuse immunore-
activity with antibodies directed against vimentin, with
focal reactivity for muscle-speciﬁc actin. Small islands
of inactive-appearing odontogenic epithelial rests may
16% 9%9%
28% 20%18%
Fig. 15-120 Odontogenic myxoma. Relative distribution
of odontogenic myxoma in the jaws.
Fig. 15-121 Odontogenic myxoma. Unilocular
radiolucency between the right mandibular lateral incisor
and cuspid.
Fig. 15-122 Odontogenic myxoma. Radiolucent lesion of
anterior maxilla showing ﬁne residual bone trabeculae
arranged at right angles to one another (“stepladder”
pattern). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 731
be scattered throughout the myxoid ground substance.
These epithelial rests are not required for the diagnosis
and are not obvious in most cases. In some patients, the
tumor may have a greater tendency to form collagen
ﬁbers; such lesions are sometimes designated as ﬁbro-
myxomas or myxoﬁbromas. There is no evidence
that the more collagenized variants deserve separate
consideration, although some investigators have sug-
gested that these may represent part of a spectrum that
includes the central odontogenic ﬁbroma at the other
endpoint.
A myxoma may be microscopically confused with
other myxoid jaw neoplasms, such as the rare chondro-
myxoid ﬁbroma (see page 657) or the myxoid neuroﬁ-
broma (see page 528). Chondromyxoid ﬁbroma should
have areas of cartilaginous differentiation, whereas
myxoid neuroﬁbromas tend to have scattered lesional
cells that are positive for antibodies directed against
S-100 protein. Myxoid change in an enlarged dental
follicle or the dental papilla of a developing tooth may
be microscopically similar to a myxoma. Evaluation of
the clinical and radiographic features, however, will
prevent overdiagnosis of these lesions as myxomas.
TREATMENT AND PROGNOSIS
Small myxomas are generally treated by curettage, but
careful periodic reevaluation is necessary for at least 5
years. For larger lesions, more extensive resection may
be required because myxomas are not encapsulated
and tend to inﬁltrate the surrounding bone. Complete
removal of a large tumor by curettage is often difﬁcult
to accomplish, and lesions of the posterior maxilla,
in particular, should be treated more aggressively in
most instances. Recurrence rates from various studies
average approximately 25%. In spite of local recur-
rences, the overall prognosis is good, and metastases
do not occur.
In rare cases the myxoma microscopically shows
marked cellularity and cellular atypism. Some have
designated these lesions as myxosarcomas or malignant
odontogenic myxoma. They appear to have a more aggres-
sive local course than do the usual myxomas. Death
because of involvement of vital structures by the tumor
has been described, but distant metastases have not
been reported.
CEMENTOBLASTOMA (TRUE
CEMENTOMA)
Many oral and maxillofacial pathologists consider
the cementoblastoma to represent an odontogenic
tumor. However, other pathologists have pointed out
that the histopathologic features of cementoblastomas
of the jaws are identical to those of a bone tumor,
Fig. 15-123 Odontogenic myxoma. Occlusal view of a
large myxoma showing buccal expansion and “soap bubble”
radiolucency similar to that seen in an ameloblastoma.
(Courtesy of Dr. Mike Rohrer.)
Fig. 15-124 Odontogenic myxoma. Gross specimen of
case shown in Fig. 15-121, demonstrating a white gelatinous
mass.
Fig. 15-125 Odontogenic myxoma. A loose, myxomatous
tumor can be seen ﬁlling the marrow spaces between the
bony trabeculae. The inset shows stellate-shaped cells and
ﬁne collagen ﬁbrils. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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732 ORAL AND MAXILLOFACIAL PATHOLOGY
osteoblastoma, seen both in the jaws and extragnathic
skeleton. Cementoblastomas are discussed in Chapter
14 (see page 655).
BIBLIOGRAPHY
Odontogenic Cysts and Tumors—General References
and Classiﬁcation
Barnes L, Eveson JW, Reichart P et al, editors: World Health
Organization classiﬁcation of tumours: pathology and genetics of
head and neck tumours, Lyon, France, 2005, IARC Press.
Jones AV, Craig GT, Franklin CD: Range and demographics of
odontogenic cysts diagnosed in a UK population over a 30-
year period, J Oral Pathol Med 35:500-507, 2006.
Kramer IRH, Pindborg JJ, Shear M: Histological typing of odonto-
genic tumors, ed 2, 1992, New York, Springer-Verlag.
Kramer IRH, Pindborg JJ, Shear M: The World Health Organiza-
tion histological typing of odontogenic tumours: introducing
the second edition, Eur J Cancer B Oral Oncol 29B:169-171,
1993.
Kreidler JF, Raubenheimer EJ, van Heerden WFP: A retrospec-
tive analysis of 367 cystic lesions of the jaw—the Ulm experi-
ence, J Craniomaxillofac Surg 21:339-341, 1993.
Nakamura T, Ishida J, Nakano Y et al: A study of cysts in the oral
region: cysts of the jaws, J Nihon Univ Sch Dent 37:33-40,
1995.
Neville BW, Damm DD, Allen CM: Odontogenic cysts and
tumors. In Gnepp D: Diagnostic surgical pathology of the head
and neck, Philadelphia, 2001, WB Saunders.
Philipsen HP, Reichart PA: The development and fate of epithe-
lial residues after completion of the human odontogenesis
with special reference to the origins of epithelial odontogenic
neoplasms, hamartomas and cysts, Oral Biosci Med 1:171-179,
2004.
Shear M: Developmental odontogenic cysts. An update, J Oral
Pathol Med 23:1-11, 1994.
Shear M, Speight P: Cysts of the oral and maxillofacial regions, ed 4,
Oxford, 2007, Blackwell.
Dentigerous Cyst
Ackermann G, Cohen MA, Altini M: The paradental cyst: a clini-
copathologic study of 50 cases, Oral Surg Oral Med Oral Pathol
64:308-312, 1987.
Adelsperger J, Campbell JH, Coates DB et al: Early soft tissue
pathosis associated with impacted third molars without peri-
coronal radiolucency, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 89:402-406, 2000.
Benn A, Altini M: Dentigerous cysts of inﬂammatory origin:
a clinicopathologic study, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 81:203-209, 1996.
Clauser C, Zuccati G, Barone R et al: Simpliﬁed surgical-
orthodontic treatment of a dentigerous cyst, J Clin Orthod
28:103-106, 1994.
Craig GT: The paradental cyst: a speciﬁc inﬂammatory odonto-
genic cyst, Br Dent J 141:9-14, 1976.
Curran AE, Damm DD, Drummond JF: Pathologically signiﬁ-
cant pericoronal lesions in adults: histopathologic evaluation,
J Oral Maxillofac Surg 60:613-617, 2002.
Daley TD, Wysocki GP: The small dentigerous cyst: a diagnostic
dilemma, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
79:77-81, 1995.
Delbem AC, Cunha RF, Afonso RL et al: Dentigerous cysts in
primary dentition: report of 2 cases, Pediatr Dent 28:269-272,
2006.
Gorlin RJ: Potentialities of oral epithelium manifest by mandibu-
lar dentigerous cysts, Oral Surg Oral Med Oral Pathol 10:271-
284, 1957.
Kusukawa J, Irie K, Morimatsu M et al: Dentigerous cyst associ-
ated with a deciduous tooth: a case report, Oral Surg Oral Med
Oral Pathol 73:415-418, 1992.
Lustmann L, Bodner L: Dentigerous cysts associated with super-
numerary teeth, Int J Oral Maxillofac Surg 17:100-102, 1988.
Motamedi MHK, Talesh KT: Management of extensive dentiger-
ous cysts, Br Dent J 198:203-206, 2005.
Takeda Y, Oikawa Y, Furuya I et al: Mucous and ciliated cell
metaplasia in epithelial linings of odontogenic inﬂammatory
and developmental cysts, J Oral Sci 47:77-81, 2005.
Ziccardi VB, Eggleston TI, Schneider RE: Using fenestration
technique to treat a large dentigerous cyst, J Am Dent Assoc
128:201-205, 1997.
Eruption Cyst
Aguiló L, Cibrián R, Bagán JV et al: Eruption cysts: retrospective
clinical study of 36 cases, ASDC J Dent Child 65:102-106,
1998.
Bodner L, Goldstein J, Sarnat H: Eruption cysts: a clinical report
of 24 new cases, J Clin Pediatr Dent 28:183-186, 2004.
Clark CA: A survey of eruption cysts in the newborn, Oral Surg
Oral Med Oral Pathol 15:917, 1962.
Kuczek A, Beikler T, Herbst H et al: Eruption cyst formation
associated with cyclosporin A: a case report, J Clin Periodontol
30:462-466, 2003.
Seward MH: Eruption cyst: an analysis of its clinical features,
J Oral Surg 31:31-35, 1973.
Primordial Cyst
Brannon RB: The odontogenic keratocyst—a clinicopathologic
study of 312 cases. Part I: Clinical features, Oral Surg Oral Med
Oral Pathol 42:54-72, 1976.
Robinson HBG: Classiﬁcation of cysts of the jaws, Am J Orthod
Oral Surg 31:370-375, 1945.
Odontogenic Keratocyst
Ahlfors E, Larsson A, Sjögren S: The odontogenic keratocyst:
a benign cystic tumor? J Oral Maxillofac Surg 42:10-19,
1984.
Ali M, Baughman RA: Maxillary odontogenic keratocyst: a
common and serious clinical misdiagnosis, J Am Dent Assoc
134:877-883, 2003.
Agaram NP, Collins BM, Barnes L et al: Molecular analysis to
demonstrate that odontogenic keratocysts are neoplastic,
Arch Pathol Lab Med 128:313-317, 2004.
Barnes L, Eveson JW, Reichart P et al, editors: World Health
Organization classiﬁcation of tumours: pathology and genetics of
head and neck tumours, Lyon, France, 2005, IARC Press.
Bataineh AB, Al Qudah MA: Treatment of mandibular odonto-
genic keratocysts, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 86:42-47, 1988.
Blanas N, Freund B, Schwartz M et al: Systematic review of the
treatment and prognosis of the odontogenic keratocyst, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 90:553-558,
1988.
Brannon RB: The odontogenic keratocyst—a clinicopathologic
study of 312 cases. Part I: Clinical features, Oral Surg Oral Med
Oral Pathol 42:54-72, 1976.
Brannon RB: The odontogenic keratocyst—a clinicopathologic
study of 312 cases. Part II: Histologic features, Oral Surg Oral
Med Oral Pathol 43:233-255, 1977.
Brøndum N, Jensen VJ: Recurrence of keratocysts and decom-
pression treatment: a long-term follow-up of forty-four cases,
Oral Surg Oral Med Oral Pathol 72:265-269, 1991. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 15 ODONTOGENIC CYSTS AND TUMORS 733
Chehade A, Daley TD, Wysocki GP et al: Peripheral odontogenic
keratocyst, Oral Surg Oral Med Oral Pathol 77:494-497,
1994.
Chi AC, Owings JR, Muller S: Peripheral odontogenic keratocyst:
report of two cases and review of the literature, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 99:71-78, 2005.
Fornatora ML, Reich RF, Chotkowski G et al: Odontogenic kera-
tocyst with mural cartilaginous metaplasia: a case report and
a review of the literature, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 92:430-434, 2001.
Forssell K, Forssell H, Kahnberg K-E: Recurrence of keratocysts:
a long-term follow-up study, Int J Oral Maxillofac Surg 17:25-
28, 1988.
Garlock JA, Pringle GA, Hicks ML: The odontogenic keratocyst:
a potential endodontic misdiagnosis, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 85:452-456, 1988.
Henley J, Summerlin D-J, Tomich C et al: Molecular evidence
supporting the neoplastic nature of odontogenic keratocyst: a
laser capture microdissection study of 15 cases, Histopathol-
ogy 47:582-586, 2005.
Ide F, Shimoyama T, Horie N: Peripheral odontogenic kerato-
cyst: a report of 2 cases, J Periodontol 73:1079-1081, 2002.
Jackson IT, Potparic Z, Fasching M et al: Penetration of the skull
base by dissecting keratocyst, J Craniomaxillofac Surg 21:319-
325, 1993.
Kakarantza-Angelopoulou E, Nicolatou O: Odontogenic kerato-
cysts: clinicopathologic study of 87 cases, J Oral Maxillofac
Surg 48:593-599, 1990.
Kolokythas A, Fernandes RP, Pazoki A et al: Odontogenic kera-
tocyst: to decompress or not to decompress? A comparative
study of decompression and enucleation versus resection/
peripheral ostectomy, J Oral Maxillofac Surg 65:640-644,
2007.
Kratochvil FJ, Brannon RB: Cartilage in the walls of odontogenic
keratocysts, J Oral Pathol Med 22:282-285, 1993.
Levanat S, Kappler R, Hemmerlein B et al: Analysis of the PTCH1
signaling pathway in ovarian dermoids, Int J Mol Med 14:793-
799, 2004.
Makowski GJ, McGuff S, van Sickels JE: Squamous cell carci-
noma in a maxillary odontogenic keratocyst, J Oral Maxillofac
Surg 59:76-80, 2001.
Meiselman F: Surgical management of the odontogenic kerato-
cyst: conservative approach, J Oral Maxillofac Surg 52:960-
963, 1994.
Morgan TA, Burton CC, Qian F: A retrospective review of treat-
ment of the odontogenic keratocyst, J Oral Maxillofac Surg
63:635-639, 2005.
Myoung H, Hong S-P, Hong S-D et al: Odontogenic keratocyst:
review of 256 cases for recurrence and clinicopathologic
parameters, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
91:328-333, 2001.
Neville BW, Damm DD, Brock TR: Odontogenic keratocysts of
the midline maxillary region, J Oral Maxillofac Surg 55:340-
344, 1997.
Pogrel MA, Jordan RCK: Marsupialization as a deﬁnitive treat-
ment for the odontogenic keratocyst, J Oral Maxillofac Surg
62:651-655, 2004.
Preston RD, Narayana N: Peripheral odontogenic keratocyst,
J Periodontol 76:2312-2315, 2005.
Rodu B, Tate AL, Martinez MG: The implications of inﬂamma-
tion in odontogenic keratocysts, J Oral Pathol 16:518-521,
1987.
Shear M: The aggressive nature of the odontogenic keratocyst: is
it a benign cystic neoplasm? Part 1. Clinical and early experi-
mental evidence of aggressive behavior, Oral Oncol 38:219-
226, 2002.
Shear M: The aggressive nature of the odontogenic keratocyst: is
it a benign cystic neoplasm? Part 2. Proliferation and genetic
studies, Oral Oncol 38:323-331, 2002.
Shear M: The aggressive nature of the odontogenic keratocyst:
is it a benign cystic neoplasm? Part 3. Immunocytochemistry
of cytokeratin and other epithelial cell markers, Oral Oncol
38:407-415, 2002.
Voorsmit RACA: The incredible keratocyst: a new approach to
treatment, Dtsch Zahnarztl Z 40:641-644, 1985.
Williams TP, Connor Jr FA: Surgical management of the odon-
togenic keratocyst: aggressive approach, J Oral Maxillofac Surg
52:964-966, 1994.
Yamazaki M, Cheng J, Nomura T et al: Maxillary odontogenic
keratocyst with respiratory epithelium: a case report, J Oral
Pathol Med 32:496-498, 2003.
Yoon JH, Kim SG, Lee SH et al: Simultaneous occurrence of an
odontogenic keratocyst and giant cell granuloma-like lesion
in the mandible, Int J Oral Maxillofac Surg 33:615-617,
2004.
Orthokeratinized Odontogenic Cysts
Crowley TE, Kaugars GE, Gunsolley JC: Odontogenic kerato-
cysts: a clinical and histologic comparison of the parakeratin
and orthokeratin variants, J Oral Maxillofac Surg 50:22-26,
1992.
Li T-J, Kitano M, Chen X-M et al: Orthokeratinized odontogenic
cyst: a clinicopathological and immunocytochemical study of
15 cases, Histopathology 32:242-251, 1998.
Siar CH, Ng KH: Orthokeratinised odontogenic keratocysts in
Malaysians, Br J Oral Maxillofac Surg 26:215-220, 1988.
Vuhahula E, Nikai H, Ijuhin N et al: Jaw cysts with orthokerati-
nization: analysis of 12 cases, J Oral Pathol Med 22:35-40,
1993.
Wright JM: The odontogenic keratocyst: orthokeratinized
variant, Oral Surg Oral Med Oral Pathol 51:609-618, 1981.
Nevoid Basal Cell Carcinoma Syndrome
Cohen MM Jr: Nevoid basal cell carcinoma syndrome: molecular
biology and new hypotheses, Int J Oral Maxillofac Surg 28:216-
223, 1999.
Evans DGR, Ladusans EJ, Rimmer S et al: Complications of the
naevoid basal cell carcinoma syndrome: results of a popula-
tion based study, J Med Genet 30:460-464, 1993.
Goldstein AM, Pastakia B, DeGiovanna JJ et al: Clinical ﬁndings
in two African-American families with the nevoid basal cell
carcinoma syndrome (NBCC), Am J Med Genet 50:272-281,
1994.
Gorlin RJ: Nevoid basal cell carcinoma (Gorlin) syndrome, Genet
Med 6:530-539, 2004.
Gorlin RJ, Goltz R: Multiple nevoid basal cell epithelioma, jaw
cysts and biﬁd rib syndrome, N Engl J Med 262:908-914,
1960.
Kimonis VE, Goldstein AM, Pastakia B et al: Clinical manifesta-
tions in 105 persons with nevoid basal cell carcinoma syn-
drome, Am J Med Genet 69:299-308, 1997.
Lo Muzio L, Nocini P, Bucci P et al: Early diagnosis of nevoid
basal cell carcinoma syndrome, J Am Dent Assoc 130:669-
674, 1999.
Lo Muzio L, Staibano S, Pannone G et al: Expression of cell cycle
and apoptosis-related proteins in sporadic odontogenic
keratocysts and odontogenic keratocysts associated with the
nevoid basal cell carcinoma syndrome, J Dent Res 78:1345-
1353, 1999.
Manfredi M, Vescovi P, Bonanini M et al: Nevoid basal cell car-
cinoma syndrome: a review of the literature, Int J Oral Maxil-
lofac Surg 33:117-124, 2004. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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734 ORAL AND MAXILLOFACIAL PATHOLOGY
Shanley S, Ratcliffe J, Hockey A et al: Nevoid basal cell carci-
noma syndrome: review of 118 affected individuals, Am J Med
Genet 50:282-290, 1994.
Woolgar JA, Rippin JW, Browne RM: A comparative histologic
study of odontogenic keratocysts in basal cell nevus syndrome
and non-syndrome patients, J Oral Pathol 16:75-80, 1987.
Woolgar JA, Rippin JW, Browne RM: The odontogenic kerato-
cyst and its occurrence in the nevoid basal cell carcinoma
syndrome, Oral Surg Oral Med Oral Pathol 64:727-730,
1987.
Gingival Cyst of the Newborn
Cataldo E, Berkman M: Cysts of the oral mucosa in newborns,
Am J Dis Child 116:44-48, 1968.
Donley CL, Nelson LP: Comparison of palatal and alveolar cysts
of the newborn in premature and full term infants, Pediatr
Dent 22:321-324, 2000.
Fromm A: Epstein’s pearls, Bohn’s nodules and inclusion cysts of
the oral cavity, J Dent Child 34:275-287, 1967.
Jorgenson RJ, Shapiro SD, Salinas CF et al: Intraoral ﬁndings and
anomalies in neonates, Pediatrics 69:577-582, 1982.
Paula JDR, Dezan CC, Frossard WTG et al: Oral and facial inclu-
sion cysts in newborns, J Clin Pediatr Dent 31:127-129,
2006.
Gingival Cyst of the Adult
Bell RC, Chauvin PJ, Tyler MT: Gingival cyst of the adult: a
review and report of eight cases, J Can Dent Assoc 63:533-535,
1997.
Breault LG, Billman MA, Lewis DM: Report of a gingival “surgical
cyst” developing secondarily to a subepithelial connective
tissue graft, J Periodontol 68:392-395, 1997.
Buchner A, Hansen LS: The histomorphologic spectrum of the
gingival cyst in the adult, Oral Surg Oral Med Oral Pathol
48:532-539, 1979.
Cairo F, Rotundo R, Ficarra G: A rare lesion of the periodontium:
the gingival cyst of the adult—a report of three cases, Int J
Periodontics Restorative Dent 22:79-83, 2002.
Cunha KG, Carvalho Neto LG, Saraiva FM et al: Gingival cyst of
the adult: a case report, Gen Dent 53:215-216, 2005.
Nxumalo TN, Shear M: Gingival cyst in adults, J Oral Pathol Med
21:309-313, 1992.
Lateral Periodontal Cyst
Altini M, Shear M: The lateral periodontal cyst: an update, J Oral
Pathol Med 21:245-250, 1992.
Baker RD, D’Onofrio ED, Corio RL: Squamous-cell carcinoma
arising in a lateral periodontal cyst, Oral Surg Oral Med Oral
Pathol 47:495-499, 1979.
Carter LC, Carney YL, Perez-Pudlewski D: Lateral periodontal
cyst: multifactorial analysis of a previously unreported series,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:210-216,
1996.
Cohen D, Neville B, Damm D et al: The lateral periodontal cyst:
a report of 37 cases, J Periodontol 55:230-234, 1984.
Fantasia JE: Lateral periodontal cyst: an analysis of forty-six cases,
Oral Surg Oral Med Oral Pathol 48:237-243, 1979.
Greer RO, Johnson M: Botryoid odontogenic cyst: clinicopatho-
logic analysis of ten cases with three recurrences, J Oral Maxil-
lofac Surg 46:574-579, 1988.
Gurol M, Burkes EJ Jr, Jacoway J: Botryoid odontogenic cyst:
analysis of 33 cases, J Periodontol 66:1069-1073, 1995.
Kerezoudis NP, Donta-Bakoyianni C, Siskos G: The lateral peri-
odontal cyst: aetiology, clinical signiﬁcance and diagnosis,
Endod Dent Traumatol 16:144-150, 2000.
Ramer M, Valauri D: Multicystic lateral periodontal cyst
and botryoid odontogenic cyst: multifactorial analysis of
previously unreported series and review of literature, N Y
State Dent J 71:47-51, 2005.
Rasmusson LG, Magnusson BC, Borrman H: The lateral peri-
odontal cyst: a histopathological and radiographic study of 32
cases, Br J Oral Maxillofac Surg 29:54-57, 1991.
Wysocki GP, Brannon RB, Gardner DG et al: Histogenesis of the
lateral periodontal cyst and the gingival cyst of the adult, Oral
Surg Oral Med Oral Pathol 50:327-334, 1980.
Calcifying Odontogenic Cyst
Barnes L, Eveson JW, Reichart P et al, editors: World Health
Organization classiﬁcation of tumours: pathology and genetics of
head and neck tumours, Lyon, France, 2005, IARC Press.
Buchner A: The central (intraosseous) calcifying odontogenic
cyst: an analysis of 215 cases, J Oral Maxillofac Surg 49:330-
339, 1991.
Buchner A, Merrell PW, Hansen LS et al: Peripheral (extraosse-
ous) calcifying odontogenic cyst, Oral Surg Oral Med Oral
Pathol 72:65-70, 1991.
Daniels JSM: Recurrent calcifying odontogenic cyst involving the
maxillary sinus, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 98:660-664, 2004.
Ellis GL: Odontogenic ghost cell tumor, Semin Diagn Pathol
16:288-292, 1999.
Ellis GL, Shmookler BM: Aggressive (malignant?) epithelial
odontogenic ghost cell tumor, Oral Surg Oral Med Oral Pathol
61:471-478, 1986.
Fregnani ER, Pires FR, Quezada RD et al: Calcifying odontogenic
cyst: clinicopathological features and immunohistochemical
proﬁle of 10 cases, J Oral Pathol Med 32:163-170, 2003.
Goldenberg D, Sciubba J, Tufano RP: Odontogenic ghost cell
carcinoma, Head Neck 26:378-381, 2004.
Gorlin RJ, Pindborg JJ, Clausen FP et al: The calcifying odonto-
genic cyst—a possible analogue to the cutaneous calcifying
epithelioma of Malherbe: an analysis of ﬁfteen cases, Oral
Surg 15:1235-1243, 1962.
Hong SP, Ellis GL, Hartman KS: Calcifying odontogenic cyst: a
review of ninety-two cases with reevaluation of their nature as
cysts or neoplasms, the nature of the ghost cells and subclas-
siﬁcation, Oral Surg Oral Med Oral Pathol 72:56-64, 1991.
Iida S, Fukuda Y, Ueda T et al: Calcifying odontogenic cyst:
radiologic ﬁndings in 11 cases, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 101:356-362, 2006.
Johnson A III, Fletcher M, Gold L et al: Calcifying odontogenic
cyst: a clinicopathologic study of 57 cases with immunohisto-
chemical evaluation for cytokeratin, J Oral Maxillofac Surg
55:679-683, 1997.
Li T-J, Yu S-F: Clinicopathologic spectrum of the so-called calcify-
ing odontogenic cysts: a study of 21 intraosseous cases with
reconsideration of the terminology and classiﬁcation, Am J
Surg Pathol 27:372-384, 2003.
Lu Y, Mock D, Takata T et al: Odontogenic ghost cell carcinoma:
report of four new cases and review of the literature, J Oral
Pathol Med 28:323-329, 1999.
Praetorius F, Hjørting-Hansen E, Gorlin RJ et al: Calcifying odon-
togenic cyst: range, variations and neoplastic potential, Acta
Odontol Scand 39:227-240, 1981.
Tajima Y, Yokose S, Sakamoto E et al: Ameloblastoma arising in
calcifying odontogenic cyst, Oral Surg Oral Med Oral Pathol
74:776-779, 1992.
Toida M: So-called calcifying odontogenic cyst: review and dis-
cussion on the terminology and classiﬁcation, J Oral Pathol
Med 27:49-52, 1998.
Yoshida M, Kumamoto H, Ooya K et al: Histopathological
and immunohistochemical analysis of calcifying odontogenic
cysts, J Oral Pathol Med 30:582-588, 2001. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 15 ODONTOGENIC CYSTS AND TUMORS 735
Glandular Odontogenic Cyst
Gardner DG, Kessler HP, Morency R et al: The glandular odon-
togenic cyst: an apparent entity, J Oral Pathol 17:359-366,
1988.
High AS, Main DMG, Khoo SP et al: The polymorphous odonto-
genic cyst, J Oral Pathol Med 25:25-31, 1996.
Hussain K, Edmondson HD, Browne RM: Glandular odonto-
genic cysts: diagnosis and treatment, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 79:593-602, 1995.
Kaplan I, Gal G, Anavi Y et al: Glandular odontogenic cyst: treat-
ment and recurrence, J Oral Maxillofac Surg 63:435-441,
2005.
Koppang HS, Johannessen S, Haugen LK et al: Glandular odon-
togenic cyst (sialo-odontogenic cyst): report of two cases and
literature review of 45 previously reported cases, J Oral Pathol
Med 27:455-462, 1998.
Magnusson B, Göransson L, Ödesjö B et al: Glandular odonto-
genic cyst: report of seven cases, Dentomaxillofac Radiol 26:26-
31, 1997.
Manor R, Anavi Y, Kaplan I et al: Radiological features of
glandular odontogenic cyst, Dentomaxillofac Radiol 32:73-79,
2003.
Noffke C, Raubenheimer EJ: The glandular odontogenic cyst:
clinical and radiological features; review of the literature and
report of nine cases, Dentomaxillofac Radiol 31:333-338,
2002.
Qin X-N, Li J-R, Chen X-M et al: The glandular odontogenic cyst:
clinicopathologic features and treatment of 14 cases, J Oral
Maxillofac Surg 63:694-699, 2005.
Shen J, Fan M, Chen X et al: Glandular odontogenic cyst in
China: report of 12 cases and immunohistochemical study,
J Oral Pathol Med 35:175-182, 2006.
Tran P-T, Cunningham CJ, Baughman RA: Glandular odonto-
genic cyst, J Endod 30:182-184, 2004.
Buccal Bifurcation Cyst
Colgan CM, Henry J, Napier SS et al: Paradental cysts: a role for
food impaction in the pathogenesis? A review of cases from
Northern Ireland, Br J Oral Maxillofac Surg 40:163-168,
2002.
Craig GT: The paradental cyst: a speciﬁc inﬂammatory odonto-
genic cyst, Br Dent J 141:9-14, 1976.
David LA, Sàndor GKB, Stoneman DW: The buccal bifurcation
cyst: is non-surgical treatment an option? J Can Dent Assoc
64:712-716, 1998.
Fowler CB, Brannon RB: The paradental cyst: a clinicopathologic
study of six new cases and review of the literature, J Oral
Maxillofac Surg 47:243-248, 1989.
Pompura JR, Sàndor GKB, Stoneman DW: The buccal bifurca-
tion cyst: a prospective study of treatment outcomes in 44
sites, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:215-
221, 1997.
Shohat I, Buchner A, Taicher S: Mandibular buccal bifurcation
cyst: enucleation without extraction, Int J Oral Maxillofac Surg
32:610-613, 2003.
Stoneman DW, Worth HM: The mandibular infected buccal
cyst-molar area, Dent Radiogr Photogr 56:1-14, 1983.
Carcinoma Arising in Odontogenic Cysts
Cavalcanti MGP, Veltrini VC, Ruprecht A et al: Squamous-cell
carcinoma arising from an odontogenic cyst—the importance
of computed tomography in the diagnosis of malignancy, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 100:365-368,
2005.
Chaisuparat R, Coletti D, Kolokythas A et al: Primary intraosse-
ous odontogenic carcinoma arising in an odontogenic cyst or
de novo: a clinicopathologic study of six new cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 101:196-202, 2006.
Gardner AF: The odontogenic cyst as a potential carcinoma:
a clinicopathologic appraisal, J Am Dent Assoc 78:746-755,
1969.
Hennis HL, Stewart WC, Neville B et al: Carcinoma arising in
an odontogenic keratocyst with orbital invasion, Doc Ophthal-
mol 77:73-79, 1991.
Makowski GJ, McGuff S, van Sickels JE: Squamous cell carci-
noma in a maxillary odontogenic keratocyst, J Oral Maxillofac
Surg 59:76-80, 2001.
Scheer M, Koch AM, Drebber U et al: Primary intraosseous car-
cinoma of the jaws arising from an odontogenic cyst—a case
report, J Craniomaxillofac Surg 32:166-169, 2004.
Stoelinga PJ, Bronkhorst FB: The incidence, multiple presenta-
tion and recurrence of aggressive cysts of the jaws, J Cranio-
maxillofac Surg 16:184-195, 1988.
Swinson BD, Jerjes W, Thomas GJ: Squamous cell carcinoma
arising in a residual odontogenic cyst: case report, J Oral Max-
illofac Surg 63:1231-1233, 2005.
van der Waal I, Rauhamaa R, van der Kwast WAM et al: Squa-
mous cell carcinoma arising in the lining of odontogenic
cysts: report of 5 cases, Int J Oral Surg 14:146-152, 1985.
Waldron CA, Mustoe TA: Primary intraosseous carcinoma of the
mandible with probable origin in an odontogenic cyst, Oral
Surg Oral Med Oral Pathol 67:716-724, 1989.
Yasuoka T, Yonemoto K, Kato Y et al: Squamous cell carcinoma
arising in a dentigerous cyst, J Oral Maxillofac Surg 58:900-
905, 2000.
Yoshida H, Onizawa K, Yusa H: Squamous cell carcinoma arising
in association with an orthokeratinized odontogenic kerato-
cyst. Report of a case, J Oral Maxillofac Surg 54:647-651,
1996.
Ameloblastoma
Buchner A, Merrell PW, Carpenter WM: Relative frequency
of central odontogenic tumors: a study of 1,088 cases from
northern California and comparison to studies from other
parts of the world, J Oral Maxillofac Surg 64:1343-1352,
2006.
Carlson ER, Marx RE: The ameloblastoma: primary, curative sur-
gical management, J Oral Maxillofac Surg 64:484-494, 2006.
Eversole LR, Leider AS, Hansen LS: Ameloblastomas with
pronounced desmoplasia, J Oral Maxillofac Surg 42:735-740,
1984.
Gardner DG: Some current concepts on the pathology of
ameloblastomas, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 82:660-669, 1996.
Gardner DG: Critique of the 1995 review by Reichart et al of
the biologic proﬁle of 3677 ameloblastomas, Oral Oncol
35:443-449, 1999.
Gardner DG, Pecak AMJ: The treatment of ameloblastoma
based on pathologic and anatomic principles, Cancer 46:
2514-2519, 1980.
Ghandhi D, Ayoub AF, Pogrel MA et al: Ameloblastoma: a sur-
geon’s dilemma, J Oral Maxillofac Surg 64:1010-1014, 2006.
Gortzak RA, Latief BS, Lekkas C et al: Growth characteristics of
large mandibular ameloblastomas: report of 5 cases with
implications for the approach to surgery, Int J Oral Maxillofac
Surg 35:691-695, 2006.
Hirota M, Aoki S, Kawabe R et al: Desmoplastic ameloblastoma
featuring basal cell ameloblastoma: a case report, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 99:160-164, 2005.
Hong J, Yun P-Y, Chung I-H et al: Long-term follow up on recur-
rence of 305 ameloblastoma cases, Int J Oral Maxillofac Surg
36:283-288, 2007. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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736 ORAL AND MAXILLOFACIAL PATHOLOGY
Keszler A, Paparella ML, Dominguez FV: Desmoplastic and non-
desmoplastic ameloblastoma: a comparative clinicopatho-
logical analysis, Oral Dis 2:228-231, 1996.
Kishino M, Murakami S, Fukuda Y et al: Pathology of the desmo-
plastic ameloblastoma, J Oral Pathol Med 30:35-40, 2001.
Leibovitch I, Schwarcz RM, Modjtahedi S et al: Orbital inva-
sion by recurrent maxillary ameloblastoma, Ophthalmology
113:1227-1230, 2006.
Leider AS, Eversole LR, Barkin ME: Cystic ameloblastoma:
a clinicopathologic analysis, Oral Surg Oral Med Oral Pathol
60:624-630, 1985.
Martins WD, Fávaro DM: Recurrence of an ameloblastoma in an
autogenous iliac bone graft, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 98:657-659, 2004.
Melrose RJ: Benign epithelial odontogenic tumors, Semin Diagn
Pathol 16:271-287, 1999.
Miller RS, Biddinger PW, Marciani RD et al: Simultaneously
occurring ameloblastoma of the maxilla and mandible: case
report, Otolaryngol Head Neck Surg 131:324-326, 2004.
Philipsen HP, Ormiston IW, Reichart PA: The desmo- and osteo-
plastic ameloblastoma: histologic variant or clinicopathologic
entity? Int J Oral Maxillofac Surg 21:352-357, 1992.
Philipsen HP, Reichart PA, Takata T: Desmoplastic ameloblas-
toma (including “hybrid” lesion of ameloblastoma): biological
proﬁle based on 100 cases from the literature and own ﬁles,
Oral Oncol 37:455-460, 2001.
Philipsen HP, Reichart PA: Classiﬁcation of odontogenic
tumours: a historical review, J Oral Pathol Med 35:525-529,
2006.
Raubenheimer EJ, van Heerden WFP, Noffke CEE: Infrequent
clinicopathological ﬁndings in 108 ameloblastomas, J Oral
Pathol Med 24:227-232, 1995.
Reichart PA, Philipsen HP, Sonner S: Ameloblastoma: biological
proﬁle of 3677 cases, Oral Oncol 31B:86-99, 1995.
Richard BM, Thyveetil M, Sharif H et al: Ameloblastoma with
stromal multinucleated giant cells, Histopathology 25:497-
499, 1994.
Sachs SA: Surgical excision with peripheral ostectomy: a
deﬁnitive, yet conservative, approach to the surgical manage-
ment of ameloblastoma, J Oral Maxillofac Surg 64:476-483,
2006.
Said-Al-Naief NAH, Lumerman H, Ramer M et al: Keratoamelo-
blastoma of the maxilla: a case report and review of the litera-
ture, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
84:535-539, 1997.
Sampson DE, Pogrel MA: Management of mandibular amelo-
blastoma: the clinical basis for a treatment algorithm, J Oral
Maxillofac Surg 57:1074-1077, 1999.
Schafer DR, Thompson LDR, Smith BC et al: Primary ameloblas-
toma of the sinonasal tract, Cancer 82:667-674, 1998.
Small IA, Waldron CA: Ameloblastoma of the jaws, Oral Surg
Oral Med Oral Pathol 8:281-297, 1955.
Takata T, Miyauchi M, Ito H et al: Clinical and histopathological
analyses of desmoplastic ameloblastoma, Pathol Res Pract
195:669-675, 1999.
Takata T, Miyauchi M, Ogawa I et al: Immunoexpression of trans-
forming growth factor β in desmoplastic ameloblastoma,
Virchows Arch 436:319-323, 2000.
Waldron CA, El-Mofty S: A histopathologic study of 116 amelo-
blastomas with special reference to the desmoplastic variant,
Oral Surg Oral Med Oral Pathol 63:441-451, 1987.
Unicystic Ameloblastoma
Ackerman GL, Altini M, Shear M: The unicystic ameloblastoma:
a clinicopathologic study of 57 cases, J Oral Pathol 17:541-
546, 1988.
Cunha EM, Fernandes AV, Versiani MA et al: Unicystic amelo-
blastoma: a possible pitfall in periapical diagnosis, Int Endod
J 38:334-340, 2005.
Gardner DG, Corio RL: The relationship of plexiform unicystic
ameloblastoma to conventional ameloblastoma, Oral Surg
Oral Med Oral Pathol 56:54-60, 1983.
Lau SL, Samman N: Recurrence related to treatment modalities
of unicystic ameloblastoma: a systematic review, Int J Oral
Maxillofac Surg 35:681-690, 2006.
Li T-J, Browne RM, Matthews JB: Expression of proliferating cell
nuclear antigen (PCNA) and Ki-67 unicystic ameloblastoma,
Histopathology 26:219-228, 1995.
Philipsen HP, Reichart PA: Unicystic ameloblastoma: a review
of 193 cases from the literature, Oral Oncol 34:317-325,
1998.
Robinson L, Martinez MG: Unicystic ameloblastoma: a prognos-
tically distinct entity, Cancer 40:2278-2285, 1977.
Vickers RA, Gorlin RJ: Ameloblastoma: delineation of early
histopathologic features of neoplasia, Cancer 26:699-710,
1970.
Peripheral (Extraosseous) Ameloblastoma
Baden E, Doyle JL, Petriella V: Malignant transformation of
peripheral ameloblastoma, Oral Surg Oral Med Oral Pathol
75:214-219, 1993.
Buchner A, Merrell PW, Carpenter WM: Relative frequency of
peripheral odontogenic tumors: a study of 45 new cases and
comparison with studies from the literature, J Oral Pathol Med
35:385-391, 2006.
Gardner DG: Peripheral ameloblastoma: a study of 21 cases
including 5 reported as basal cell carcinoma of the gingiva,
Cancer 39:1625-1633, 1977.
Ide F, Kusama K: Difﬁculty in predicting biological behavior of
peripheral ameloblastoma, Oral Oncol 40:651-652, 2004.
Ide F, Kusama K, Tanaka A et al: Peripheral ameloblastoma is
not a hamartoma but rather more of a neoplasm, Oral Oncol
38:318-320, 2002.
LeCorn DW, Bhattacharyya I, Vertucci FJ: Peripheral ameloblas-
toma: a case report and review of the literature, J Endod
32:152-154, 2006.
Martelli-Júnior H, Souza LN, Santos LA et al: Peripheral amelo-
blastoma: a case report, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 99:e31-e33, 2005.
Philipsen HP, Reichart PA, Nikai H et al: Peripheral ameloblas-
toma: biological proﬁle based on 160 cases from the litera-
ture, Oral Oncol 37:17-27, 2001.
Woo SB, Smith-Williams JE, Sciubba JJ et al: Peripheral amelo-
blastoma of the buccal mucosa: case report and review of the
English language literature, Oral Surg Oral Med Oral Pathol
63:78-84, 1987.
Yamanishi T, Ando S, Aikawa T et al: A case of extragingival
peripheral ameloblastoma in the buccal mucosa, J Oral Pathol
Med 36:184-186, 2007.
Malignant Ameloblastoma and Ameloblastic Carcinoma
Akrish S, Buchner JA, Shoshani Y et al: Ameloblastic carcinoma:
report of a new case, literature review, and comparison to
ameloblastoma, J Oral Maxillofac Surg 65:777-783, 2007.
Corio RL, Goldblatt LI, Edwards PA et al: Ameloblastic carci-
noma: a clinicopathologic assessment of eight cases, Oral Surg
Oral Med Oral Pathol 64:570-576, 1987.
Eliasson A, Moser RJ III, Tenholder MF: Diagnosis and treatment
of metastatic ameloblastoma, South Med J 82:1165-1168,
1989.
Eversole LR: Malignant epithelial odontogenic tumors, Semin
Diagn Pathol 16:317-324, 1999. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 15 ODONTOGENIC CYSTS AND TUMORS 737
Goldenberg D, Sciubba J, Koch W et al: Malignant odontogenic
tumors: a 22-year experience, Laryngoscope 114:1770-1774,
2004.
Hall JM, Weathers DR, Unni KK: Ameloblastic carcinoma: an
analysis of 14 cases, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod103:799-807, 2007.
Lau SK, Tideman H, Wu PC: Ameloblastic carcinoma of the jaws:
a report of two cases, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 85:78-81, 1998.
Okada H, Davies JE, Yamamoto H: Malignant ameloblastoma: a
case study and review, J Oral Maxillofac Surg 57:725-730,
1999.
Simko EJ, Brannon RB, Eibling DE: Ameloblastic carcinoma of
the mandible, Head Neck 20:654-659, 1998.
Slootweg PJ, Müller H: Malignant ameloblastoma or ameloblas-
tic carcinoma, Oral Surg Oral Med Oral Pathol 57:168-176,
1984.
Suomalainen A, Hietanen J, Robinson S et al: Ameloblastic car-
cinoma of the mandible resembling odontogenic cyst in a
panoramic radiograph, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 101:638-642, 2006.
Üzüm N, Akyol G, Asal K et al: Ameloblastic carcinoma contain-
ing melanocyte and melanin pigment in the mandible: a case
report and review of the literature, J Oral Pathol Med 34:618-
620, 2005.
Clear Cell Odontogenic Tumor
August M, Faquin W, Troulis M et al: Clear cell odontogenic
carcinoma: evaluation of reported cases, J Oral Maxillofac Surg
61:580-586, 2003.
Bang G, Koppang HS, Hansen LS et al: Clear cell odontogenic
carcinoma: report of three cases and lymph node metastasis,
J Oral Pathol Med 18:113-118, 1989.
Brandwein M, Said-Al-Naief N, Gordon R et al: Clear cell
odontogenic carcinoma: report of a case and analysis of the
literature, Arch Otolaryngol Head Neck Surg 128:1089-1095,
2002.
Ebert CS, Dubin MG, Hart CF et al: Clear cell odontogenic car-
cinoma: a comprehensive analysis of treatment strategies,
Head Neck 27:536-542, 2005.
Eversole LR: On the differential diagnosis of clear cell tumours
of the head and neck, Eur J Cancer B Oral Oncol 29B:173-179,
1993.
Fan J, Kubota E, Imamura H et al: Clear cell odontogenic carci-
noma: a case report with massive invasion of neighboring
organs and lymph node metastasis, Oral Surg Oral Med Oral
Pathol 74:768-775, 1992.
Hansen LS, Eversole LR, Green TL et al: Clear cell odontogenic
tumor—a new histologic variant with aggressive potential,
Head Neck Surg 8:115-123, 1985.
Kumamoto H, Kawamura H, Ooya K: Clear cell odontogenic
tumor in the mandible: report of a case with an immunohis-
tochemical study of epithelial cell markers, Pathol Int 48:618-
622, 1998.
Kumamoto H, Yamazaki S, Sato A et al: Clear cell odontogenic
tumor in the mandible: report of a case with duct-like appear-
ances and dentinoid induction, J Oral Pathol Med 29:43-47,
2000.
Waldron CA, Small IA, Silverman H: Clear cell ameloblastoma—
an odontogenic carcinoma, J Oral Maxillofac Surg 43:709-717,
1985.
Yamamoto H, Inui M, Mori A et al: Clear cell odontogenic car-
cinoma. A case report and literature review of odontogenic
tumors with clear cells, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 86:86-89, 1998.
Adenomatoid Odontogenic Tumor
Courtney RM, Kerr DA: The odontogenic adenomatoid tumor:
a comprehensive review of 21 cases, Oral Surg Oral Med Oral
Pathol 39:424-435, 1975.
Damm DD, White DK, Drummond JF et al: Combined epithelial
odontogenic tumor: adenomatoid odontogenic tumor and
calcifying epithelial odontogenic tumor, Oral Surg Oral Med
Oral Pathol 55:487-496, 1983.
Giansanti JS, Someren A, Waldron CA: Odontogenic adenoma-
toid tumor (adenoameloblastoma), Oral Surg Oral Med Oral
Pathol 30:69-86, 1970.
Leon JE, Mata GM, Fregnani ER et al: Clinicopathological and
immunohistochemical study of 39 cases of adenomatoid
odontogenic tumour: a multicentric study, Oral Oncol 41:835-
842, 2005.
Miyake M, Nagahata S, Nishihara J et al: Combined adenomatoid
odontogenic tumor and calcifying epithelial odontogenic
tumor: report of a case and ultrastructural study, J Oral Maxil-
lofac Surg 54:788-793, 1996.
Philipsen HP, Reichart PA: Adenomatoid odontogenic tumour:
facts and ﬁgures, Oral Oncol 35:125-131, 1999.
Philipsen HP, Srisuwan T, Reichart PA: Adenomatoid odonto-
genic tumor mimicking a periapical (radicular) cyst: a case
report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
94:246-248, 2002.
Poulson TC, Greer RO: Adenomatoid odontogenic tumor: clini-
copathologic and ultrastructural concepts, J Oral Maxillofac
Surg 41:818-824, 1983.
Calcifying Epithelial Odontogenic Tumor
Anavi Y, Kaplan I, Citir M et al: Clear-cell variant of calcifying
epithelial odontogenic tumor: clinical and radiographic char-
acteristics, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
95:332-339, 2003.
Aviel-Ronen S, Liokumovich P, Rahima D et al: The amyloid
deposit in calcifying epithelial odontogenic tumor is immu-
noreactive for cytokeratins, Arch Pathol Lab Med 124:872-
876, 2000.
Basu MK, Matthews JB, Sear AJ et al: Calcifying epithelial odon-
togenic tumour: a case showing features of malignancy, J Oral
Pathol 13:310-319, 1984.
Bridle C, Visram K, Piper K et al: Maxillary calcifying epithelial
odontogenic (Pindborg) tumor presenting with abnormal eye
signs: case report and literature review, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 102:e12-e15, 2006.
Cheng Y-SL, Wright JM, Walstad WR et al: Calcifying epithelial
odontogenic tumor showing microscopic features of potential
malignant behavior, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 93:287-295, 2002.
Dantas da Silveira EJ, Gordón-Núñez MA, Guerra Seabra FR
et al: Peripheral calcifying epithelial odontogenic tumor asso-
ciated with generalized drug-induced gingival growth: a case
report, J Oral Maxillofac Surg 65:341-345, 2007.
Franklin CD, Pindborg JJ: The calcifying epithelial odontogenic
tumor: a review and analysis of 113 cases, Oral Surg Oral Med
Oral Pathol 42:753-765, 1976.
Germanier Y, Bornstein MM, Stauffer E et al: Calcifying epithe-
lial odontogenic (Pindborg) tumor of the mandible with clear
cell component treated by conservative surgery: report of a
case, J Oral Maxillofac Surg 63:1377-1382, 2005.
Gopalakrishnan R, Simonton S, Rohrer MD et al: Cystic variant
of calcifying epithelial odontogenic tumor, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 102:773-777, 2006.
Houston GD, Fowler CB: Extraosseous calcifying epithelial
odontogenic tumor: report of two cases and review of the `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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738 ORAL AND MAXILLOFACIAL PATHOLOGY
literature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
83:577-583, 1997.
Kaplan I, Buchner A, Calderon S et al: Radiological and clinical
features of calcifying epithelial odontogenic tumour, Dento-
maxillofac Radiol 30:22-28, 2001.
Kawano K, Ono K, Yada N et al: Malignant calcifying epithelial
odontogenic tumor of the mandible: report of a case with
pulmonary metastasis showing remarkable response to plati-
num derivatives, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 104:76-81, 2007.
Kumamoto H, Sato I, Tateno H et al: Clear cell variant of calcify-
ing epithelial odontogenic tumor (CEOT) in the maxilla:
report of a case with immunohistochemical and ultrastruc-
tural investigations, J Oral Pathol Med 28:187-191, 1999.
Philipsen HP, Reichart PA: Calcifying epithelial odontogenic
tumour: biological proﬁle based on 181 cases from the litera-
ture, Oral Oncol 36:17-26, 2000.
Pindborg JJ: A calcifying epithelial odontogenic tumor, Cancer
11:838-843, 1958.
Seim P, Regezi JA, O’Ryan F: Hybrid ameloblastoma and calcify-
ing epithelial odontogenic tumor: case report, J Oral Maxillofac
Surg 63:852-855, 2005.
Solomon A, Murphy CL, Weaver K et al: Calcifying epithelial
odontogenic (Pindborg) tumor-associated amyloid consists of
a novel human protein, J Lab Clin Med 142:348-355, 2003.
Veness MJ, Morgan G, Collins AP et al: Calcifying epithelial
odontogenic (Pindborg) tumor with malignant transforma-
tion and metastatic spread, Head Neck 23:692-696, 2001.
Squamous Odontogenic Tumor
Baden E, Doyle J, Mesa M et al: Squamous odontogenic tumor:
report of three cases including the ﬁrst extraosseous case,
Oral Surg Oral Med Oral Pathol 75:733-738, 1993.
Goldblatt LI, Brannon RB, Ellis GL: Squamous odontogenic
tumor: report of ﬁve cases and review of the literature, Oral
Surg Oral Med Oral Pathol 54:187-196, 1982.
Haghighat K, Kalmar JR, Mariotti AJ: Squamous odontogenic
tumor: diagnosis and management, J Periodontol 73:653-656,
2002.
Ide F, Shimoyama T, Horie N et al: Intraosseous squamous cell
carcinoma arising in association with a squamous odonto-
genic tumour of the mandible, Oral Oncol 35:431-434,
1999.
Kim K, Mintz SM, Stevens J: Squamous odontogenic tumor
causing erosion of the lingual cortical plate in the mandible:
a report of 2 cases, J Oral Maxillofac Surg 65:1227-1231,
2007.
Krithika C, Vardhan BG, Saraswathy K et al: Radiolucency in
the anterior maxilla associated with an impacted tooth, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 103:164-168,
2007.
Kusama K, Kawashima A, Nagai H et al: Squamous odontogenic
tumor of the maxilla: report of a case, J Oral Sci 40:119-122,
1998.
Leider AS, Jonker A, Cook HE: Multicentric familial squamous
odontogenic tumor, Oral Surg Oral Med Oral Pathol 68:175-
181, 1989.
Mills WP, Davilla MA, Beattenmuller EA et al: Squamous odon-
togenic tumor: report of a case with lesions in three quad-
rants, Oral Surg Oral Med Oral Pathol 61:557-563, 1986.
Philipsen HP, Reichart PA: Squamous odontogenic tumor (SOT):
a benign neoplasm of the periodontium. A review of 36
reported cases, J Clin Periodontol 23:922-926, 1996.
Pullon PA, Shafer WG, Elzay RP et al: Squamous odontogenic
tumor: report of six cases of a previously undescribed lesion,
Oral Surg Oral Med Oral Pathol 40:616-630, 1975.
Wright JM: Squamous odontogenic tumor-like proliferations in
odontogenic cysts, Oral Surg Oral Med Oral Pathol 47:354-358,
1979.
Mixed Odontogenic Tumors
Gardner DG: The mixed odontogenic tumors, Oral Surg Oral Med
Oral Pathol 58:166-168, 1984.
Hansen LS, Ficarra G: Mixed odontogenic tumors: an analysis of
23 new cases, Head Neck Surg 10:330-343, 1988.
Philipsen HP, Reichart PA: Classiﬁcation of odontogenic tumors:
a historical review, J Oral Pathol Med 35:525-529, 2006.
Philipsen HP, Reichart PA, Praetorius F: Mixed odontogenic
tumours and odontomas. Considerations on interrelation-
ship. Review of the literature and presentation of 134 new
cases of odontomas, Oral Oncol 33:86-99, 1997.
Slootweg PJ: An analysis of the interrelationship of the mixed
odontogenic tumors—ameloblastic ﬁbroma, ameloblastic
ﬁbro-odontoma and the odontomas, Oral Surg Oral Med
Oral Pathol 51:266-276, 1981.
Tomich CE: Benign mixed odontogenic tumors, Semin Diagn
Pathol 16:308-316, 1999.
Ameloblastic Fibroma
Chen Y, Li T-J, Gao Y et al: Ameloblastic ﬁbroma and related
lesions: a clinicopathologic study with reference to their
nature and interrelationship, J Oral Pathol Med 34:588-595,
2005.
Cohen DM, Bhattacharyya I: Ameloblastic ﬁbroma, ameloblastic
ﬁbro-odontoma, and odontoma, Oral Maxillofac Surg Clin North
Am 16:375-384, 2004.
Dallera P, Bertoni F, Marchetti C et al: Ameloblastic ﬁbroma: a
follow-up of six cases, Int J Oral Maxillofac Surg 25:199-202,
1996.
Darling MR, Daley TD: Peripheral ameloblastic ﬁbroma, J Oral
Pathol Med 35:190-192, 2006.
Lin C-C, Chen C-H, Lin L-M et al: Calcifying odontogenic cyst
with ameloblastic ﬁbroma: report of three cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 98:451-460, 2004.
Mosby EL, Russell D, Noren S et al: Ameloblastic ﬁbroma in a
7-week-old infant: a case report and review of the literature,
J Oral Maxillofac Surg 56:368-372, 1998.
Sawyer DR, Nwoku AL, Mosadomi A: Recurrent ameloblastic
ﬁbroma: report of 2 cases, Oral Surg Oral Med Oral Pathol
53:19-24, 1982.
Takeda Y: Ameloblastic ﬁbroma and related lesions: current
pathologic concept, Oral Oncol 35:535-540, 1999.
Trodahl JN: Ameloblastic ﬁbroma: a survey of cases from the
Armed Forces Institute of Pathology, Oral Surg Oral Med Oral
Pathol 33:547-558, 1972.
Yoon JH, Kim HJ, Yook JI et al: Hybrid odontogenic tumor of
calcifying odontogenic cyst and ameloblastic ﬁbroma, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 98:80-84, 2004.
Zallen RD, Preskar MH, McClary SA: Ameloblastic ﬁbroma,
J Oral Maxillofac Surg 40:513-517, 1982.
Ameloblastic Fibro-Odontoma
Chang H, Shimizu MS, Precious DS: Ameloblastic ﬁbro-
odontoma: a case report, J Can Dent Assoc 68:243-246,
2002.
Cohen DM, Bhattacharyya I: Ameloblastic ﬁbroma, ameloblastic
ﬁbro-odontoma, and odontoma, Oral Maxillofac Surg Clin North
Am 16:375-384, 2004.
Dhanuthai K, Kongin K: Ameloblastic ﬁbro-odontoma: a case
report, J Clin Pediatr Dent 29:75-78, 2004.
Favia GF, Di Alberti L, Scarano A et al: Ameloblastic ﬁbro-
odontoma: report of two cases, Oral Oncol 33:444-446,
1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 15 ODONTOGENIC CYSTS AND TUMORS 739
Furst I, Pharoah M, Phillips J: Recurrence of an ameloblastic
ﬁbro-odontoma in a 9-year-old boy, J Oral Maxillofac Surg
57:620-623, 1999.
Howell RM, Burkes EJ: Malignant transformation of ameloblastic
ﬁbro-odontoma to ameloblastic ﬁbrosarcoma, Oral Surg Oral
Med Oral Pathol 43:391-401, 1977.
Miller AS, Lopez CF, Pullon PA et al: Ameloblastic ﬁbro-
odontoma, Oral Surg Oral Med Oral Pathol 41:354-365, 1976.
Sekine J, Kitamura A, Ueno K et al: Cell kinetics in mandibular
ameloblastic ﬁbro-odontoma evaluated by bromodeoxyuri-
dine and proliferating cell nuclear antigen immunohisto-
chemistry: case report, Br J Oral Maxillofac Surg 34:450-453,
1996.
Slootweg PJ: Epithelio-mesenchymal morphology in ameloblas-
tic ﬁbro-odontoma: a light and electron microscopic study,
J Oral Pathol 9:29-40, 1980.
Van Wyk CW, Van der Vyver PC: Ameloblastic ﬁbroma with
dentinoid formation/immature dentinoma: a microscopic
and ultrastructural study of the epithelial-connective tissue
interface, J Oral Pathol 12:37-46, 1983.
Ameloblastic Fibrosarcoma
Altini M, Thompson SH, Lownie JF et al: Ameloblastic sarcoma
of the mandible, J Oral Maxillofac Surg 43:789-794, 1985.
Carlos-Bregni R, Mosqueda-Taylor A, Meneses-Garcia A: Amelo-
blastic ﬁbrosarcoma of the mandible: report of two cases and
review of the literature, J Oral Pathol Med 30:316-320,
2001.
Chomette G, Auriol M, Guilbert F et al: Ameloblastic ﬁbrosar-
coma of the jaws—report of three cases, Pathol Res Pract
178:40-47, 1983.
DeLair D, Bejarano PA, Peleg M et al: Ameloblastic carcinosar-
coma of the mandible arising in ameloblastic ﬁbroma: a case
report and review of the literature, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 103:516-520, 2007.
Kobayashi K, Murakami R, Fujii T et al: Malignant transforma-
tion of ameloblastic ﬁbroma to ameloblastic ﬁbrosarcoma:
case report and review of the literature, J Craniomaxillofac
Surg 33:352-355, 2005.
Kunkel M, Ghalibaﬁan M, Radner H et al: Ameloblastic ﬁbrosar-
coma or odontogenic carcinosarcoma: a matter of classiﬁca-
tion? Oral Oncol 40:444-449, 2004.
Leider AS, Nelson JF, Trodahl JN: Ameloblastic ﬁbrosarcoma of
the jaws, Oral Surg Oral Med Oral Pathol 33:559-569, 1972.
Muller S, Parker DC, Kapadia SB et al: Ameloblastic ﬁbrosar-
coma of the jaws: a clinicopathologic and DNA analysis of ﬁve
cases and review of the literature with discussion of its rela-
tionship to ameloblastic ﬁbroma, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 79:469-477, 1995.
Slater LJ: Odontogenic sarcoma and carcinosarcoma, Semin
Diagn Pathol 16:325-332, 1999.
Williams MD, Hanna EY, El-Naggar AK: Anaplastic ameloblastic
ﬁbrosarcoma arising from recurrent ameloblastic ﬁbroma:
restricted molecular abnormalities of certain genes to the
malignant transformation, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 104:72-75, 2007.
Wood RM, Markle TL, Barker BF et al: Ameloblastic ﬁbrosar-
coma, Oral Surg Oral Med Oral Pathol 66:74-77, 1988.
Odontoameloblastoma
Mosqueda-Taylor A, Carlos-Bregni R, Ramírez-Amador V et al:
Odontoameloblastoma. Clinico-pathologic study of three
cases and critical review of the literature, Oral Oncol 38:800-
805, 2002.
Gupta DS, Gupta MK: Odontoameloblastoma, J Oral Maxillofac
Surg 44:146-148, 1986.
Kaugars GE: Ameloblastic odontoma (odonto-ameloblastoma),
Oral Surg Oral Med Oral Pathol 71:371-373, 1991.
LaBriola JD, Steiner M, Bernstein ML et al: Odontoameloblas-
toma, J Oral Surg 38:139-143, 1980.
Odontoma
Ashkenazi M, Greenberg BP, Chodik G et al: Postoperative prog-
nosis of unerupted teeth after removal of supernumerary
teeth or odontomas, Am J Orthod Dentofacial Orthop 131:614-
619, 2007.
Budnick SD: Compound and complex odontomas, Oral Surg Oral
Med Oral Pathol 42:501-506, 1976.
Cohen DM, Bhattacharyya I: Ameloblastic ﬁbroma, ameloblastic
ﬁbro-odontoma, and odontoma, Oral Maxillofac Surg Clin North
Am 16:375-384, 2004.
Ide F, Shimoyama T, Horie N: Gingival peripheral odontoma in
an adult: case report, J Periodontol 71:830-832, 2000.
Kaugars GE, Miller ME, Abbey LM: Odontomas, Oral Surg Oral
Med Oral Pathol 67:172-176, 1989.
Miki Y, Oda Y, Iwaya N et al: Clinicopathological studies of
odontoma in 47 patients, J Oral Sci 41:173-176, 1999.
Owens BM, Schuman NJ, Mincer HH et al: Dental odontomas:
a retrospective study of 104 cases, J Clin Pediatr Dent 21:261-
264, 1997.
Sapp JP, Gardner DG: An ultrastructural study of the calciﬁca-
tions in calcifying odontogenic cysts and odontomas, Oral
Surg Oral Med Oral Pathol 44:754-766, 1977.
Sedano HO, Pindborg JJ: Ghost cell epithelium in odontomas,
J Oral Pathol 4:27-30, 1975.
Tomizawa M, Otsuka Y, Noda T: Clinical observations of odon-
tomas in Japanese children: 39 cases including one recurrent
case, Int J Paediatr Dent 15:37-43, 2005.
Central Odontogenic Fibroma
Allen CM, Hammond HL, Stimson PG: Central odontogenic
ﬁbroma WHO type: a report of 3 cases with an unusual asso-
ciated giant cell reaction, Oral Surg Oral Med Oral Pathol
73:62-66, 1992.
Daniels JSM: Central odontogenic ﬁbroma of the mandible: a
case report and review of the literature, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 98:295-300, 2004.
Dunlap CL: Odontogenic ﬁbroma, Semin Diagn Pathol 16:293-
296, 1999.
Gardner DG: The central odontogenic ﬁbroma: an attempt at
clariﬁcation, Oral Surg Oral Med Oral Pathol 50:425-432,
1980.
Gardner DG: Central odontogenic ﬁbroma current concepts,
J Oral Pathol Med 25:556-561, 1996.
Handlers JP, Abrams AM, Melrose RJ et al: Central odontogenic
ﬁbroma: clinicopathologic features of 19 cases and review of
the literature, J Oral Maxillofac Surg 49:46-54, 1991.
Ide F, Sakashita H, Kusama K: Ameloblastomatoid, central odon-
togenic ﬁbroma: an epithelium-rich variant, J Oral Pathol Med
31:612-614, 2002.
Kaffe I, Buchner A: Radiologic features of central odontogenic
ﬁbroma, Oral Surg Oral Med Oral Pathol 78:811-818, 1994.
Mosqueda Taylor A, Bermudez Flores V, Diaz Franco MA: Com-
bined central odontogenic ﬁbroma and giant cell granuloma-
like lesion of the mandible: report of a case and review of the
literature, J Oral Maxillofac Surg 57:1258-1262, 1999.
Odell EW, Lombardi T, Barrett AW et al: Hybrid central giant
cell granuloma and central odontogenic ﬁbroma-like lesions
of the jaws, Histopathology 30:165-171, 1997.
Ramer M, Buonocore P, Krost B: Central odontogenic ﬁbroma—
report of a case and review of the literature, Periodontal Clin
Investig 24:27-30, 2002. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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740 ORAL AND MAXILLOFACIAL PATHOLOGY
Slootweg PJ, Müller H: Central ﬁbroma of the jaw: odontogenic
or desmoplastic, Oral Surg Oral Med Oral Pathol 56:61-70,
1983.
Peripheral Odontogenic Fibroma
Baden E, Moskow BS, Moskow R: Odontogenic epithelial ham-
artoma, J Oral Surg 26:702-714, 1968.
Buchner A: Peripheral odontogenic ﬁbroma, J Craniomaxillofac
Surg 17:134-138, 1989.
Buchner A, Ficarra G, Hansen LS: Peripheral odontogenic
ﬁbroma, Oral Surg Oral Med Oral Pathol 64:432-438, 1987.
Buchner A, Merrell PW, Carpenter WM: Relative frequency of
peripheral odontogenic tumors: a study of 45 new cases and
comparison with studies from the literature, J Oral Pathol Med
35:385-391, 2006.
Daley TD, Wysocki GP: Peripheral odontogenic ﬁbroma, Oral
Surg Oral Med Oral Pathol 78:329-336, 1994.
Ficarra G, Sapp JP, Eversole LR: Multiple peripheral odonto-
genic ﬁbroma, World Health Organization type, and central
giant cell granuloma: a case report of an unusual association,
J Oral Maxillofac Surg 51:325-328, 1993.
Ide F, Obara K, Mishima K et al: Peripheral odontogenic tumor:
a clinicopathologic study of 30 cases. General features and
hamartomatous lesions, J Oral Pathol Med 34:552-557,
2005.
Martelli-Junior H, Mesquita RA, de Paula AM et al: Peripheral
odontogenic ﬁbroma (WHO type) of the newborn: a case
report, Int J Paediatr Dent 16:376-379, 2006.
Siar CH, Ng KH: Clinicopathological study of peripheral odon-
togenic ﬁbromas (WHO-type) in Malaysians (1967-95), Br J
Oral Maxillofac Surg 38:19-22, 2000.
Slabben H, Altini M: Peripheral odontogenic ﬁbroma: a clinico-
pathologic study, Oral Surg Oral Med Oral Pathol 72:86-90,
1991.
Weber A, van Heerden WF, Ligthelm AJ et al: Diffuse peripheral
odontogenic ﬁbroma: report of 3 cases, J Oral Pathol Med
21:82-84, 1992.
Granular Cell Odontogenic Tumor
Brannon RB, Goode RK, Eversole LR et al: The central granular
cell odontogenic tumor: report of 5 new cases, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 94:614-621, 2002.
Gesek DJ, Adrian JC, Reid EN: Central granular cell odontogenic
tumor: a case report including light microscopy, immunohis-
tochemistry, and literature review, J Oral Maxillofac Surg
53:945-949, 1995.
Meer S, Altini M, Coleman H et al: Central granular cell odon-
togenic tumor: immunohistochemistry and ultrastructure,
Am J Otolaryngol 25:73-78, 2004.
Orsini Machado de Sousa S, Soares de Araújo N, Maia Melhado
R et al: Central odontogenic granular cell tumor: immunohis-
tochemical study of two cases, J Oral Maxillofac Surg 56:787-
791, 1998.
Piattelli A, Rubini C, Goteri G et al: Central granular cell odon-
togenic tumour: report of the ﬁrst malignant case and review
of the literature, Oral Oncol 39:78-82, 2003.
Rinaggio J, Cleveland D, Koshy R et al: Peripheral granular cell
odontogenic ﬁbroma, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 104:676-679, 2007.
Vincent SD, Hammond HL, Ellis GL et al: Central granular cell
odontogenic ﬁbroma, Oral Surg Oral Med Oral Pathol 63:715-
721, 1987.
Waldron CA, Thompson CW, Conner WA: Granular cell amelo-
blastic ﬁbroma, Oral Surg Oral Med Oral Pathol 16:1202-1213,
1963.
White DK, Chen S-Y, Hartman KS et al: Central granular cell
tumor of the jaws (the so-called granular cell ameloblastic
ﬁbroma), Oral Surg Oral Med Oral Pathol 45:396-405, 1978.
Yih W-Y, Thompson C, Meshul CK et al: Central odontogenic
granular cell tumor of the jaw: report of case and immuno-
histochemical and electron microscopic study, J Oral Maxillo-
fac Surg 53:453-459, 1995.
Myxoma
Barker BF: Odontogenic myxoma, Semin Diagn Pathol 16:297-
301, 1999.
Barros RE, Domingnez PV, Cabrini RL: Myxoma of the jaws, Oral
Surg Oral Med Oral Pathol 27:225-236, 1969.
Chiodo AA, Strumas N, Gilbert RW et al: Management of odon-
togenic myxoma of the maxilla, Otolaryngol Head Neck Surg
117:S73-76, 1997.
Goldblatt LI: Ultrastructural study of an odontogenic myxoma,
Oral Surg Oral Med Oral Pathol 42:206-220, 1976.
Gosh BC, Huvos AG, Gerald FP et al: Myxoma of the jaw bones,
Cancer 31:237-240, 1973.
Kaffe I, Naor H, Buchner A: Clinical and radiological features
of odontogenic myxoma of the jaws, Dentomaxillofac Radiol
26:299-303, 1997.
Lamberg MA, Calonius BP, Makinen JE et al: A case of malignant
myxoma (myxosarcoma) of the maxilla, Scan J Dent Res
92:352-357, 1984.
Li T-J, Sun L-S, Luo H-Y: Odontogenic myxomas: a clinicopatho-
logic study of 25 cases, Arch Pathol Lab Med 130:1799-1806,
2006.
Lo Muzio L, Nocini PF, Favia G et al: Odontogenic myxoma of
the jaws: a clinical, radiologic, immunohistochemical, and
ultrastructural study, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 82:426-433, 1996.
Noffke CEE, Raubenheimer EJ, Chabikuli NJ et al: Odontogenic
myxoma: review of the literature and report of 30 cases from
South Africa, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
104:101-109, 2007.
Pahl S, Henn W, Binger T et al: Malignant odontogenic myxoma
of the maxilla: case with cytogenetic conﬁrmation, J Laryngol
Otol 114:533-535, 2000.
Peltola J, Magnusson B, Happonen R-P et al: Odontogenic
myxoma—a radiographic study of 21 tumours, Br J Oral Maxil-
lofac Surg 32:298-302, 1994.
Schmidt-Westhausen A, Becker J, Schuppan D et al: Odonto-
genic myxoma—characterisation of the extracellular matrix
(ECM) of the tumour stroma, Eur J Cancer B Oral Oncol
30B:377-380, 1994.
Simon ENM, Merkx MAW, Vuhahula E et al: Odontogenic
myxomas: a clinicopathologic study of 33 cases, Int J Oral
Maxillofac Surg 33:333-337, 2004.
White DK, Chen SY, Mohnae AM et al: Odontogenic myxoma:
a clinical and ultrastructural study, Oral Surg Oral Med Oral
Pathol 39:901-917, 1975.
Zhao M, Lu Y, Takata T et al: Immunohistochemical and histo-
chemical characterisation of the mucosubstances of odonto-
genic myxoma: histogenesis and differential diagnosis, Pathol
Res Pract 195:391-397, 1999.
Zimmerman DC, Dahlin DC: Myxomatous tumors of the jaws,
Oral Surg Oral Med Oral Pathol 11:1069-1080, 1958. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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741
16
Dermatologic Diseases
CHAPTER OUTLINE
Ectodermal Dysplasia
White Sponge Nevus
Hereditary Benign Intraepithelial
Dyskeratosis
Pachyonychia Congenita
Dyskeratosis Congenita
Xeroderma Pigmentosum
Hereditary Mucoepithelial Dysplasia
Incontinentia Pigmenti
Darier’s Disease
Warty Dyskeratoma
Peutz-Jeghers Syndrome
Hereditary Hemorrhagic Telangiectasia
Ehlers-Danlos Syndromes
Tuberous Sclerosis
Multiple Hamartoma Syndrome
Epidermolysis Bullosa
and their chromosomal locations have been identiﬁed.
Systematically classifying these conditions can be chal-
lenging because of their wide-ranging clinical features;
however, some investigators have suggested that a clas-
siﬁcation scheme based on the molecular genetic alter-
ation associated with each type might be appropriate.
Thus groups of ectodermal dysplasia syndromes could
be categorized as being caused by mutations in genes
encoding cell-cell signals, genes encoding adhesion
molecules, or genes regulating transcription.
CLINICAL FEATURES
Perhaps the best known of the ectodermal dysplasia
syndromes is hypohidrotic ectodermal dysplasia.
In most instances, this disorder seems to show an
ECTODERMAL DYSPLASIA
Ectodermal dysplasia represents a group of inherited
conditions in which two or more ectodermally derived
anatomic structures fail to develop. Thus depending on
the type of ectodermal dysplasia, hypoplasia or aplasia
of tissues (e.g., skin, hair, nails, teeth, sweat glands) may
be seen. The various types of this disorder may be
inherited in any one of several genetic patterns, includ-
ing autosomal dominant, autosomal recessive, and
X-linked patterns. Even though by some accounts more
than 170 different subtypes of ectodermal dysplasia
can be deﬁned, these disorders are considered to be
relatively rare, with an estimated frequency of seven
cases occurring in every 10,000 births. For fewer than
20% of these conditions, the speciﬁc genetic mutations
IMMUNE-MEDIATED DISEASES AND
THEIR EVALUATION
Pemphigus
Paraneoplastic Pemphigus
Mucous Membrane Pemphigoid
Linear IgA Dermatosis
Angina Bullosa Hemorrhagica
Epidermolysis Bullosa Acquisita
Bullous Pemphigoid
Erythema Multiforme
Erythema Migrans
Reactive Arthritis
Lichen Planus
Chronic Ulcerative Stomatitis
Graft-Versus-Host Disease
Psoriasis
Lupus Erythematosus
Systemic Sclerosis
CREST Syndrome
Acanthosis Nigricans `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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742 ORAL AND MAXILLOFACIAL PATHOLOGY
X-linked inheritance pattern, with the gene mapping
to Xq12-q13.1; therefore, a male predominance is
usually seen. However, a few families have been identi-
ﬁed that show autosomal recessive or autosomal domi-
nant patterns of inheritance.
Affected individuals typically display heat intoler-
ance because of a reduced number of eccrine sweat
glands. Sometimes the diagnosis is made during infancy
because the baby appears to have a fever of undeter-
mined origin; however, the infant simply cannot regu-
late body temperature appropriately because of the
decreased number of sweat glands. Uncommonly,
death results from the markedly elevated body tem-
perature, although this generally happens only when
the condition is not identiﬁed. Sometimes, as a diag-
nostic aid, a special impression can be made of the
patient’s ﬁngertips and then examined microscopically
to count the density of the sweat glands. Such ﬁndings
should be interpreted in conjunction with appropriate
age-matched controls.
Other signs of this disorder include ﬁne, sparse hair,
including a reduced density of eyebrow and eyelash
hair (Fig. 16-1). The periocular skin may show a ﬁne
wrinkling with hyperpigmentation (Fig. 16-2), and
midface hypoplasia is frequently observed, often result-
ing in protuberant lips. Because the salivary glands are
ectodermally derived, these glands may be hypoplastic
or absent, and patients may exhibit varying degrees of
xerostomia. The nails may also appear dystrophic and
brittle.
The teeth are usually markedly reduced in number
(oligodontia or hypodontia), and their crown shapes
are characteristically abnormal (Fig. 16-3). The incisor
crowns usually appear tapered, conical, or pointed, and
the molar crowns are reduced in diameter. Complete
lack of tooth development (anodontia) has also been
reported, but this appears to be uncommon.
Female patients may show partial expression of the
abnormal gene; that is, their teeth may be reduced in
number or may have mild structural changes. This
incomplete presentation can be explained by the Lyon
hypothesis, with half of the female patient’s X chro-
Fig. 16-1 Ectodermal dysplasia. The sparse hair, periocular
hyperpigmentation, and mild midfacial hypoplasia are
characteristic features evident in this affected patient.
Fig. 16-2 Ectodermal dysplasia. Closer view of the same
patient depicted in Fig. 16-1. Fine periocular wrinkling, as
well as sparse eyelash and eyebrow hair, can be observed.
Fig. 16-3 Ectodermal dysplasia. Oligodontia and conical
crown forms are typical oral manifestations. (Courtesy of Dr.
Charles Hook and Dr. Bob Gellin.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 16 DERMATOLOGIC DISEASES 743
mosomes expressing the normal gene, and the other
half expressing the defective gene.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of the skin from a patient
with hypohidrotic ectodermal dysplasia shows a
decreased number of sweat glands and hair follicles.
The adnexal structures that are present are hypoplastic
and malformed.
TREATMENT AND PROGNOSIS
Management of hypohidrotic ectodermal dysplasia
warrants genetic counseling for the parents and the
patient. The dental problems are best managed by
prosthetic replacement of the dentition with complete
dentures, overdentures, or ﬁxed appliances, depending
on the number and location of the remaining teeth.
With careful site selection, endosseous dental implants
may be considered for facilitating prosthetic manage-
ment of patients older than 5 years of age.
WHITE SPONGE NEVUS (CANNON’S
DISEASE; FAMILIAL WHITE
FOLDED DYSPLASIA)
White sponge nevus is a relatively rare genoderma-
tosis (a genetically determined skin disorder) that is
inherited as an autosomal dominant trait displaying a
high degree of penetrance and variable expressivity.
This condition is due to a defect in the normal kerati-
nization of the oral mucosa. In the 30-member family
of keratin ﬁlaments, the pair of keratins known as
keratin 4 and keratin 13 is speciﬁcally expressed in the
spinous cell layer of mucosal epithelium. Mutations in
either of these keratin genes have been shown to be
responsible for the clinical manifestations of white
sponge nevus.
CLINICAL FEATURES
The lesions of white sponge nevus usually appear at
birth or in early childhood, but sometimes the condi-
tion develops during adolescence. Symmetrical, thick-
ened, white, corrugated or velvety, diffuse plaques
affect the buccal mucosa bilaterally in most instances
(Fig. 16-4). Other common intraoral sites of involve-
ment include the ventral tongue, labial mucosa, soft
palate, alveolar mucosa, and ﬂoor of the mouth,
although the extent of involvement can vary from
patient to patient. Extraoral mucosal sites, such as the
nasal, esophageal, laryngeal, and anogenital mucosa,
appear to be less commonly affected. Patients are
usually asymptomatic.
HISTOPATHOLOGIC FEATURES
The microscopic features of white sponge nevus are
characteristic but not necessarily pathognomonic.
Prominent hyperparakeratosis and marked acanthosis
with clearing of the cytoplasm of the cells in the spinous
layer are common features (Figs. 16-5 and 16-6);
however, similar microscopic ﬁndings may be associ-
ated with leukoedema and hereditary benign intra-
epithelial dyskeratosis (HBID). In some instances, an
eosinophilic condensation is noted in the perinuclear
region of the cells in the superﬁcial layers of the epi-
thelium, a feature that is unique to white sponge nevus.
Ultrastructurally, this condensed material can be iden-
tiﬁed as tangled masses of keratin tonoﬁlaments.
Exfoliative cytologic studies may provide more
deﬁnitive diagnostic information. A cytologic prepara-
tion stained with the Papanicolaou method often shows
Fig. 16-4 White sponge nevus. Diffuse, thickened white
plaques of the buccal mucosa.
Fig. 16-5 White sponge nevus. This low-power
photomicrograph shows prominent hyperparakeratosis,
marked thickening (acanthosis), and vacuolation of the
spinous cell layer. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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744 ORAL AND MAXILLOFACIAL PATHOLOGY
the eosinophilic perinuclear condensation of the epi-
thelial cell cytoplasm to a greater extent than does the
histopathologic section (Fig. 16-7).
TREATMENT AND PROGNOSIS
Because this is a benign condition, no treatment is nec-
essary. The prognosis is good.
HEREDITARY BENIGN
INTRAEPITHELIAL
DYSKERATOSIS (WITKOP-
VON SALLMANN SYNDROME)
Hereditary benign intraepithelial dyskeratosis
(HBID) is a rare autosomal dominant genodermatosis
primarily affecting descendants of a triracial isolate
(Native American, black, and white) of people who
originally lived in North Carolina. Examples of HBID
have sporadically been reported from other areas of
the United States because of migration of affected indi-
viduals, and descriptions of affected patients with no
apparent connection to North Carolina have also
appeared in the literature.
CLINICAL FEATURES
The lesions of HBID usually develop during childhood,
in most instances affecting the oral and conjunctival
mucosa. The oral lesions are similar to those of white
sponge nevus, with both conditions showing thick, cor-
rugated white plaques involving the buccal and labial
mucosa (Fig. 16-8). Milder cases may exhibit the opal-
escent appearance of leukoedema. Other oral mucosal
sites, such as the ﬂoor of the mouth and lateral tongue,
may also be affected. These oral lesions may exhibit a
superimposed candidal infection as well.
The most interesting feature of HBID is the ocular
lesions, which begin to develop very early in life. These
appear as thick, opaque, gelatinous plaques affecting
the bulbar conjunctiva adjacent to the cornea (Fig.
16-9) and sometimes involving the cornea itself. When
the lesions are active, patients may experience tearing,
photophobia, and itching of the eyes. In many patients,
the plaques are most prominent in the spring and tend
to regress during the summer or autumn. Sometimes
blindness may result from the induction of vascularity
of the cornea secondary to the shedding process.
HISTOPATHOLOGIC FEATURES
The histopathologic features of HBID include promi-
nent parakeratin production in addition to marked
acanthosis. A peculiar dyskeratotic process, similar to
Fig. 16-6 White sponge nevus. This high-power
photomicrograph shows vacuolation of the cytoplasm of the
cells of the spinous layer, with no evidence of epithelial
atypia. Perinuclear condensation of keratin tonoﬁlaments can
also be observed in some cells.
Fig. 16-7 White sponge nevus. This high-power
photomicrograph of a Papanicolaou-stained cytologic
preparation shows the pathognomonic perinuclear
condensation of keratin tonoﬁlaments.
Fig. 16-8 Hereditary benign intraepithelial dyskeratosis
(HBID). Oral lesions appear as corrugated white plaques of
the buccal mucosa. (Courtesy of Dr. John McDonald.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 745
that of Darier’s disease, is scattered throughout the
upper spinous layer of the surface oral epithelium (Fig.
16-10). With this dyskeratotic process, an epithelial
cell appears to be surrounded or engulfed by an adja-
cent epithelial cell, resulting in the so-called cell-within-
a-cell phenomenon.
TREATMENT AND PROGNOSIS
Because HBID is a benign condition, no treatment is
generally required or indicated for the oral lesions. If
superimposed candidiasis develops, then an antifungal
medication can be used. Patients with symptomatic
ocular lesions should be referred to an ophthalmolo-
gist. Typically, the plaques that obscure vision must be
surgically excised. This procedure, however, is recog-
nized as a temporary measure because the lesions
often recur.
PACHYONYCHIA CONGENITA
(JADASSOHN-LEWANDOWSKY TYPE;
JACKSON-LAWLER TYPE)
Pachyonychia congenita is a group of rare genoder-
matoses that are usually inherited as an autosomal
dominant trait. The nails are dramatically affected in
most patients, but oral lesions are seen only in patients
affected by the Jadassohn-Lewandowsky form of the
disease (pachyonychia congenita type 1). Fewer than
500 cases have been reported. Speciﬁc mutations in
either the keratin 6a or keratin 16 gene have been
detected for the Jadassohn-Lewandowsky type of
pachyonychia congenita, whereas mutations of either
the keratin 6b or keratin 17 gene are associated with
the Jackson-Lawler form (pachyonychia congenita
type 2).
CLINICAL FEATURES
Virtually all patients with pachyonychia congenita
exhibit characteristic nail changes, either at birth or in
the early neonatal period. The free margins of the nails
are lifted up because of an accumulation of keratin-
aceous material in the nail beds. This results in a
pinched, tubular conﬁguration. Ultimately, nail loss
may occur (Fig. 16-11).
Fig. 16-9 Hereditary benign intraepithelial dyskeratosis
(HBID). Ocular lesions appear as gelatinous plaques (arrow)
of the bulbar conjunctivae. (Courtesy of Dr. Carl Witkop.)
A
B
Fig. 16-10 Hereditary benign intraepithelial dyskeratosis
(HBID). A, Medium-power photomicrograph exhibiting
hyperparakeratosis, acanthosis, and dyskeratosis. B, Higher
magniﬁcation showing dyskeratotic cells.
Fig. 16-11 Pachyonychia congenita. Loss of ﬁngernails.
(Courtesy of Dr. John Lenox.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

746 ORAL AND MAXILLOFACIAL PATHOLOGY
Other skin changes that may occur include marked
hyperkeratosis of the palmar and plantar surfaces, pro-
ducing thick, callouslike lesions (Fig. 16-12). Hyperhi-
drosis of the palms and soles is also commonly present.
The rest of the skin shows punctate papules, represent-
ing an abnormal accumulation of keratin in the hair
follicles. One disabling feature of the syndrome is the
formation of painful blisters on the soles of the feet
after a few minutes of walking during warm weather.
The oral lesions seen in the Jadassohn-Lewandowsky
form consist of thickened white plaques that involve
the lateral margins and dorsal surface of the tongue.
Other oral mucosal regions that are frequently exposed
to mild trauma, such as the palate, buccal mucosa, and
alveolar mucosa, may also be affected (Fig. 16-13).
Neonatal teeth have been reported in patients affected
by the Jackson-Lawler form, but these individuals do
not have oral white lesions. Hoarseness and dyspnea
have been described in some patients as a result of
laryngeal mucosal involvement.
HISTOPATHOLOGIC FEATURES
Microscopic examination of lesional oral mucosa
shows marked hyperparakeratosis and acanthosis with
perinuclear clearing of the epithelial cells.
TREATMENT AND PROGNOSIS
Because the oral lesions of pachyonychia congenita
show no apparent tendency for malignant transforma-
tion, no treatment is required. The nails are often lost
or may need to be surgically removed because of the
deformity. In addition, the keratin accumulation on the
palms and soles can be quite uncomfortable and dis-
tressing to many of the affected individuals. Most
patients have to pay continuous attention to removal of
the excess keratin, and issues related to quality of life
often arise. Patients should receive genetic counseling,
as an aid in family planning. Identiﬁcation of the
various keratin mutations associated with these disor-
ders is now possible, using molecular techniques to
evaluate material obtained from chorionic villus sam-
pling, thereby allowing prenatal diagnosis.
DYSKERATOSIS CONGENITA
(COLE-ENGMAN SYNDROME;
ZINSSER-COLE-ENGMAN SYNDROME)
Dyskeratosis congenita is a rare genodermatosis that
is usually inherited as an X-linked recessive trait, result-
ing in a striking male predilection. Autosomal domi-
nant and autosomal recessive forms, although less
common, have been reported. Mutations in the DKC1
gene have been determined to cause the X-linked form
of dyskeratosis congenita. The mutated gene appears
to disrupt the normal maintenance of telomerase, an
enzyme that is critical in determining normal cellular
longevity. The clinician should be aware of the condi-
tion because the oral lesions may undergo malignant
transformation, and patients are susceptible to aplastic
anemia.
Fig. 16-12 Pachyonychia congenita. The soles of the feet
of affected patients typically show marked calluslike
thickenings. (Courtesy of Dr. Lou Young.)
Fig. 16-13 Pachyonychia congenita. Although tongue
lesions are more common in patients with pachyonychia
congenita, other oral mucosal sites exposed to minor trauma,
such as the alveolar mucosa, may develop thickened white
patches. (Courtesy of Dr. John Lenox.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 747
CLINICAL FEATURES
Dyskeratosis congenita usually becomes evident during
the ﬁrst 10 years of life. A reticular pattern of skin
hyperpigmentation develops, affecting the face, neck,
and upper chest. In addition, abnormal, dysplastic
changes of the nails are evident at this time (Fig.
16-14).
Intraorally, the tongue and buccal mucosa develop
bullae; these are followed by erosions and, eventually,
leukoplakic lesions (Fig. 16-15). The leukoplakic lesions
are considered to be premalignant, and approximately
one third of them become malignant in a 10- to 30-
year period. The actual rate of transformation may be
higher, but this may not be appreciated because of
the shortened life span of these patients. Rapidly
progressive periodontal disease has been reported
sporadically.
Thrombocytopenia is usually the ﬁrst hematologic
problem that develops, typically during the second
decade of life, followed by anemia. Ultimately, aplastic
anemia develops in approximately 70% of these patients
(see page 580). Mild to moderate mental retardation
may also be present. Generally, the autosomal reces-
sive and X-linked recessive forms show a more severe
pattern of disease expression.
HISTOPATHOLOGIC FEATURES
Biopsy specimens of the early oral mucosal lesions
show hyperorthokeratosis with epithelial atrophy. As
the lesions progress, epithelial dysplasia develops until
frank squamous cell carcinoma evolves.
TREATMENT AND PROGNOSIS
The discomfort of the oral lesions is managed symp-
tomatically, and careful periodic oral mucosal ex-
a minations are performed to check for evidence of
malignant transformation. Routine medical evaluation
is warranted to monitor the patient for the develop-
ment of aplastic anemia. Selected patients may be con-
sidered for allogeneic bone marrow transplantation
once the aplastic anemia is identiﬁed.
As a result of these potentially life-threatening com-
plications, the prognosis is guarded. The average life
span for the more severely affected patients is 32 years
of age. The parents and the patient should receive
genetic counseling, but identiﬁcation of the DKC1 gene
should allow for accurate conﬁrmation of carriers of
the gene and for prenatal diagnosis.
XERODERMA PIGMENTOSUM
Xeroderma pigmentosum is a rare genodermatosis
in which numerous cutaneous malignancies develop
at a very early age. The prevalence of the condition in
the United States is estimated to be 1 in 250,000 to
500,000. The condition is inherited as an autosomal
recessive trait and is caused by one of several defects
in the excision repair and/or postreplication repair
mechanism of DNA. As a result of the inability of the
epithelial cells to repair ultraviolet (UV) light-induced
damage, mutations in the epithelial cells occur, leading
to the development of skin cancer at a rate 1000 to
4000 times what would normally be expected in people
younger than 20 years of age.
CLINICAL FEATURES
During the ﬁrst few years of life, patients affected by
xeroderma pigmentosum show a markedly increased
tendency to sunburn. Skin changes, such as atrophy,
freckled pigmentation, and patchy depigmentation,
soon follow (Fig. 16-16). In early childhood, actinic
keratoses begin developing, a process that normally
Fig. 16-14 Dyskeratosis congenita. Dysplastic nail
changes.
Fig. 16-15 Dyskeratosis congenita. Atrophy and
hyperkeratosis of the dorsal tongue mucosa are visible. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

748 ORAL AND MAXILLOFACIAL PATHOLOGY
does not take place before 40 years of age. These lesions
quickly progress to squamous cell carcinoma, with
basal cell carcinoma also appearing; consequently, in
most patients a nonmelanoma skin cancer develops
during the ﬁrst decade of life. Melanoma develops in
about 5% of patients with xeroderma pigmentosum, but
it evolves at a slightly later time. As a consequence of
sun exposure, the head and neck region is the site most
frequently affected by these cutaneous malignancies.
Neurologic manifestations include subnormal intelli-
gence in 80% of affected individuals.
Oral manifestations, which often occur before 20
years of age, include development of squamous cell
carcinoma of the lower lip and the tip of the tongue.
This latter site is most unusual for oral cancer, and its
involvement is again undoubtedly related to the
increased sun exposure, however minimal, which
this area receives in contrast to the rest of the oral
mucosa.
The diagnosis of xeroderma pigmentosum is usually
made when the patient is evaluated for the cutaneous
lesions, because it is highly unusual for a very young
person to have skin cancer. Because xeroderma pig-
mentosum is an autosomal recessive trait, a family
history of the disorder is not likely to be present, but
the possibility of a consanguineous relationship of the
affected child’s parents should be investigated.
HISTOPATHOLOGIC FEATURES
The histopathologic features of xeroderma pigmento-
sum are relatively nonspeciﬁc, in that the cutaneous
premalignant lesions and malignancies that occur are
microscopically indistinguishable from those observed
in unaffected patients.
TREATMENT AND PROGNOSIS
Treatment of xeroderma pigmentosum is challenging
because in most instances signiﬁcant sun damage has
already occurred by the time of diagnosis. Patients are
advised to avoid sunlight and unﬁltered ﬂuorescent
light and to wear appropriate protective clothing and
sunscreens if they cannot avoid sun exposure. Before
receiving dental treatment, a calibrated UV light meter
should be used to evaluate the amount of UV light
being emitted from various sources in the dental ofﬁce,
such as the examination light, the radiograph viewbox,
computer screens in the area, ﬁber-optic lights, or
lights that are used for curing composite restorations.
Some authors have suggested that any reading greater
than 0 nm/cm
2
would be unacceptable. A dermatolo-
gist should evaluate the patient every 3 months to
monitor the development of cutaneous lesions.
Topical chemotherapeutic agents (e.g., 5-ﬂuoroura-
cil) may be used to treat actinic keratoses. Nonmela-
noma skin cancers should be excised conservatively,
preferably with microscopically controlled excision
(Mohs surgery) to preserve as much normal tissue as
possible. Patients should also receive genetic counsel-
ing, because a high number of consanguineous mar-
riages have been reported in some series.
The prognosis is still poor. Most patients die 30
years earlier than the normal population, either directly
from cutaneous malignancy or from complications
associated with the treatment of the cancer.
HEREDITARY MUCOEPITHELIAL
DYSPLASIA
Hereditary mucoepithelial dysplasia is a rare disor-
der that may occur sporadically or may be inherited as
an autosomal dominant trait. Approximately 30 cases
have been reported. For reasons that are not entirely
understood, the mucosal epithelial cells do not develop
in a normal fashion, and for this reason the designation
of dysplasia has been given. However, in this situation,
no increased risk of malignant transformation is seen.
When a cervical exfoliative cytologic preparation (“Pap
smear”) is done, the epithelial cells that are harvested
Fig. 16-16 Xeroderma pigmentosum. The atrophic
changes and pigmentation disturbances shown are
characteristic of xeroderma pigmentosum. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 749
may be interpreted as appearing cytologically unusual
or atypical; in the past, some female patients have been
advised to undergo hysterectomy because of this mis-
interpretation. Consequently, accurate identiﬁcation
of this disorder is extremely important for these
patients.
CLINICAL FEATURES
Hereditary mucoepithelial dysplasia is characterized
by both cutaneous and mucosal abnormalities. Patients
typically have sparse, coarse hair with nonscarring alo-
pecia. Eyelashes and eyebrows are generally affected
(Fig. 16-17). Severe photophobia develops at an early
age, and most of these patients will have evidence of
cataracts beginning in childhood or early adult life.
Corneal vascularization, keratitis, and nystagmus are
also commonly described. As would be expected, vision
is usually markedly impaired for these patients. Other
skin manifestations include a prominent perineal rash
that appears during infancy, as well as a widespread
rough, dry texture because of follicular keratosis.
Pulmonary complications related to mucoepithelial
dysplasia can range in severity, presumably because of
the degree of gene expression. In one family, cavitary
bullae were reported to form within the lung paren-
chyma, and these led to recurrent bouts of pneumonia,
often resulting in life-threatening complications.
The oral manifestations of hereditary mucoepithe-
lial dysplasia are usually quite striking, appearing as
demarcated ﬁery-red erythema of the hard palate (Fig.
16-18), with generally less involvement of the attached
gingivae and tongue mucosa. These mucosal altera-
tions are typically asymptomatic, despite their remark-
able clinical appearance. The nasal, conjunctival,
vaginal, cervical, urethral, and bladder mucosa may
have the same unusual erythematous features.
HISTOPATHOLOGIC FEATURES
Biopsies of the mucosal lesions of hereditary mucoepi-
thelial dysplasia show epithelium with minimal kerati-
nization and a disorganized maturation pattern. The
squamous epithelial cells may have a relatively high
nuclear/cytoplasmic ratio, but signiﬁcant nuclear or
cellular pleomorphism is not observed. Cytoplasmic
vacuoles have been described and may appear as
grayish inclusions (Fig. 16-19). These vacuoles also
may be observed in exfoliative cytology samples. Ultra-
structurally, the lesional cells have been described as
Fig. 16-17 Hereditary mucoepithelial dysplasia. Sparse
hair is noted on the eyebrows and eyelashes.
Fig. 16-18 Hereditary mucoepithelial dysplasia. Marked
erythema of the anterior hard palate.
Fig. 16-19 Hereditary mucoepithelial dysplasia.
Disorganized epithelium exhibiting scattered intracytoplasmic
vacuoles. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

750 ORAL AND MAXILLOFACIAL PATHOLOGY
having reduced numbers of desmosomes and internal-
ized gap junctions.
TREATMENT AND PROGNOSIS
Given the genetic nature of this disease, supportive
care and genetic counseling are typically offered.
Affected patients should be monitored for develop-
ment of pulmonary disease.
INCONTINENTIA PIGMENTI (BLOCH-
SULZBERGER SYNDROME)
Incontinentia pigmenti is a relatively rare inherited
disorder, with approximately 800 cases reported
worldwide. It typically evolves in several stages, pri-
marily affecting the skin, eyes, and central nervous
system (CNS), as well as oral structures. There is a
marked female predilection, with a 37:1 female-to-
male ratio reported. The condition is inherited as an
X-linked dominant trait, with the single unpaired gene
on the X chromosome being lethal for most males. The
mutated gene responsible for producing the pheno-
typic features of incontinentia pigmenti maps to the
Xq28 locus, where the genetic information related to
nuclear factor-κB essential modulator (NEMO) is found.
Of the few males who survive, a small percentage have
Klinefelter syndrome (XXY karyotype), whereas the
rest usually show mosaicism for the NEMO gene, sug-
gesting a postzygotic mutation.
CLINICAL FEATURES
The clinical manifestations of incontinentia pigmenti
usually begin in the ﬁrst few weeks of infancy. There
are four stages:
1. Vesicular stage—Vesiculobullous lesions appear on
the skin of the trunk and limbs. Spontaneous resolu-
tion occurs within 4 months.
2.Verrucous stage—Verrucous cutaneous plaques
develop, affecting the limbs. These clear by 6 months
of age, evolving into the third stage.
3.Hyperpigmentation stage—Macular, brown skin
lesions appear, characterized by a strange swirling
pattern (Fig. 16-20), although these tend to fade
around the time of puberty.
4.Atrophy and depigmentation stage—Atrophy and
depigmentation of the skin ultimately occur.
CNS abnormalities occur in approximately 30% of
affected patients. The most common problems are
mental retardation, seizure disorders, and motor difﬁ-
culties. Ocular problems (e.g., strabismus, nystagmus,
cataracts, retinal vascular abnormalities, optic nerve
atrophy) may also be identiﬁed in nearly 35% of these
patients.
The oral manifestations of incontinentia pigmenti,
noted in 70% to 95% of the cases, include oligodontia
(hypodontia), delayed eruption, and hypoplasia of the
teeth (Fig. 16-21). The teeth are small and cone shaped;
both the primary and permanent dentitions are
affected.
HISTOPATHOLOGIC FEATURES
The microscopic ﬁndings in incontinentia pigmenti
vary, depending on when a biopsy of the skin lesions is
performed.
In the initial vesicular stage, intraepithelial clefts
ﬁlled with eosinophils are observed. During the verru-
cous stage, hyperkeratosis, acanthosis, and papilloma-
tosis are noted. The hyperpigmentation stage shows
numerous melanin-containing macrophages (melanin
incontinence) in the subepithelial connective tissue,
the feature from which the disorder derives its name.
Fig. 16-20 Incontinentia pigmenti. Swirling pattern of
pigmentation on the abdomen of an infant.
Fig. 16-21 Incontinentia pigmenti. Hypodontia and
conical teeth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 751
TREATMENT AND PROGNOSIS
Treatment of incontinentia pigmenti is directed
toward the various abnormalities. Dental management
includes appropriate prosthodontic and restorative
care, although this is sometimes difﬁcult if CNS prob-
lems are severe. Prenatal genetic testing can be per-
formed, but currently this is not widely available.
DARIER’S DISEASE (KERATOSIS
FOLLICULARIS; DYSKERATOSIS
FOLLICULARIS; DARIER-
WHITE DISEASE)
Darier’s disease is an uncommon genodermatosis
with rather striking skin involvement and relatively
subtle oral mucosal lesions. The condition is inherited
as an autosomal dominant trait, having a high degree
of penetrance and variable expressivity. A lack of cohe-
sion among the surface epithelial cells characterizes
this disease, and mutation of a gene that encodes an
intracellular calcium pump has been identiﬁed as the
cause for abnormal desmosomal organization in the
affected epithelial cells. Estimates of the prevalence of
Darier’s disease in Northern European populations
range from 1 in 36,000 to 1 in 100,000.
CLINICAL FEATURES
Patients with Darier’s disease have numerous erythem-
atous, often pruritic, papules on the skin of the trunk
and the scalp that develop during the ﬁrst or second
decade of life (Fig. 16-22). An accumulation of keratin,
producing a rough texture, may be seen in association
with the lesions, and a foul odor may be present as a
result of bacterial degradation of the keratin. The
process generally becomes worse during the summer
months, either because of sensitivity of some patients
to UV light or because increased heat results in sweat-
ing, which induces more epithelial clefting. The palms
and soles often exhibit pits and keratoses. The nails
show longitudinal lines, ridges, or painful splits.
The oral lesions are typically asymptomatic and are
discovered on routine examination. The frequency of
occurrence of oral lesions ranges from 15% to 50%.
They consist of multiple, normal-colored or white, ﬂat-
topped papules that, if numerous enough to be conﬂu-
ent, result in a cobblestone mucosal appearance (Fig.
16-23). These lesions affect the hard palate and alveo-
lar mucosa primarily, although the buccal mucosa or
tongue may be occasionally involved. If the palatal
lesions are prominent, then the condition may resem-
ble inﬂammatory papillary hyperplasia or nicotine
stomatitis. Some patients with this condition also expe-
rience recurrent obstructive parotid swelling second-
ary to duct abnormalities.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the cutaneous or mucosal
lesions shows a dyskeratotic process characterized by
a central keratin plug that overlies epithelium exhibit-
ing a suprabasilar cleft (Fig. 16-24). This intraepithelial
clefting phenomenon, also known as acantholysis, is
not unique to Darier’s disease and may be seen in con-
ditions such as pemphigus vulgaris (see page 765). In
addition, the epithelial rete ridges associated with the
lesions appear narrow, elongated, and “test tube”–
shaped. Closer inspection of the epithelium reveals
varying numbers of two types of dyskeratotic cells,
called corps ronds (round bodies) or grains (because
they resemble cereal grains).
Fig. 16-22 Darier’s disease. Erythematous cutaneous
papules on the chest.
Fig. 16-23 Darier’s disease. The oral mucosa may show
multiple white papules. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

752 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
Treatment of Darier’s disease depends on the severity
of involvement. Photosensitive patients should use a
sunscreen, and all patients should minimize unneces-
sary exposure to hot environments. For relatively mild
cases, keratolytic agents or emollients may be the only
treatment required. For more severely affected patients,
systemic retinoids are often beneﬁcial, but the side
effects of such medications are often quite bothersome
to the patient and can be signiﬁcant; therefore, the
physician should carefully monitor their use. Although
the condition is not premalignant or otherwise life
threatening, genetic counseling is appropriate.
WARTY DYSKERATOMA (ISOLATED
DARIER’S DISEASE; ISOLATED
DYSKERATOSIS FOLLICULARIS;
FOCAL ACANTHOLYTIC
DYSKERATOSIS; FOLLICULAR
DYSKERATOMA)
The warty dyskeratoma is a distinctly uncommon
solitary lesion that can occur on skin or oral mucosa. It
is histopathologically identical to Darier’s disease. For
this reason the lesion has been termed isolated Dari-
er’s disease. The lesion is not otherwise related to
Darier’s disease, however, and its cause remains
unknown.
CLINICAL FEATURES
The cutaneous warty dyskeratoma typically appears as
a solitary, asymptomatic, umbilicated papule on the
skin of the head or neck of an older adult. The intraoral
lesion also develops in patients older than age 40, and
a slight male predilection has been identiﬁed. The
intraoral warty dyskeratoma appears as a pink or white,
umbilicated papule located on the keratinized mucosa,
especially the hard palate and the alveolar ridge (Fig.
16-25). A warty or roughened surface is noted in some
lesions. Most warty dyskeratomas are smaller than
0.5 cm in diameter.
HISTOPATHOLOGIC FEATURES
Histopathologically, the warty dyskeratoma appears
very similar to keratosis follicularis. Both conditions
display dyskeratosis, basilar hyperplasia, and a supra-
basilar cleft (Fig. 16-26). The warty dyskeratoma is a
solitary lesion, however, and the formation of corps
ronds and grains is not a prominent feature.
Fig. 16-24 Darier’s disease. Low-power photomicrograph
showing a thick keratin plug, intraepithelial clefting, and
elongated rete ridges.
Fig. 16-25 Warty dyskeratoma. Umbilicated papule on
the hard palate. (Courtesy of Dr. Greg Adams.)
Fig. 16-26 Warty dyskeratoma. Well-circumscribed
invagination ﬁlled with a thick parakeratin plug. There is
hyperplasia of the basilar cells with a suprabasilar cleft. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 753
TREATMENT AND PROGNOSIS
Treatment of the warty dyskeratoma consists of conser-
vative excision. The prognosis is excellent; these lesions
have not been reported to recur, and they have no
apparent malignant potential. Careful histopathologic
evaluation of the tissue should be performed, because
some epithelial dysplasias may show a marked lack of
cellular cohesiveness, resulting in a similar acantho-
lytic appearance microscopically.
PEUTZ-JEGHERS SYNDROME
Peutz-Jeghers syndrome is a relatively rare but well-
recognized condition, having a prevalence of approxi-
mately 1 in 100,000 to 200,000 births. It is characteri-
zed by freckle-like lesions of the hands, perioral skin,
and oral mucosa, in conjunction with intestinal polypo-
sis and predisposition for affected patients to develop
cancer. The syndrome is generally inherited as an auto-
somal dominant trait, although as many as 35% of cases
represent new mutations. Mutation of the STK11 gene
(also known as LKB1) on chromosome 19p13.3, which
encodes for a serine/threonine kinase, is responsible
for most cases of Peutz-Jeghers syndrome.
CLINICAL FEATURES
The skin lesions of Peutz-Jeghers syndrome usually
develop early in childhood and involve the perioriﬁcial
areas (e.g., mouth, nose, anus, genital region). The skin
of the extremities is affected in about 50% of patients
(Fig. 16-27). The lesions resemble freckles, but they do
not wax and wane with sun exposure, as do true
freckles.
The intestinal polyps, generally considered to be
hamartomatous growths, are scattered throughout the
mucus-producing areas of the gastrointestinal tract.
The jejunum and ileum are most commonly affected.
Patients often have problems with intestinal obstruc-
tion because of intussusception (“telescoping” of a
proximal segment of the bowel into a distal portion),
a problem that usually becomes evident during the
third decade of life. Most of these episodes are self-
correcting, but surgical intervention is sometimes nec-
essary to prevent ischemic necrosis of the bowel, with
subsequent peritonitis. Gastrointestinal adenocarci-
noma develops in a signiﬁcant percentage of affected
patients, although the polyps themselves do not appear
to be premalignant. In one large series of cases, 9% of
the patients had developed gastrointestinal malignancy
by 40 years of age and 33% by 60 years of age. This
compares to 0.1% and 1.0%, respectively, in the general
population. Other tumors affecting the pancreas, male
and female genital tract, breast, and ovary may also
develop. In women, the risk of developing breast cancer
approaches 50% by 60 years of age. The increased fre-
quency of malignancy in these patients overall is esti-
mated to be approximately 18 times greater than
normal.
The oral lesions essentially represent an extension
of the perioral freckling. These 1- to 4-mm brown to
blue-gray macules primarily affect the vermilion zone,
the labial and buccal mucosa, and the tongue; they are
seen in more than 90% of these patients (Fig. 16-28).
The number of lesions and the extent of involvement
can vary markedly from patient to patient. Some degree
of fading of the pigmented lesions may be noted during
adolescence.
Fig. 16-27 Peutz-Jeghers syndrome. Cutaneous lesions
appear as brown, macular, frecklelike areas, often
concentrated around the mouth or on the hands. (Courtesy of
Dr. Ahmed Uthman.)
Fig. 16-28 Peutz-Jeghers syndrome. Oral manifestations
include multiple, dark, frecklelike lesions of the lips. (Courtesy
of Dr. Ahmed Uthman.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

754 ORAL AND MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
The gastrointestinal polyps of Peutz-Jeghers syndrome
histopathologically represent benign overgrowths of
intestinal glandular epithelium supported by a core of
smooth muscle. Epithelial atypia is not usually a promi-
nent feature, unlike the polyps of Gardner syndrome
(see page 651).
Microscopic evaluation of the pigmented cutaneous
lesions shows slight acanthosis of the epithelium with
elongation of the rete ridges. No apparent increase in
melanocyte number is detected by electron micros-
copy, but the dendritic processes of the melanocytes
are elongated. Furthermore, the melanin pigment
appears to be retained in the melanocytes rather than
being transferred to adjacent keratinocytes.
TREATMENT AND PROGNOSIS
Patients with Peutz-Jeghers syndrome should be moni-
tored for development of intussusception or tumor for-
mation. Genetic counseling is also appropriate.
HEREDITARY HEMORRHAGIC
TELANGIECTASIA (OSLER-WEBER-
RENDU SYNDROME)
Hereditary hemorrhagic telangiectasia (HHT) is an
uncommon mucocutaneous disorder that is inherited
as an autosomal dominant trait, and recent epidemio-
logic studies suggest a prevalence of at least 1 in 10,000
people. Mutation of either one of two different genes
at two separate loci is responsible for the condition.
HHT1 is caused by a mutation of the ENG (endoglin)
gene on chromosome 9, whereas mutation of ALK1
(activin receptor-like kinase-1; ACVRL1), a gene located
on chromosome 12, produces HHT2. The proteins
produced by these genes may play a role in blood vessel
wall integrity. With both types of HHT, numerous vas-
cular hamartomas develop, affecting the skin and
mucosa; however, other vascular problems, such as
arteriovenous ﬁstulas, may also be seen. Patients
affected with HHT1 tend to have more pulmonary
involvement, whereas those with HHT2 generally have
a later onset of their telangiectasias and a greater
degree of hepatic involvement. The clinician should be
familiar with HHT because the oral lesions are often
the most dramatic and most easily identiﬁed compo-
nent of this syndrome.
CLINICAL FEATURES
Patients with HHT are often diagnosed initially because
of frequent episodes of epistaxis. On further examina-
tion, the nasal and oropharyngeal mucosae exhibit
numerous scattered red papules, 1 to 2 mm in size,
which blanch when diascopy is used. This blanching
indicates that the red color is due to blood contained
within blood vessels (in this case, small collections of
dilated capillaries [telangiectasias] that are close to
the surface of the mucosa). These telangiectatic vessels
are most frequently found on the vermilion zone of the
lips, tongue, and buccal mucosa, although any oral
mucosal site may be affected (Figs. 16-29 and 16-30).
With aging, the telangiectasias tend to become more
numerous and slightly larger.
In many patients, telangiectasias are seen on the
hands and feet. The lesions are often distributed
throughout the gastrointestinal mucosa, the genitouri-
nary mucosa, and the conjunctival mucosa. The gastro-
intestinal telangiectasias have a tendency to rupture,
which may cause signiﬁcant blood loss. Chronic iron-
deﬁciency anemia is often a problem for such individu-
Fig. 16-29 Hereditary hemorrhagic telangiectasia (HHT).
The tongue of this patient shows multiple red papules, which
represent superﬁcial collections of dilated capillary spaces.
Fig. 16-30 Hereditary hemorrhagic telangiectasia (HHT).
Red macules similar to the tongue lesions are observed on
the buccal mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 755
als. Signiﬁcantly, arteriovenous ﬁstulas may develop in
the lungs (30% of HHT patients), liver (30%), or brain
(10% to 20%). The brain lesions seem to predispose
these patients to the development of brain abscesses.
In at least one instance, periodontal vascular malfor-
mations were felt to be the cause of septic pulmonary
emboli that resolved only after several teeth with peri-
odontal abscesses were extracted.
A diagnosis of HHT can be made if a patient has
three of the following four criteria:
1. Recurrent spontaneous epistaxis
2. Telangiectasias of the mucosa and skin
3. Arteriovenous malformation involving the lungs,
liver, or CNS
4. Family history of HHT
In some instances, CREST syndrome (Calcinosis
cutis, Raynaud’s phenomenon, Esophageal dysfunc-
tion, Sclerodactyly, and Telangiectasia) (see page 801)
must be considered in the differential diagnosis. In
these cases, serologic studies for anticentromere auto-
antibodies often help to distinguish between the two
conditions because these antibodies typically would be
present only in CREST syndrome.
HISTOPATHOLOGIC FEATURES
If one of the telangiectasias is submitted for biopsy, the
microscopic features essentially show a superﬁcially
located collection of thin-walled vascular spaces that
contain erythrocytes (Fig. 16-31).
TREATMENT AND PROGNOSIS
For mild cases of HHT, no treatment may be required.
Moderate cases may be managed by selective cryosur-
gery or electrocautery of the most bothersome of the
telangiectatic vessels. Laser ablation of the telangiec-
tatic lesions has also been used, although this approach
appears to be most successful for patients with mild
to moderate disease. More severely affected patients,
particularly those troubled by repeated episodes of
epistaxis, may require a surgical procedure of the nasal
septum (septal dermoplasty). The involved nasal
mucosa is removed and replaced by a skin graft;
however, some long-term follow-up studies suggest
that the grafts eventually become revascularized,
resulting in recurrence of the problem. Nasal closure
is another surgical technique that has been performed
for patients with severe epistaxis in whom other
methods have failed.
Combined progesterone and estrogen therapy may
beneﬁt some patients, but because of the potentially
serious side effects, this should be limited to the most
severely affected individuals. Iron replacement therapy
is indicated for the iron-deﬁcient patient, and occasion-
ally blood transfusions may be necessary to compen-
sate for blood loss.
From a dental standpoint, some authors recom-
mend the use of prophylactic antibiotics before dental
procedures that might cause bacteremia in patients
with HHT and evidence of a pulmonary arteriovenous
malformation. For patients with a history of HHT, such
antibiotics are advocated until a pulmonary arteriove-
nous malformation is ruled out because of the 1% prev-
alence of brain abscesses in affected individuals.
Researchers believe that antibiotic coverage, similar to
that for endocarditis prophylaxis, may prevent this
serious complication. Patients with a history of HHT
should be screened for arteriovenous malformations,
which can be eliminated by embolization or other
vasodestructive techniques using interventional radio-
logic methods.
The prognosis is generally good, although a 1% to 2%
mortality rate is reported from complications related
to blood loss. For patients with brain abscesses, the
mortality rate is 10%, even with early diagnosis and
appropriate therapy.
EHLERS-DANLOS SYNDROMES
The Ehlers-Danlos syndromes, a group of inherited
connective tissue disorders, are relatively heteroge-
neous. At least 10 types have been described over the
years, but recent clinical and molecular evidence sug-
gests that seven categories of this disease may be more
appropriate. The patient exhibits problems that are
usually attributed to the production of abnormal colla-
gen, the protein that is the main structural component
of the connective tissue. Because the production of col-
lagen necessitates many biochemical steps that are
controlled by several genes, the potential exists for any
Fig. 16-31 Hereditary hemorrhagic telangiectasia (HHT).
This low-power photomicrograph shows multiple dilated
vascular spaces located immediately subjacent to the
epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

756 ORAL AND MAXILLOFACIAL PATHOLOGY
one of these genes to mutate, producing selective
defects in collagen synthesis. The various forms of
abnormal collagen result in many overlapping clinical
features for each of the types of the Ehlers-Danlos syn-
drome (Table 16-1). This discussion concentrates on
the most common and signiﬁcant forms of this group
of conditions.
Typical clinical ﬁndings include hypermobility of
the joints, easy bruisability, and marked elasticity of the
skin. Some patients have worked in circus sideshows
as the “rubber” man and the “contortionist” as a result
of their pronounced joint mobility and ability to stretch
the skin.
CLINICAL FEATURES
The pattern of inheritance and the clinical manifesta-
tions vary with the type of Ehlers-Danlos syndrome
being examined. About 80% of patients have the clas-
sical type in either the mild or severe form. Classical
Ehlers-Danlos syndrome is inherited as an autosomal
dominant trait, and defects of type I collagen have been
reported in some families, whereas problems with type
V collagen have been identiﬁed in others, suggesting
genetic heterogeneity. Hyperelasticity of the skin (Fig.
16-32) and cutaneous fragility can be observed. An
unusual healing response that often occurs with rela-
Table 16-1 Ehlers-Danlos Syndromes
Type Clinical Features Inheritance Defect
Classical (severe) Hyperextensible skin, easy bruising,
hypermobile joints, papyraceous
scarring of skin
AD Collagen type V mutations
Classical (mild) Less severe classical manifestationsAD Collagen type V mutations
Hypermobility Soft skin, no scarring, marked joint
hyperextensibility
AD Not known
Vascular Severe bruising, arterial and uterine
rupture
AD, AR Collagen type III mutations
Kyphoscoliosis Ocular fragility, hyperextensible skin,
hypermobile joints, scoliosis
AR Lysyl hydroxylase point mutations
Arthrochalasis Congenital hip dislocation, joint
hypermobility, normal scarring,
mandibular hypoplasia
AD Collagen type I mutations
Dermatosparaxis Severe skin fragility, sagging skinAR Procollagen peptidase deﬁciency
Other (includes X-linked,
periodontal, and
ﬁbronectin types)
X-linked and periodontal similar to
mild classic type; ﬁbronectin has
platelet defect
XLR, AD, AR Not known; possible collagen
type III defect; possible defect
in ﬁbronectin
AD, Autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.
Fig. 16-32 Ehlers-Danlos syndrome. The hyperelasticity of
the skin is evident in this patient affected by the mild form of
classical Ehlers-Danlos syndrome. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 757
tively minor injury to the skin is termed papyraceous
scarring because it resembles crumpled cigarette
paper (Fig. 16-33).
Patients with the hypermobility type of Ehlers-
Danlos syndrome exhibit remarkable joint hypermo-
bility but no evidence of scarring.
The vascular type of Ehlers-Danlos used to be
known as the ecchymotic type because of the exten-
sive bruising that occurs with everyday trauma. Defects
in type III collagen have been identiﬁed in this disor-
der. This form is inherited in an autosomal dominant
pattern, and the patient may be mistaken for a victim
of child abuse. The life expectancy of these patients is
often greatly reduced because of the tendency for
aortic aneurysm formation and rupture.
One rare form of Ehlers-Danlos syndrome (origi-
nally reported as type VIII) was described as having
dental manifestations as a hallmark feature, with
patients showing marked periodontal disease activity
at a relatively early age. Although these patients may
have overlapping features with either the classical or
vascular forms of the disease, recent studies examining
ﬁve affected families in Sweden have suggested that
this form of Ehlers-Danlos syndrome is linked to a spe-
ciﬁc mutation of a gene that has been mapped to chro-
mosome 12p13.
The oral manifestations of Ehlers-Danlos syndrome
include the ability of 50% of these patients to touch the
tip of their nose with their tongue (Gorlin sign), a feat
that can be achieved by less than 10% of the general
population. Some authors have noted easy bruising and
bleeding during minor manipulations of the oral
mucosa; others state that oral mucosal friability is
present. A tendency for recurrent subluxation of the
temporomandibular joint (TMJ) and the development
of other TMJ disorders has also been reported.
Most patients with Ehlers-Danlos syndrome have
normal teeth. A variety of dental abnormalities have
been described, however, including malformed,
stunted tooth roots, large pulp stones, and hypoplastic
enamel. Although most of these ﬁndings have not been
consistently correlated with any particular type of
the syndrome, pulp stones seem to occur more com-
monly in patients affected by classical Ehlers-Danlos
syndrome.
TREATMENT AND PROGNOSIS
The prognosis for the patient with Ehlers-Danlos syn-
drome depends on the type. Some forms, such as the
vascular type, can be very serious, with sudden death
occurring from rupture of the aorta secondary to the
weakened, abnormal collagen that constitutes the
vessel wall. The mild classical type is generally compat-
ible with a normal life span, although affected women
may have problems with placental tearing and hemor-
rhage during gestation.
Accurate diagnosis is important because it affects
the prognosis heavily. Similarly, because the various
types of this syndrome show a variety of inheritance
patterns, an accurate diagnosis is required so that
appropriate genetic counseling can be provided.
TUBEROUS SCLEROSIS (EPILOIA;
BOURNEVILLE-PRINGLE SYNDROME)
Tuberous sclerosis is an uncommon syndrome that is
classically characterized by mental retardation, seizure
disorders, and angioﬁbromas of the skin. The condition
is often inherited as an autosomal dominant trait, but
two thirds of the cases are sporadic and appear to rep-
resent new mutations. These mutations involve either
one of two genes: TSC1 (found on chromosome 9) or,
more commonly, TSC2 (found on chromosome 16).
Both of these gene products are believed to contribute
to the same intracellular biochemical pathway that
seems to have a tumor suppressor function. The multi-
ple hamartomatous growths that are seen in this disor-
der are thought to arise from disruption of the normal
tumor suppressor function of these genes. Tuberous
sclerosis has a wide range of clinical severity, although
Fig. 16-33 Ehlers-Danlos syndrome. Scarring that
resembles crumpled cigarette paper (papyraceous scarring) is
associated with minimal trauma in patients with Ehlers-
Danlos syndromes. These lesions involve the skin of the
knee. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

758 ORAL AND MAXILLOFACIAL PATHOLOGY
patients who have the TSC2 mutation have a more
severe expression of the disease than patients who
have the TSC1 mutation. Milder forms of tuberous scle-
rosis may be difﬁcult to diagnose.
The prevalence is at least 1 in 10,000 in the general
population, although in some long-term care facilities
tuberous sclerosis accounts for as high as 1% of the
mentally retarded patients.
CLINICAL FEATURES
Several clinical features characterize tuberous sclero-
sis. The ﬁrst of these, facial angioﬁbromas, used to be
called adenoma sebaceum. Because these lesions are
neither adenomas nor sebaceous, the use of that term
should be discontinued. Facial angioﬁbromas appear
as multiple, smooth-surfaced papules and occur pri-
marily in the nasolabial fold area (Fig. 16-34). Similar
lesions, called ungual or periungual ﬁbromas, are seen
around or under the margins of the nails (Fig. 16-35).
Two other characteristic skin lesions are connective
tissue hamartomas called shagreen patches and ovoid
areas of hypopigmentation called ash-leaf spots. Even
though approximately 5% of the general population
may have an ash-leaf spot, studies have reported that
60% to 97% of children with tuberous sclerosis display
these lesions. The shagreen patches, so named because
of their resemblance to sharkskin-derived shagreen
cloth, affect the skin of the trunk. The ash-leaf spots
may appear on any cutaneous surface and may be best
visualized using UV (Wood’s lamp) illumination.
CNS manifestations include seizure disorders in
70% to 80% of affected patients and mental retardation
in 33% to 45%. In addition, hamartomatous prolifera-
tions in the CNS develop into the potato-like growths
(“tubers”) seen at autopsy, from which the term tuber-
ous sclerosis is derived (Fig. 16-36). The tuberous ham-
artomas can best be visualized using T2-weighted
magnetic resonance imaging (MRI) and are present in
80% to 95% of these patients.
A relatively rare tumor of the heart muscle, called
cardiac rhabdomyoma, is also typically associated
with this syndrome. This lesion, which probably repre-
sents a hamartoma rather than a true neoplasm, occurs
in approximately 30% to 50% of affected patients and
is typically identiﬁed in childhood. Problems with
myocardial function often develop as a result of this
process, but many of these tumors undergo spontane-
ous regression.
Another hamartomatous type of growth related to
this disorder is the angiomyolipoma. This is a benign
neoplasm composed of vascular smooth muscle and
adipose tissue and occurs primarily in the kidney.
Oral manifestations of tuberous sclerosis include
developmental enamel pitting on the facial aspect of
the anterior permanent dentition in 50% to 100% of
patients. These pits are more readily appreciated after
applying a dental plaque–disclosing solution to the
Fig. 16-34 Tuberous sclerosis. Patients typically have
multiple papular facial lesions that microscopically are
angioﬁbromas.
Fig. 16-35 Tuberous sclerosis. Examination of the ﬁngers
often shows periungual ﬁbromas.
Fig. 16-36 Tuberous sclerosis. Patchy calciﬁcations
(arrows) associated with intracranial hamartoma formation are
seen on this lateral skull radiograph. (Courtesy of Dr. Reg Munden.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 759
teeth. Multiple ﬁbrous papules affect 11% to 56% of
patients. The ﬁbrous papules are seen predominantly
on the anterior gingival mucosa (Fig. 16-37), although
the lips, buccal mucosa, palate, and tongue may be
involved. Diffuse ﬁbrous gingival enlargement is
reported in affected patients who are not taking phe-
nytoin; however, most cases of gingival hyperplasia in
these individuals are probably related to medication
taken to control seizures. Some patients with tuberous
sclerosis may also exhibit radiolucencies of the jaws
that represent dense ﬁbrous connective tissue prolif-
erations (Fig. 16-38).
The diagnosis of tuberous sclerosis can be based on
ﬁnding at least two of the following major features:
● Facial angioﬁbromas
●Ungual or periungual ﬁbromas
●Hypomelanotic macules (three or more)
● Shagreen patch
● CNS hamartomas
● Cardiac rhabdomyoma
● Renal angiomyolipoma
●Multiple retinal nodular hamartomas
The presence of one major and two minor features
may also conﬁrm the diagnosis. The minor features
include the following:
●Multiple, randomly distributed enamel pits
● Gingival ﬁbromas
●Bone “cysts” (actually ﬁbrous proliferations)
●Multiple renal cysts
●Hamartomatous rectal polyps
HISTOPATHOLOGIC FEATURES
Microscopic examination of the ﬁbrous papules of the
oral mucosa or the enlarged gingivae shows a nonspe-
ciﬁc ﬁbrous hyperplasia. Similarly, the radiolucent jaw
lesions consist of dense ﬁbrous connective tissue that
resembles desmoplastic ﬁbroma or the simple type of
central odontogenic ﬁbroma. The angioﬁbroma of the
skin is a benign aggregation of delicate ﬁbrous connec-
tive tissue characterized by plump, uniformly spaced
ﬁbroblasts with numerous interspersed thin-walled
vascular channels.
TREATMENT AND PROGNOSIS
For patients with tuberous sclerosis, most of the treat-
ment is directed toward the management of the
seizure disorder with anticonvulsant agents. Periodic
MRI of the head may be done to screen for intracra-
nial lesions, whereas ultrasound evaluation is per-
formed for evaluation of kidney involvement. Mentally
retarded patients may have problems with oral hygiene
procedures, and poor oral hygiene contributes to phe-
nytoin-induced gingival hyperplasia. Patients affected
by this condition have a slightly reduced life span
compared with the general population, with death
usually related to CNS or kidney disease. Genetic
counseling is also appropriate for affected patients,
and genetic testing is available for both TSC1 and
TSC2 mutations if prenatal or preimplantation family
planning is desired.
Fig. 16-37 Tuberous sclerosis. Patients often exhibit
gingival hyperplasia, which may be secondary to phenytoin
medications used to control seizures in some cases. Fibrous
papules of the gingiva (arrows) may also be present.
Fig. 16-38 Tuberous sclerosis. Periapical radiograph
exhibiting a well-deﬁned radiolucency apical to the maxillary
left lateral incisor. Biopsy revealed an intraosseous ﬁbrous
proliferation. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

760 ORAL AND MAXILLOFACIAL PATHOLOGY
MULTIPLE HAMARTOMA SYNDROME
(COWDEN SYNDROME; PTEN
HAMARTOMA-TUMOR SYNDROME)
Multiple hamartoma syndrome is a rare condition
that has important implications for the affected patient,
because malignancies, in addition to the benign ham-
artomatous growths, develop in a high percentage of
these individuals. Usually, the syndrome is inherited as
an autosomal dominant trait showing a high degree
of penetrance and a range of expressivity. The gene
responsible for this disorder has been mapped to chro-
mosome 10, and a mutation of the PTEN (phosphatase
and tensin homolog deleted on chromosome 10) gene
has been implicated in its pathogenesis. The estimated
prevalence of this condition is approximately 1 in
200,000, and more than 300 affected patients have
been described in the literature. In recent years,
overlapping clinical features of multiple hamartoma
syndrome with Lhermitte-Duclos disease, Bannayan-
Riley-Ruvalcaba syndrome, and Proteus-like syn-
drome have been noted, and all of these disorders
have demonstrated mutations of the PTEN gene.
CLINICAL FEATURES
Cutaneous manifestations are present in almost all
patients with multiple hamartoma syndrome, usually
developing during the second decade of life. The major-
ity of the skin lesions appear as multiple, small (less
than 1 mm) papules, primarily on the facial skin, espe-
cially around the mouth, nose, and ears (Fig. 16-39).
Microscopically, most of these papules represent hair
follicle hamartomas called trichilemmomas. Other
commonly noted skin lesions are acral keratosis, a
warty-appearing growth that develops on the dorsal
surface of the hand, and palmoplantar keratosis, a
prominent calluslike lesion on the palms or soles. Cuta-
neous hemangiomas, neuromas, xanthomas, and
lipomas have also been described.
Other problems can appear in these patients as well.
Thyroid disease usually appears as either a goiter or a
thyroid adenoma, but follicular adenocarcinoma may
develop. In women, ﬁbrocystic disease of the breast
is frequently observed. Unfortunately, breast cancer
occurs with a relatively high frequency (25% to 50%)
in these patients. The mean age at diagnosis of breast
malignancy is 40 years, which is much younger than
usual. In the gastrointestinal tract, multiple benign
hamartomatous polyps may be present. In addition,
several types of benign and malignant tumors of the
female genitourinary tract occur more often than in
the normal population.
The oral lesions vary in severity from patient to
patient and usually consist of multiple papules affect-
ing the gingivae, dorsal tongue, and buccal mucosa
(Figs. 16-40 and 16-41). These lesions have been
reported in more than 80% of affected patients and
generally produce no symptoms. Other possible oral
ﬁndings include a high-arched palate, periodontitis,
and extensive dental caries, although it is unclear
whether the latter two conditions are signiﬁcantly
related to the syndrome.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the oral lesions are
rather nonspeciﬁc, essentially representing ﬁbroepi-
thelial hyperplasia. Other lesions associated with this
syndrome have their own characteristic histopatho-
logic ﬁndings, depending on the hamartomatous or
neoplastic tissue origin.
Fig. 16-39 Multiple hamartoma syndrome. These tiny
cutaneous facial papules represent hair follicle hamartomas
(trichilemmomas).
Fig. 16-40 Multiple hamartoma syndrome. Multiple,
irregular ﬁbroepithelial papules involve the tongue (center)
and alveolar ridge mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 761
DIAGNOSIS
The diagnosis can be based on the ﬁnding of two of the
following three pathognomonic signs:
1. Multiple facial trichilemmomas
2. Multiple oral papules
3. Acral keratoses
A variety of other major and minor diagnostic crite-
ria, as well as a positive family history, are also helpful
in conﬁrming the diagnosis. Genetic testing for muta-
tions of the PTEN gene are clinically available, but 20%
of patients who otherwise have characteristic multiple
hamartoma syndrome will not demonstrate a genetic
abnormality; therefore, a negative test does not neces-
sarily preclude the diagnosis of multiple hamartoma
syndrome.
TREATMENT AND PROGNOSIS
Treatment of multiple hamartoma syndrome is con-
troversial. Although most of the tumors that develop
are benign, the prevalence of malignancy is higher
than in the general population; therefore, annual physi-
cal examinations that focus speciﬁcally on anatomic
sites of increased tumor prevalence are appropriate.
Some investigators recommend bilateral prophylactic
mastectomies as early as the third decade of life for
female patients because of the associated increased
risk of breast cancer.
EPIDERMOLYSIS BULLOSA
The term epidermolysis bullosa describes a hetero-
geneous group of inherited blistering mucocutaneous
disorders. Each has a speciﬁc defect in the attachment
mechanisms of the epithelial cells, either to each other
or to the underlying connective tissue. Recent advances
in the understanding of the clinical, epidemiologic, and
molecular genetic abnormalities of these conditions
have led to the identiﬁcation of approximately 25 dif-
ferent forms. Depending on the defective mechanism
of cellular cohesion, there are four broad categories:
1. Simplex
2. Junctional
3. Dystrophic
4. Hemidesmosomal
Each category consists of several forms of the disor-
der. A variety of inheritance patterns may be seen,
depending on the particular form. The degree of sever-
ity can range from relatively mild, annoying forms,
such as the simplex types, through a spectrum that
includes severe, fatal disease. For example, many cases
of junctional epidermolysis bullosa result in death at
birth because of the signiﬁcant sloughing of the skin
during passage through the birth canal. Speciﬁc muta-
tions in the genes encoding keratin 5 and keratin 14
have been identiﬁed as being responsible for most of
the simplex types, whereas mutations in the genetic
codes for the α3, β3, and γ2 subunits of laminin have
been documented for the junctional types. Most of the
dystrophic types appear to be caused by mutations in
the genes responsible for type VII collagen production,
with nearly 200 distinctly different mutations identi-
ﬁed to date. The hemidesmosomal type is the most
recently characterized pattern of this group of disor-
ders, and mutations of genes associated with various
hemidesmosomal attachment proteins, such as plectin,
type XVII collagen (BP180), and α6β4 integrin, have
been established.
A few representative examples of the types of epi-
dermolysis bullosa are summarized in Table 16-2.
Because oral lesions are most commonly observed in
the dystrophic forms, this discussion centers on these
forms. Dental abnormalities, such as anodontia, enamel
hypoplasia, pitting of the enamel, neonatal teeth, and
severe dental caries, have been variably associated
with several of the different types of epidermolysis
bullosa, although studies have suggested that the prev-
alence of dental abnormalities is signiﬁcantly increased
only with the junctional type. A disorder termed epi-
dermolysis bullosa acquisita is mentioned because
of the similarity of its name; however, this appears to
be an unrelated condition, having an autoimmune
(rather than a genetic) origin (see page 744).
CLINICAL FEATURES
DOMINANT DYSTROPHIC TYPES
The dystrophic forms of epidermolysis bullosa that
are inherited in an autosomal dominant fashion are not
usually life threatening, although they may certainly be
disﬁguring and pose many problems. The initial lesions
Fig. 16-41 Multiple hamartoma syndrome. Multiple
papules on the left buccal mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

762 ORAL AND MAXILLOFACIAL PATHOLOGY
are vesicles or bullae, which are seen early in life and
develop on areas exposed to low-grade, chronic trauma,
such as the knuckles or knees (Fig. 16-42). The bullae
rupture, resulting in erosions or ulcerations that ulti-
mately heal with scarring. In the process, appendages
such as ﬁngernails may be lost.
The oral manifestations are typically mild, with
some gingival erythema and tenderness. Gingival
recession and reduction in the depth of the buccal
vestibule may be observed (Fig. 16-43).
RECESSIVE DYSTROPHIC TYPES
Generalized recessive dystrophic epidermolysis bullosa
represents one of the more debilitating forms of the
disease. Vesicles and bullae form with even minor
trauma. Secondary infections are often a problem
because of the large surface areas that may be involved.
If the patient manages to survive into the second
decade, then hand function is often greatly diminished
because of the repeated episodes of cutaneous break-
Table 16-2 Examples of Epidermolysis Bullosa
Form Inheritance Clinical Features Defect
EB simplex AD Blistering of the hands and feet; mucosal
involvement uncommon; blisters heal
without scarring; prognosis usually good
Keratin gene defects
Junctional EB,
generalized gravis
variant
AR Severe blistering at birth; granulation tissue
around the mouth; oral erosions common;
pitted enamel hypoplasia; often fatal
(previously called EB letalis)
Defects of hemidesmosomes
Dominant, dystrophic EB,
Pasini type
AD Generalized blistering, white papules Defect in type VII collagen
Dominant, dystrophic EB,
Cockayne-Touraine
type
AD Extremities primarily affected Defect in type VII collagen
Recessive, dystrophic EB,
generalized gravis type
AR Severe mucosal involvement; mittenlike
scarring; deformities of hands and feet;
patients usually do not survive past early
adulthood
Defect in type VII collagen
Recessive, dystrophic EB,
inverse type
AR Involvement of groin and axilla; severe oral and
esophageal lesions
Defect in type VII collagen
EB, Epidermolysis bullosa; AD, autosomal dominant; AR, autosomal recessive.
Fig. 16-42 Epidermolysis bullosa. A young girl, affected by
the dominant dystrophic form of epidermolysis bullosa,
shows the characteristic hemorrhagic bullae, scarring, and
erosion associated with minimal trauma to the hands.
Fig. 16-43 Epidermolysis bullosa. A teenaged boy,
affected by dominant dystrophic epidermolysis bullosa,
shows a reduced depth of the labial vestibule caused by
repeated mucosal tearing and healing with scarring. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 763
down and healing with scarring, resulting in fusion of
the ﬁngers into a mittenlike deformity (Fig. 16-44).
The oral problems are no less severe. Bulla and
vesicle formation is induced by virtually any food
having some degree of texture. Even with a soft diet,
the repeated cycles of scarring often result in microsto-
mia (Fig. 16-45) and ankyloglossia. Similar mucosal
injury and scarring may cause severe stricture of the
esophagus. Because a soft diet is usually highly cario-
genic, carious destruction of the dentition at an early
age is common.
HISTOPATHOLOGIC FEATURES
The histopathologic features of epidermolysis bullosa
vary with the type being examined. The simplex form
shows intraepithelial clefting by light microscopy.
Junctional, dystrophic, and hemidesmosomal forms
show subepithelial clefting (Fig. 16-46). Electron
microscopic examination, which is still considered the
diagnostic “gold standard,” reveals clefting at the level
of the lamina lucida of the basement membrane in the
junctional forms and below the lamina densa of the
basement membrane in the dystrophic forms. In con-
trast, the hemidesmosomal form shows clefting just
below the basal cell layer, at its interface with the
lamina lucida. Immunohistochemical evaluation of
perilesional tissue may help to identify speciﬁc defects
to classify and subtype the condition further. Molecular
genetic analysis is now being used to conﬁrm the diag-
nosis in some instances.
TREATMENT AND PROGNOSIS
Treatment of epidermolysis bullosa varies with the
type. For milder cases, no treatment other than local
wound care may be needed. Sterile drainage of larger
blisters and the use of topical antibiotics are often indi-
cated in these situations. For the more severe cases,
intensive management with oral antibiotics may be
necessary if cellulitis develops; despite intensive
medical care, some patients die as a result of infectious
complications.
The “mitten” deformity of the hands, seen in reces-
sive dystrophic epidermolysis bullosa, can be corrected
with plastic surgery, but the problem usually recurs
after a period of time, and surgical intervention is
required every 2 years on average. With esophageal
involvement, dysphagia may be a signiﬁcant problem,
resulting in malnutrition and weight loss. Placement of
a gastrostomy tube may be necessary at times. Patients
Fig. 16-44 Epidermolysis bullosa. A 19-year-old man,
affected by recessive dystrophic epidermolysis bullosa, shows
the typical mittenlike deformity of the hand caused by
scarring of the tissue after damage associated with normal
activity.
Fig. 16-45 Epidermolysis bullosa. Same patient as
depicted in Fig. 16-44. Microstomia has been caused by
repeated trauma and healing with scarring. Note the severe
dental caries activity associated with a soft cariogenic diet.
Fig. 16-46 Epidermolysis bullosa. Complete separation of
the epithelium from the connective tissue is seen in this
photomicrograph of a tissue section obtained from a patient
affected by a junctional form of epidermolysis bullosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

764 ORAL AND MAXILLOFACIAL PATHOLOGY
with the recessive dystrophic forms are also predis-
posed to development of cutaneous squamous cell
carcinoma. This malignancy often develops in areas of
chronic ulceration during the second through third
decades of life and represents a signiﬁcant cause of
death for these patients. Infrequently, the lingual
mucosa of affected patients has been reported to
undergo malignant transformation as well.
Management of the oral manifestations also depends
on the type of the disease. For patients who are suscep-
tible to mucosal bulla formation, dental manipulation
should be kept to a minimum. To achieve this, topical
1% neutral sodium ﬂuoride solution should be admin-
istered daily to prevent dental caries. A soft diet that is
as noncariogenic as possible, as well as atraumatic oral
hygiene procedures, should be encouraged. Maintain-
ing adequate nutrition for affected patients is critical to
ensure optimal wound healing.
If dental restorative care is required, the lips should
be lubricated to minimize trauma. Injections for local
anesthesia can usually be accomplished by depositing
the anesthetic slowly and deeply within the tissues. For
extensive dental care, endotracheal anesthesia may
be performed without signiﬁcant problems in most
cases.
Unfortunately, because of the genetic nature of these
diseases, no cure exists. Genetic counseling of affected
families is indicated. Both prenatal diagnosis and pre-
implantation diagnosis are available as adjuncts to
family planning.
Immune-Mediated Diseases
and Their Evaluation
Several conditions discussed in this chapter are the
result of inappropriate production of antibodies by
the patient (autoantibodies). These autoantibodies are
directed against various constituents of the molecular
apparatus that hold epithelial cells together or that
bind the surface epithelium to the underlying connec-
tive tissue. The ensuing damage produced by the inter-
action of these autoantibodies with the host tissue is
seen clinically as a disease process, often termed an
immunobullous disease. Because each disease is
characterized by production of speciﬁc types of auto-
antibodies, identiﬁcation of the antibodies and the
tissues against which they are targeted is important
diagnostically. The two techniques that are widely used
to investigate the immunobullous diseases are (1)
direct immunoﬂuorescence and (2) indirect immuno-
ﬂuorescence studies. Following is a brief overview of
how they work.
Direct immunoﬂuorescence is used to detect auto-
antibodies that are bound to the patient’s tissue. Before
testing can take place, several procedures must occur.
Inoculating human immunoglobulins into a goat
creates antibodies directed against these human immu-
noglobulins. The antibodies raised in response to the
human immunoglobulins are harvested from the
animal and tagged with ﬂuorescein, a dye that glows
when viewed with ultraviolet (UV) light. As illustrated
on the left side of Fig. 16-47, a frozen section of the
patient’s tissue is placed on a slide, and this is incu-
bated with ﬂuorescein-conjugated goat antihuman
antibodies. These antibodies bind to the tissue at any
site where human immunoglobulin is present. The
excess antibody suspension is washed off, and the
section is then viewed with a microscope having a UV
light source.
Direct
immunofluorescence
Indirect
immunofluorescence
Apply
fluorescein-conjugated
anti-human Ig
antibodies
Apply
fluorescein-conjugated
anti-human Ig
antibodies
Patient's
tissue
specimen
Wash off excess Wash off excess
Wash off excess
View with UV
microscope
View with UV
microscope
Apply patient's
serum, antibodies
bind to homologous
structures
Section of
monkey
esophagus
Fig. 16-47 Immunoﬂuorescence techniques. Comparison
of the techniques for direct and indirect
immunoﬂuorescence. The left side depicts the direct
immunoﬂuorescent ﬁndings in cicatricial pemphigoid, a
disease that has autoantibodies directed toward the
basement zone. The right side shows the indirect
immunoﬂuorescent ﬁndings for pemphigus vulgaris, a disease
that has autoantibodies directed toward the intercellular
areas between the spinous cells of the epithelium.
Ig, Immunoglobulin; UV, ultraviolet. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 765
With indirect immunoﬂuorescence studies, the
patient is being evaluated for presence of antibodies
that are circulating in the blood. As shown on the right
side of Fig. 16-47, a frozen section of tissue that is
similar to human oral mucosa (e.g., Old World monkey
esophagus) is placed on a slide and incubated with the
patient’s serum. If there are autoantibodies directed
against epithelial attachment structures in the patient’s
serum, then they will attach to the homologous struc-
tures on the monkey esophagus. The excess serum is
washed off, and ﬂuorescein-conjugated goat antihu-
man antibody is incubated with the section. The excess
is washed off, and the section is examined with UV
light to detect the presence of autoantibodies that
might have been in the serum.
Examples of the molecular sites of attack of the auto-
antibodies are seen diagrammatically in Fig. 16-48.
Each site is distinctive for a particular disease; however,
the complexities of the epithelial attachment mecha-
nisms are still being elucidated, and more precise
mapping may be possible in the future. A summary of
the clinical, microscopic, and immunopathologic fea-
tures of the more important immune-mediated muco-
cutaneous diseases is found in Table 16-3.
PEMPHIGUS
The condition known as pemphigus represents four
related diseases of an autoimmune origin:
1. Pemphigus vulgaris
2. Pemphigus vegetans
3. Pemphigus erythematosus
4. Pemphigus foliaceus
Only the ﬁrst two of these affect the oral mucosa,
and the discussion is limited to pemphigus vulgaris.
Pemphigus vegetans is rare; most authorities now
feel it represents simply a variant of pemphigus
vulgaris.
Pemphigus vulgaris is the most common of these
disorders (vulgaris is Latin for common). Even so, it is not
seen very often. The estimated incidence is one to ﬁve
cases per million people diagnosed each year in the
general population. Nevertheless, pemphigus vulgaris
is an important condition because, if untreated, it often
results in the patient’s death. Furthermore, the oral
lesions are often the ﬁrst sign of the disease, and they
are the most difﬁcult to resolve with therapy. This has
prompted the description of the oral lesions as “the ﬁrst
to show, and the last to go.”
The blistering that typiﬁes this disease is due to an
abnormal production, for unknown reasons, of autoan-
tibodies that are directed against the epidermal cell
surface glycoproteins, desmoglein 3 and desmoglein 1.
These desmogleins are components of desmosomes
(structures that bond epithelial cells to each other), and
the autoantibodies attach to these desmosomal compo-
nents, effectively inhibiting the molecular interaction
that is responsible for adherence. As a result of this
immunologic attack on the desmosomes, a split devel-
ops within the epithelium, causing a blister to form.
Desmoglein 3 is preferentially expressed in the para-
basal region of the epidermis and oral epithelium,
Normal structures Targeted structures
for immune-mediated
diseases
Basal cell layer
Hemidesmosome
Basement membrane
Connective tissue
Anchoring fibrils
Pemphigus (desmoglein 3
of desmosome)
Pemphigoid (various components
of BMZ or hemidesmosome)
Epidermolysis bullosa acquisita
(type VII collagen of anchoring
fibrils)
Desmosome
Fig. 16-48 Epithelial attachment apparatus. Schematic diagram demonstrating targeted
structures in several immune-mediated diseases. BMZ, Basement membrane zone. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

766 ORAL AND MAXILLOFACIAL PATHOLOGY
whereas desmoglein 1 is found primarily in the super-
ﬁcial portion of the epidermis, with minimal expres-
sion in oral epithelium. Patients who have developed
autoantibodies directed against desmoglein 3, with or
without desmoglein 1, will histopathologically show
intraepithelial clefting just above the basal layer, and
clinically oral mucosal blisters of pemphigus vulgaris
will form. Patients who develop autoantibodies directed
against only desmoglein 1 will histopathologically show
superﬁcial intraepithelial clefting of the epidermis, but
oral mucosa will not be affected. Clinically, the ﬁne
scaly red lesions of pemphigus foliaceous or pemphi-
gus erythematosus will be evident.
Occasionally, a pemphigus-like oral and cutaneous
eruption may occur in patients taking certain medi-
cations (e.g., penicillamine, angiotensin-converting
enzyme [ACE] inhibitors, nonsteroidal antiinﬂamma-
tory drugs [NSAIDs]) or in patients with malignancy,
especially lymphoreticular malignancies (so-called
paraneoplastic pemphigus) (see page 769). Simi-
larly, a variety of other conditions may produce chronic
vesiculoulcerative or erosive lesions of the oral mucosa,
and these often need to be considered in the differen-
tial diagnosis (see Table 16-3). In addition, a rare
genetic condition termed chronic benign familial
pemphigus or Hailey-Hailey disease may have
erosive cutaneous lesions, but oral involvement in that
process appears to be uncommon.
CLINICAL FEATURES
The initial manifestations of pemphigus vulgaris often
involve the oral mucosa, typically in adults. The average
age at diagnosis is 50 years, although rare cases may
be seen in childhood. No sex predilection is observed,
and the condition seems to be more common in persons
of Mediterranean, South Asian, or Jewish heritage.
Patients usually complain of oral soreness, and
examination shows superﬁcial, ragged erosions and
ulcerations distributed haphazardly on the oral mucosa
(Figs. 16-49 to 16-52). Such lesions may affect virtually
any oral mucosal location, although the palate, labial
Table 16-3 Chronic Vesiculoulcerative Diseases
Condition
Mean
Age
Sex
Predilection
Clinical
Features
Histopathologic
Features
Direct
Immunoﬂuorescence
Indirect
Immunoﬂuorescence
Pemphigus
vulgaris
Fourth to
sixth
decade
Equal Vesicles,
erosions, and
ulcerations
on any oral
mucosal or
skin surface
Intraepithelial
clefting
Positive intercellularPositive
Paraneoplastic
pemphigus
Sixth to
seventh
decade
Equal Vesicles,
erosions, and
ulcerations
on any
mucosal or
skin surface
Subepithelial and
intraepithelial
clefting
Positive, intercellular
and basement
membrane zone
Positive (rat bladder)
Mucous
membrane
pemphigoid
Sixth to
seventh
decade
Female Primarily
mucosal
lesions
Subepithelial
clefting
Positive, basement
membrane zone
Negative
Bullous
pemphigoid
Seventh to
eighth
decade
Equal Primarily skin
lesions
Subepithelial
clefting
Positive, basement
membrane zone
Positive
Erythema
multiforme
Third to
fourth
decade
Male Skin and
mucosa
involved;
target lesions
on skin
Subepithelial
edema and
perivascular
inﬂammations
Nondiagnostic Negative
Lichen planusFifth to
sixth
decade
Female Oral and/or
skin lesions;
may or may
not be
erosive
Hyperkeratosis,
saw-toothed
rete ridges,
bandlike
inﬁltrate of
lymphocytes
Fibrinogen, basement
membrane zone
Negative `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 767
mucosa, buccal mucosa, ventral tongue, and gingivae
are often involved. Patients rarely report vesicle or
bulla formation intraorally, and such lesions can seldom
be identiﬁed by the examining clinician, probably
because of early rupture of the thin, friable roof of the
blisters. More than 50% of the patients have oral
mucosal lesions before the onset of cutaneous lesions,
sometimes by as much as 1 year or more. Eventually,
however, nearly all patients have intraoral involve-
ment. The skin lesions appear as ﬂaccid vesicles and
bullae (Fig. 16-53) that rupture quickly, usually within
hours to a few days, leaving an erythematous, denuded
surface. Infrequently ocular involvement may be seen,
usually appearing as bilateral conjunctivitis. Unlike
cicatricial pemphigoid, the ocular lesions of pemphi-
gus do not tend to produce scarring and symblepharon
formation (see page 772).
Fig. 16-49 Pemphigus vulgaris. Multiple erosions of the
left buccal mucosa.
Fig. 16-50 Pemphigus vulgaris. Large, irregularly shaped
ulcerations involving the ﬂoor of the mouth and ventral
tongue.
Fig. 16-51 Pemphigus vulgaris. Multiple erosions affecting
the marginal gingiva.
Fig. 16-52 Pemphigus vulgaris. The patient, with a known
diagnosis of pemphigus vulgaris, had been treated with
immunosuppressive therapy. The oral erosions shown here
were the only persistent manifestation of her disease.
Fig. 16-53 Pemphigus vulgaris. This ﬂaccid cutaneous
bulla is characteristic of skin involvement. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

768 ORAL AND MAXILLOFACIAL PATHOLOGY
Without proper treatment, the oral and cutaneous
lesions tend to persist and progressively involve more
surface area. A characteristic feature of pemphigus
vulgaris is that a bulla can be induced on normal-
appearing skin if ﬁrm lateral pressure is exerted. This
is called a positive Nikolsky sign.
HISTOPATHOLOGIC FEATURES
Biopsy specimens of perilesional tissue show charac-
teristic intraepithelial separation, which occurs just
above the basal cell layer of the epithelium (Fig.
16-54). Sometimes the entire superﬁcial layers of the
epithelium are stripped away, leaving only the basal
cells, which have been described as resembling a “row
of tombstones.” The cells of the spinous layer of the
surface epithelium typically appear to fall apart, a
feature that has been termed acantholysis, and the
loose cells tend to assume a rounded shape (Fig.
16-55). This feature of pemphigus vulgaris can be used
in making a diagnosis based on the identiﬁcation of
these rounded cells (Tzanck cells) in an exfoliative
cytologic preparation. A mild-to-moderate chronic
inﬂammatory cell inﬁltrate is usually seen in the under-
lying connective tissue.
The diagnosis of pemphigus vulgaris should be con-
ﬁrmed by direct immunoﬂuorescence examination of
fresh perilesional tissue or tissue submitted in Michel’s
solution. With this procedure, antibodies (usually IgG
or IgM) and complement components (usually C3) can
be demonstrated in the intercellular spaces between
the epithelial cells (Fig. 16-56) in almost all patients
with this disease. Indirect immunoﬂuorescence is also
typically positive in 80% to 90% of cases, demonstrating
the presence of circulating autoantibodies in the
patient’s serum. Enzyme-linked immunosorbent assays
(ELISAs) have been developed to detect circulating
autoantibodies as well.
It is critical that perilesional tissue be obtained for
both light microscopy and direct immunoﬂuorescence
to maximize the probability of a diagnostic sample. If
ulcerated mucosa is submitted for testing, then the
results are often inconclusive because of either a lack
of an intact interface between the epithelium and
connective tissue or a great deal of nonspeciﬁc
inﬂammation.
TREATMENT AND PROGNOSIS
A diagnosis of pemphigus vulgaris should be made as
early in its course as possible because control is gener-
ally easier to achieve. Pemphigus is a systemic disease;
Fig. 16-54 Pemphigus vulgaris. Low-power
photomicrograph of perilesional mucosa affected by
pemphigus vulgaris. An intraepithelial cleft is located just
above the basal cell layer.
Fig. 16-55 Pemphigus vulgaris. High-power
photomicrograph showing rounded, acantholytic epithelial
cells sitting within the intraepithelial cleft.
Fig. 16-56 Pemphigus vulgaris. Photomicrograph
depicting the direct immunoﬂuorescence pattern of
pemphigus vulgaris. Immunoreactants are deposited in the
intercellular areas between the surface epithelial cells. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 769
therefore, treatment consists primarily of systemic cor-
ticosteroids (usually prednisone), often in combination
with other immunosuppressive drugs (so-called steroid-
sparing agents), such as azathioprine. Although some
clinicians have advocated the use of topical corticoste-
roids in the management of oral lesions, the observed
improvement is undoubtedly because of the absorption
of the topical agents, resulting in a greater systemic
dose. The potential side effects associated with the
long-term use of systemic corticosteroids are signiﬁ-
cant and include the following:
● Diabetes mellitus
● Adrenal suppression
● Weight gain
● Osteoporosis
● Peptic ulcers
●Severe mood swings
●Increased susceptibility to a wide range of
infections
Ideally, a physician with expertise in immunosup-
pressive therapy should manage the patient. The most
common approach is to use relatively high doses of
systemic corticosteroids initially to clear the lesions,
then attempt to maintain the patient on as low a dose
of corticosteroids as is necessary to control the condi-
tion. Often the clinician can monitor the success of
therapy by measuring the titers of circulating autoanti-
bodies using indirect immunoﬂuorescence, because
disease activity frequently correlates with the abnor-
mal antibody levels. Pemphigus may undergo complete
resolution, although remissions and exacerbations
are common. One study suggested that up to 75% of
patients will have disease resolution after 10 years of
treatment.
Before the development of corticosteroid therapy, as
many as 60% to 90% of these patients died, primarily
as a result of infections and electrolyte imbalances.
Even today, the mortality rate associated with pemphi-
gus vulgaris is in the range of 5% to 10%, usually because
of the complications of long-term systemic corticoste-
roid use.
PARANEOPLASTIC PEMPHIGUS
(NEOPLASIA-INDUCED PEMPHIGUS;
PARANEOPLASTIC AUTOIMMUNE
MULTIORGAN SYNDROME)
Paraneoplastic pemphigus is a rare vesiculobullous
disorder that affects patients who have a neoplasm,
usually lymphoma or chronic lymphocytic leuke-
mia. Approximately 150 cases have been documented.
Although the precise pathogenetic mechanisms are
unknown, some evidence suggests abnormal levels of
the cytokine, interleukin 6 (IL-6), could be produced
by host lymphocytes in response to the patient’s tumor.
IL-6 may then be responsible for stimulating the abnor-
mal production of antibodies directed against antigens
associated with the desmosomal complex and the base-
ment membrane zone of the epithelium. In addition
to a variety of different antibodies that attack these
epithelial adherence structures, recent reports have
described cutaneous and mucosal damage that appears
to be mediated by cytotoxic T lymphocytes in some
cases of paraneoplastic pemphigus. As a result of this
multifaceted immunologic attack, the disease mani-
fests in an array of clinical features, histopathologic
ﬁndings, and immunopathologic ﬁndings that may be
perplexing if the clinician is unfamiliar with this
condition.
CLINICAL FEATURES
Patients typically have a history of a malignant lympho-
reticular neoplasm, or less commonly, a benign lym-
phoproliferative disorder such as angiofollicular lymph
node hyperplasia (Castleman’s disease) or thymoma.
In approximately one third of reported cases, paraneo-
plastic pemphigus developed before a malignancy was
identiﬁed, thus signaling the presence of a tumor. The
neoplastic disease may or may not be under control at
the time of onset of the paraneoplastic condition. Signs
and symptoms of paraneoplastic pemphigus usually
begin suddenly and may appear polymorphous. In
some instances, multiple vesiculobullous lesions affect
the skin (Fig. 16-57) and oral mucosa. Palmar or plantar
bullae may be evident, a feature that is uncommon in
pemphigus vulgaris. For other patients, skin lesions can
appear more papular and pruritic, similar to cutaneous
lichen planus. The lips often show hemorrhagic crust-
ing similar to that of erythema multiforme (Fig. 16-58).
The oral mucosa shows multiple areas of erythema and
Fig. 16-57 Paraneoplastic pemphigus. The bulla and
crusted ulcerations on this patient’s arm are representative of
the polymorphous cutaneous lesions. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

770 ORAL AND MAXILLOFACIAL PATHOLOGY
diffuse, irregular ulceration (Fig. 16-59), affecting vir-
tually any oral mucosal surface. If the lesions remain
untreated, then they persist and worsen. Some patients
may develop only oropharyngeal lesions, without cuta-
neous involvement.
Other mucosal surfaces are also commonly affected,
with 70% of patients having involvement of the con-
junctival mucosa. In this area, a cicatrizing (scarring)
conjunctivitis develops, similar to that seen with cica-
tricial pemphigoid (Fig. 16-60). The vaginal mucosa
and mucosa of the respiratory tract may be involved.
HISTOPATHOLOGIC FEATURES
The features of paraneoplastic pemphigus on light
microscopic examination may be as diverse as the
clinical features. In most cases, a lichenoid mucositis is
seen, usually with subepithelial clefting (like pemphi-
goid) or intraepithelial clefting (like pemphigus) (Fig.
16-61).
Direct immunoﬂuorescence studies may show a
weakly positive deposition of immunoreactants (IgG
and complement) in the intercellular zones of the epi-
thelium and/or a linear deposition of immunoreactants
at the basement membrane zone. Indirect immuno-
ﬂuorescence should be conducted using a transitional
type of epithelium (e.g., rat urinary bladder mucosa) as
the substrate. This shows a fairly speciﬁc pattern of
antibody localization to the intercellular areas of the
epithelium. Immunoprecipitation studies remain the
gold standard for the diagnosis of paraneoplastic pem-
phigus, however, because the various antibodies that
characterize this condition can be identiﬁed with a
considerable degree of speciﬁcity. Antibodies directed
against desmoplakin I and II, major bullous pemphi-
goid antigen, envoplakin, and periplakin, in addition to
desmoglein 1 and 3, are typically detected. Examples
of paraneoplastic pemphigus that show only a lichen-
Fig. 16-58 Paraneoplastic pemphigus. Crusted,
hemorrhagic lip lesions may be mistaken for erythema
multiforme or herpes simplex infection.
Fig. 16-59 Paraneoplastic pemphigus. These diffuse oral
ulcerations are quite painful.
Fig. 16-60 Paraneoplastic pemphigus. Ocular
involvement.
Fig. 16-61 Paraneoplastic pemphigus. This medium-
power photomicrograph shows both intraepithelial and
subepithelial clefting. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 771
oid reaction with no demonstrable autoantibody pro-
duction have infrequently been described.
TREATMENT AND PROGNOSIS
Paraneoplastic pemphigus is often a very serious con-
dition with a high morbidity and mortality rate. For the
infrequent cases associated with a benign lymphopro-
liferative condition, surgical removal of the tumor may
result in regression of the paraneoplastic pemphigus.
For those cases associated with malignancy, treatment
essentially consists of systemic prednisone, typically
combined with another immunosuppressive agent,
such as azathioprine, methotrexate, or cyclophospha-
mide. As with pemphigus vulgaris, the skin lesions
usually respond more quickly to treatment than the
oral lesions. Unfortunately, although the immunosup-
pressive therapy often manages to control the autoim-
mune disease, this immunosuppression often seems to
trigger a reactivation of the malignant neoplasm. Thus
a high mortality rate is seen, with patients succumbing
to complications of the vesiculobullous lesions, compli-
cations of immune suppressive therapy, or progression
of malignant disease. Occasionally, long-term survivors
are reported, but these seem to be in the minority. As
more of these patients are identiﬁed, therapeutic strat-
egies can be better evaluated and modiﬁed for optimal
care in the future.
MUCOUS MEMBRANE PEMPHIGOID
(CICATRICIAL PEMPHIGOID; BENIGN
MUCOUS MEMBRANE PEMPHIGOID)
Evidence has accumulated to suggest that mucous
membrane pemphigoid represents a group of chronic,
blistering, mucocutaneous autoimmune diseases in
which tissue-bound autoantibodies are directed against
one or more components of the basement membrane.
As such, this condition has a heterogeneous origin,
with autoantibodies being produced against any one of
a variety of basement membrane components, all of
which produce similar clinical manifestations. The
precise incidence is unknown, but most authors believe
that it is at least twice as common as pemphigus
vulgaris.
The term pemphigoid is used because clinically it
often appears similar (the meaning of the -oid sufﬁx) to
pemphigus. The prognosis and microscopic features
of pemphigoid, however, are very different.
Although a variety of terms have been used over the
decades to designate this condition, a group of experts
from both medicine and dentistry met in 1999 and
came to an agreement that mucous membrane pem-
phigoid would be the most appropriate name for the
disease. Cicatricial pemphigoid, another commonly
used name for this process, is derived from the word
cicatrix, meaning scar. When the conjunctival mucosa
is affected, the scarring that results is the most signiﬁ-
cant aspect of this disorder because it invariably results
in blindness unless the condition is recognized and
treated. Interestingly, the oral lesions seldom exhibit
this tendency for scar formation.
CLINICAL FEATURES
Mucous membrane pemphigoid usually affects older
adults, with an average age of 50 to 60 years at the
onset of disease. Females are affected more frequently
than males by a 2:1 ratio. Oral lesions are seen in most
patients, but other sites, such as conjunctival, nasal,
esophageal, laryngeal, and vaginal mucosa, as well as
the skin (Fig. 16-62), may be involved.
The oral lesions of pemphigoid begin as either vesi-
cles or bullae that may occasionally be identiﬁed clini-
cally (Fig. 16-63). In contrast, patients with pemphigus
rarely display such blisters. The most likely explanation
for this difference is that the pemphigoid blister forms
in a subepithelial location, producing a thicker, strong-
er roof than the intraepithelial, acantholytic pemphi-
gus blister. Eventually, the oral blisters rupture, leaving
large, superﬁcial, ulcerated, and denuded areas of
mucosa (Fig. 16-64). The ulcerated lesions are usually
painful and persist for weeks to months if untreated.
Often this process is seen diffusely throughout the
mouth, but it may be limited to certain areas, especially
the gingiva (Fig. 16-65). Gingival involvement produces
a clinical reaction pattern termed desquamative gin-
givitis (see page 162). This pattern may also be seen in
other conditions, such as erosive lichen planus or,
much less frequently, pemphigus vulgaris.
Fig. 16-62 Mucous membrane pemphigoid. Although
cutaneous lesions are not common, tense bullae such as
these may develop on the skin of 20% of affected patients.
(Courtesy of Dr. Charles Camisa.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

772 ORAL AND MAXILLOFACIAL PATHOLOGY
The most signiﬁcant complication of mucous mem-
brane pemphigoid, however, is ocular involvement.
Although exact ﬁgures are not available, up to 25% of
patients with oral lesions may eventually develop
ocular disease. One eye may be affected before the
other. The earliest change is subconjunctival ﬁbrosis,
which usually can be detected by an ophthalmologist
using slit-lamp examination. As the disease progresses,
the conjunctiva becomes inﬂamed and eroded.
Attempts at healing lead to scarring between the bulbar
(lining the globe of the eye) and palpebral (lining the
inner surface of the eyelid) conjunctivae. Adhesions
called symblepharons result (Fig. 16-66). Without
treatment the inﬂammatory changes become more
severe, although conjunctival vesicle formation is rarely
seen (Fig. 16-67). Scarring can ultimately cause the
eyelids to turn inward (entropion). This causes the
eyelashes to rub against the cornea and globe (trichia-
sis) (Fig. 16-68). The scarring closes off the openings
of the lacrimal glands as well, and with the loss of tears,
the eye becomes extremely dry. The cornea then pro-
duces keratin as a protective mechanism; however,
keratin is an opaque material, and blindness ensues.
End-stage ocular involvement may also be character-
ized by adhesions between the upper and lower eyelids
themselves (Fig. 16-69).
Other mucosal sites may also be involved and
cause considerable difﬁculty for the patient. In females,
the vaginal mucosal lesions may cause con siderable
pain during attempts at intercourse (dyspareunia).
Laryngeal lesions, which are fairly uncommon, may
be especially signiﬁcant because of the possibility of
airway obstruction by the bullae that are formed.
Patients who experience a sudden change in vocaliza-
Fig. 16-63 Mucous membrane pemphigoid. One or more
intraoral vesicles, as seen on the soft palate, may be detected
in patients with cicatricial pemphigoid. Usually, ulcerations of
the oral mucosa are also present.
Fig. 16-64 Mucous membrane pemphigoid. Large,
irregular oral ulcerations characterize the lesions after the
initial bullae rupture.
Fig. 16-65 Mucous membrane pemphigoid. Often the
gingival tissues are the only affected site, resulting in a
clinical pattern known as desquamative gingivitis. Such a
pattern may also be seen with lichen planus and pemphigus
vulgaris.
Fig. 16-66 Mucous membrane pemphigoid. Although the
earliest ocular changes are difﬁcult to identify, patients with
ocular involvement may show adhesions (symblepharons)
between the bulbar and palpebral conjunctivae before severe
ocular damage occurs. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 773
Fig. 16-67 Mucous membrane pemphigoid. The disease
has caused the upper eyelid of this patient to turn inward
(entropion), resulting in the eyelashes rubbing against the eye
itself (trichiasis). Also note the obliteration of the lower fornix
of the eye.
Fig. 16-68 Mucous membrane pemphigoid. A patient
with ocular involvement shows severe conjunctival
inﬂammation. An ophthalmologist removed the lower
eyelashes because of trichiasis associated with entropion.
Fig. 16-69 Mucous membrane pemphigoid. In this
patient, the ocular involvement has resulted in nearly
complete scarring between the conjunctival mucosa and the
eyelids themselves, producing blindness.
Fig. 16-70 Mucous membrane pemphigoid. Medium-
power photomicrograph of perilesional tissue shows
characteristic subepithelial clefting.
Fig. 16-71 Mucous membrane pemphigoid. Direct
immunoﬂuorescence studies show a deposition of
immunoreactants at the basement membrane zone of the
epithelium. (Courtesy of Dr. Ronald Grimwood.)
tion or who have difﬁculty breathing should undergo
examination with laryngoscopy.
HISTOPATHOLOGIC FEATURES
Biopsy of perilesional mucosa shows a split between
the surface epithelium and the underlying connective
tissue in the region of the basement membrane (Fig.
16-70). A mild chronic inﬂammatory cell inﬁltrate is
present in the superﬁcial submucosa.
Direct immunoﬂuorescence studies of perilesional
mucosa show a continuous linear band of immunore-
actants at the basement membrane zone in nearly 90%
of affected patients (Fig. 16-71). The immune deposits
consist primarily of IgG and C3, although IgA and IgM `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

774 ORAL AND MAXILLOFACIAL PATHOLOGY
may also be identiﬁed. One study has suggested that,
when IgG and IgA deposits are found in the same
patient, the disease may be more severe. All of these
immunoreactants may play a role in the pathogenesis
of the subepithelial vesicle formation by weakening the
attachment of the basement membrane through a
variety of mechanisms, including complement activa-
tion with recruitment of inﬂammatory cells, particu-
larly neutrophils.
Indirect immunoﬂuorescence is positive in only 5%
to 25% of these patients, indicating a relatively consis-
tent lack of readily detectable circulating autoanti-
bodies. One type of mucous membrane pemphigoid
produces low levels of circulating autoantibodies to
epiligrin (laminin-5), a component of the basement
membrane. Antiepiligrin mucous membrane pemphi-
goid seems to have more widespread involvement,
affecting oral, nasal, ocular, and laryngeal mucosa,
compared with other forms of mucous membrane
pemphigoid. In contrast, another group of investigators
has shown that pemphigoid patients with only oral
mucosal involvement have circulating autoantibodies
to α6 integrin, a component of the hemidesmosome.
For an accurate diagnosis, perilesional tissue—rather
than the ulcerated lesion itself—should be obtained.
Often the epithelium in the area of the lesion is so loose
that it strips off as the clinician attempts to perform the
biopsy. Such tissue is not usually adequate for diagnos-
tic purposes because the interface between the epithe-
lium and connective tissue is no longer intact (although
some investigators have shown positive immunoﬂuo-
rescence with this tissue).
Other relatively rare conditions can mimic pemphi-
goid histopathologically. These include linear IgA
bullous dermatosis, angina bullosa hemorrhagica,
and epidermolysis bullosa acquisita.
LINEAR IgA BULLOUS DERMATOSIS
Linear IgA bullous dermatosis, as the name indicates,
is characterized by the linear deposition of only IgA
along the basement membrane zone. Even though
some cases of mucous membrane pemphigoid may
have IgA antibodies, linear IgA bullous dermatosis pre-
dominantly affects the skin and, therefore, can usually
be distinguished from mucous membrane pemphigoid
on a clinical basis.
ANGINA BULLOSA HEMORRHAGICA
Angina bullosa hemorrhagica is a rare, poorly charac-
terized oral mucosal disorder that exhibits variably
painful, blood-ﬁlled vesicles or bullae, usually affecting
the soft palate of middle-aged or older adults. The blis-
ters typically rupture spontaneously and heal without
scarring. A subepithelial cleft is noted microscopically.
No hematologic or immunopathologic abnormalities
have been detected, and although the cause is unknown,
many patients have a history of trauma or corticoste-
roid inhaler use.
EPIDERMOLYSIS BULLOSA ACQUISITA
Epidermolysis bullosa acquisita is an immunologically
mediated condition characterized by autoantibodies
directed against type VII collagen, the principal com-
ponent of the anchoring ﬁbrils. The anchoring ﬁbrils
play an important role in bonding the epithelium to the
underlying connective tissue. As a result, their immu-
nologic destruction leads to the formation of bullous
lesions of the skin and mucosa with minimal trauma.
Oral lesions are present in nearly 50% of the cases,
although such lesions are uncommon in the absence of
cutaneous lesions. To distinguish epidermolysis bullosa
acquisita from other immunobullous diseases with
subepithelial clefting, a special technique is performed.
A sample of the patient’s perilesional skin is incubated
in a concentrated salt solution; this causes the epithe-
lium to separate from the connective tissue, forming an
artiﬁcially induced bulla. Immunohistochemical evalu-
ation shows deposition of IgG autoantibodies on the
ﬂoor (connective tissue side) of the bulla where type
VII collagen resides. This ﬁnding is in contrast to that
of most forms of mucous membrane pemphigoid, in
which the autoantibodies are usually localized to the
roof of the induced blister.
TREATMENT AND PROGNOSIS
Once the diagnosis of mucous membrane pemphigoid
has been established by light microscopy and direct
immunoﬂuorescence, the patient should be referred to
an ophthalmologist who is familiar with the ocular
lesions of this condition for a baseline examination of
the conjunctivae. This should be done whether or not
the patient is experiencing ocular complaints. In addi-
tion, if the patient is experiencing symptoms at other
anatomic sites, then the appropriate specialist should
be consulted.
Because this condition is characterized by heteroge-
neous pathogenetic mechanisms, it is not surprising
that treatments advocated over the years have been
varied. In fact, there is no single good therapy for every
patient; treatment must be individualized, depending
on lesional distribution, disease activity, and therapeu-
tic response. Perhaps as the various forms of pemphi-
goid are better deﬁned immunopathologically, more
speciﬁc, directed therapy can be devised.
TOPICAL AGENTS
If only oral lesions are present, sometimes the disease
can be controlled with application of one of the more
potent topical corticosteroids to the lesions several `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 775
times each day. Once control is achieved, the applica-
tions can be discontinued, although the lesions are
certain to ﬂare up again. Sometimes alternate-day
application prevents such exacerbations of disease
activity.
Patients with only gingival lesions often beneﬁt from
good oral hygiene measures, which can help to decrease
the severity of the lesions and reduce the amount of
topical corticosteroids required. As an additional aid in
treating gingival lesions, a ﬂexible mouth guard may be
fabricated to use as a carrier for the corticosteroid
medication.
SYSTEMIC AGENTS
If topical corticosteroids are unsuccessful, systemic
corticosteroids plus other immunosuppressive agents
(particularly cyclophosphamide) may be used if the
patient has no medical contraindications. This type of
aggressive treatment is absolutely indicated in the pres-
ence of advancing ocular disease. Recent studies have
suggested that treatment with intravenous (IV) human
immunoglobulin may be more effective in managing
ocular lesions of pemphigoid than systemic corticoste-
roid therapy. Attempts at surgical correction of any
symblepharons that might have formed must be done
when the disease is under control or quiescent; other-
wise, the manipulation often induces an acute ﬂare of
the ocular lesions.
For patients with mild-to-moderate involvement by
mucous membrane pemphigoid, an alternative sys-
temic therapy that may produce fewer serious side
effects is the use of dapsone, a sulfa drug derivative.
Some centers report good results with dapsone, but
others observe that a minority of patients respond ade-
quately. Contraindications to its use include glucose-6-
phosphate dehydrogenase deﬁciency or allergy to sulfa
drugs.
Another alternative systemic therapy that may be
used for patients with less severe disease is tetracycline
or minocycline and niacinamide (nicotinamide). Sys-
temic daily divided doses of 0.5 to 2.0 g of each drug
have been reported (in open-label trials) to be effective
in controlling mucous membrane pemphigoid. Double-
blind, placebo-controlled studies on larger groups of
patients should be done to conﬁrm this form of therapy,
however.
BULLOUS PEMPHIGOID
Bullous pemphigoid is the most common of the auto-
immune blistering conditions, occurring at an esti-
mated rate of 10 cases per million population per year.
The disease is characterized by the production of auto-
antibodies directed against components of the base-
ment membrane. In many respects, bullous pemphigoid
resembles mucous membrane pemphigoid, but most
investigators note that there are enough differences to
consider these diseases as distinct but related entities.
One signiﬁcant difference is that the clinical course in
patients with bullous pemphigoid is usually limited,
whereas the course in patients with cicatricial pemphi-
goid is usually protracted and progressive.
CLINICAL FEATURES
Bullous pemphigoid typically develops in older people;
most patients are between 60 and 80 years of age. No
sex or racial predilection is generally reported, although
one group of investigators noted that men are over-
represented in this disease by a 2:1 margin when one
corrects for the skewing of the aging population toward
the female gender. Pruritus may be an early symptom.
This is followed by the development of multiple, tense
bullae on either normal or erythematous skin (Fig.
16-72). These lesions eventually rupture after several
days, causing a superﬁcial crust to form. Eventually,
healing takes place without scarring.
Oral mucosal involvement is uncommon, although
the reported prevalence in several series of cases has
ranged from 8% to 39%. Referral bias may explain the
discrepancy in prevalence rates. The oral lesions, like
the skin lesions, begin as bullae, but they tend to rupture
sooner, probably as a result of the constant low-grade
trauma to which the oral mucosa is subjected. Large,
shallow ulcerations with smooth, distinct margins are
present after the bullae rupture (Fig. 16-73).
HISTOPATHOLOGIC FEATURES
Microscopic examination of tissue obtained from the
perilesional margin of a bulla shows separation of the
epithelium from the connective tissue at the basement
Fig. 16-72 Bullous pemphigoid. Cutaneous
vesiculobullous lesions of the heel. The bullae eventually
rupture, leaving hemorrhagic crusted areas. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

776 ORAL AND MAXILLOFACIAL PATHOLOGY
membrane zone, resulting in a subepithelial separa-
tion. Modest numbers of both acute and chronic inﬂam-
matory cells are typically seen in the lesional area, and
the presence of eosinophils within the bulla itself is
characteristic.
Direct immunoﬂuorescence studies show a continu-
ous linear band of immunoreactants, usually IgG and
C3, localized to the basement membrane zone in 90%
to 100% of affected patients. These antibodies may bind
to proteins associated with hemidesmosomes, struc-
tures that bind the basal cell layer of the epithelium to
the basement membrane and the underlying connec-
tive tissue. These proteins have been designated as
bullous pemphigoid antigens (BP180 and BP230),
and immunoelectron microscopy has demonstrated
the localization of BP180 to the upper portion of the
lamina lucida of the basement membrane.
In addition to the tissue-bound autoantibodies, 50%
to 90% of the patients also have circulating autoanti-
bodies in the serum, producing an indirect immuno-
ﬂuorescent pattern that is identical to that of the direct
immunoﬂuorescence. Unlike pemphigus vulgaris, the
antibody titers seen in bullous pemphigoid do not
appear to correlate with disease activity. The antibod-
ies alone do not appear to be capable of inducing bullae
in this disease. Instead, binding of the antibodies to the
basement membrane initiates the complement cascade,
which in turn results in degranulation of mast cells,
with recruitment of neutrophils and eosinophils to the
area. The damage to the basement membrane is thought
to be mediated by elastases and matrix metalloprotein-
ases released by these inﬂammatory cells.
TREATMENT AND PROGNOSIS
Management of the patient with bullous pemphigoid
consists of systemic immunosuppressive therapy. Mod-
erate daily doses of systemic prednisone usually control
the condition, after which alternate-day therapy may
be given to reduce the risk of corticosteroid complica-
tions. If the lesions do not respond to prednisone alone,
then another immunosuppressive agent, such as aza-
thioprine, may be added to the regimen. Dapsone, a
sulfa derivative, may be used as an alternative thera-
peutic agent, and tetracycline and niacinamide therapy
is reported to be effective for some patients. The more
severe, resistant cases require prednisone combined
with cyclophosphamide; however, this regimen has the
potential for signiﬁcant side effects.
The prognosis is generally good, with many patients
experiencing spontaneous remission after 2 to 5 years.
Problems may develop with immunosuppressive
therapy in this older adult population, however, and
mortality rates of up to 27% have been reported in
some series.
ERYTHEMA MULTIFORME
Erythema multiforme is a blistering, ulcerative muco-
cutaneous condition of uncertain etiopathogenesis.
This is probably an immunologically mediated process,
although the cause is poorly understood. In about 50%
of the cases, the clinician can identify either a preced-
ing infection, such as herpes simplex or Mycoplasma
pneumoniae, or exposure to any one of a variety of drugs
and medications, particularly antibiotics or analgesics.
These agents may trigger the immunologic derange-
ment that produces the disease. Sophisticated tech-
niques in molecular biology have demonstrated the
presence of herpes simplex DNA in patients with recur-
rent erythema multiforme, thus supporting the concept
of an immunologic precipitating event. Interestingly,
direct and indirect immunoﬂuorescence studies are
nonspeciﬁc and are not really very useful diagnostically
except to rule out other vesiculobullous diseases.
A spectrum of severity of this disease has been rec-
ognized for many years, ranging from erythema mul-
tiforme minor through erythema multiforme major
(traditionally thought to be synonymous with Stevens-
Johnson syndrome) and toxic epidermal necrolysis
(Lyell’s disease). Recent publications have suggested
that erythema multiforme minor and major may rep-
resent a distinctly different process from the latter two
conditions. However, considerable overlap in the clini-
cal features of erythema multiforme major and Stevens-
Johnson syndrome is seen, and this classiﬁcation
scheme remains controversial.
CLINICAL FEATURES
Erythema multiforme usually has an acute onset and
may display a wide spectrum of clinical disease. On the
mild end of the spectrum, ulcerations develop, affect-
Fig. 16-73 Bullous pemphigoid. These oral lesions appear
as large, shallow ulcerations involving the soft palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 777
ing the oral mucosa primarily. In its most severe form,
diffuse sloughing and ulceration of the entire skin and
mucosal surfaces may be seen (toxic epidermal necrol-
ysis or Lyell’s disease).
Patients affected by erythema multiforme are usually
young adults in their 20s or 30s. Men are affected more
frequently than women.
Prodromal symptoms include fever, malaise, head-
ache, cough, and sore throat, occurring approximately
1 week before onset. Although the disease is self-limit-
ing, usually lasting 2 to 6 weeks, about 20% of patients
experience recurrent episodes, usually in the spring
and autumn.
Erythematous skin lesions develop in about 50% of
cases. A variety of appearances (multiforme means
many forms) may be present. Typically, early lesions
appear on the extremities and are ﬂat, round, and
dusky-red in hue. These become slightly elevated
and may evolve into bullae with necrotic centers.
Sometimes particular skin lesions develop that are
highly characteristic for the disease. These lesions
appear as concentric circular erythematous rings
resembling a target or bull’s-eye (target lesions) (Fig.
16-74).
The oral lesions begin as erythematous patches that
undergo epithelial necrosis and evolve into large,
shallow erosions and ulcerations with irregular borders
(Fig. 16-75). Hemorrhagic crusting of the vermilion
zone of the lips is common (Fig. 16-76). These oral
lesions, like the skin lesions, emerge quickly and are
uncomfortable. Sometimes patients are dehydrated
because they are unable to ingest liquids as a result of
mouth pain. The ulcerations often have a diffuse distri-
bution. The lips, labial mucosa, buccal mucosa, tongue,
ﬂoor of the mouth, and soft palate are the most common
sites of involvement. Usually, the gingivae and hard
palate are relatively spared.
ERYTHEMA MULTIFORME MAJOR
A more severe form of the disease, known as erythema
multiforme major or Stevens-Johnson syndrome, is usually
triggered by a drug rather than infection. For such a
diagnosis to be made, either the ocular (Fig. 16-77) or
genital (Fig. 16-78) mucosae should be affected in con-
junction with the oral and skin lesions. With severe
ocular involvement, scarring (symblepharon forma-
tion) may occur, similar to that in cicatricial pemphi-
goid (see page 772).
TOXIC EPIDERMAL NECROLYSIS
Many dermatologists consider toxic epidermal necrol-
ysis to represent the most severe form of erythema
Fig. 16-74 Erythema multiforme. The concentric
erythematous pattern of the cutaneous lesions on the ﬁngers
resembles a target or bull’s-eye.
Fig. 16-75 Erythema multiforme. Diffuse ulcerations and
erosions involving the dorsal surface of this patient’s tongue.
Fig. 16-76 Erythema multiforme. Ulceration of the labial
mucosa, with hemorrhagic crusting of the vermilion zone of
the lips. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

778 ORAL AND MAXILLOFACIAL PATHOLOGY
multiforme. It is almost always triggered by drug
exposure, with more than 200 different medications
having been implicated. Recent studies have shown
that the damage to the epithelium is due to increased
apoptosis of the epithelial cells. Diffuse sloughing of a
signiﬁcant proportion of the skin and mucosal surfaces
makes it appear as if the patient had been badly scalded
(Figs. 16-79 and 16-80). In contrast to erythema mul-
tiforme major, toxic epidermal necrolysis tends to
occur in older people. A female predilection is observed.
If the patient survives, then the cutaneous process
resolves in 2 to 4 weeks; however, oral lesions may take
longer to heal, and signiﬁcant residual ocular damage
is evident in half the patients. These more severe pre-
sentations of erythema multiforme are rare. Erythema
multiforme major occurs at an average rate of ﬁve
cases per million population per year, and toxic epider-
mal necrolysis occurs at a rate of about one case per
million per year.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of the perilesional mucosa
in erythema multiforme reveals a pattern that is char-
acteristic but not pathognomonic. Subepithelial or
intraepithelial vesiculation may be seen in association
with necrotic basal keratinocytes (Fig. 16-81). A mixed
inﬂammatory inﬁltrate is present, consisting of lym-
phocytes, neutrophils, and often eosinophils. Some-
times these cells are arranged in a perivascular
orientation (Fig. 16-82). Because the immunopatho-
logic features are also nonspeciﬁc, the diagnosis is
often based on the clinical presentation and the exclu-
sion of other vesiculobullous disorders.
Fig. 16-77 Stevens-Johnson syndrome. With erythema
multiforme major (Stevens-Johnson syndrome), other mucosal
surfaces may show involvement, such as the severe
conjunctivitis depicted in this photograph.
Fig. 16-78 Stevens-Johnson syndrome. Genital
ulcerations, demonstrated in this patient by the involvement
of the glans penis, may also be a component.
Fig. 16-79 Toxic epidermal necrolysis. This severe form of
erythema multiforme exhibits diffuse bullous skin lesions.
(Courtesy of Dr. Peter Larsen.)
Fig. 16-80 Toxic epidermal necrolysis. The desquamation
of the skin of the foot is characteristic of the diffuse sloughing
cutaneous lesions. (Courtesy of Dr. Peter Larsen.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 779
TREATMENT AND PROGNOSIS
Management of erythema multiforme, in many
respects, remains controversial. In the past, the use of
systemic or topical corticosteroids was often advocated,
especially in the early stages of the disease. There is
little good clinical evidence that such treatment alters
the course of this disease, however. If a causative drug
is identiﬁed or suspected, then it should be discontin-
ued immediately.
If the patient is dehydrated as a result of an inability
to eat because of oral pain, then intravenous rehydra-
tion may be necessary along with topical anesthetic
agents to decrease discomfort.
If recurrent episodes of erythema multiforme are a
problem, then an initiating factor, such as recurrent
herpesvirus infection or drug exposure, should be
sought. If disease is triggered by herpes simplex, then
continuous oral acyclovir or valacyclovir therapy can
prevent recurrences.
Generally, erythema multiforme is not life threaten-
ing except in its most severe forms. The mortality rate
in patients with toxic epidermal necrolysis historically
has been approximately 34%; the rate in those with
Stevens-Johnson syndrome is 2% to 10%. Corticoste-
roids should be avoided in the management of toxic
epidermal necrolysis because some investigators have
found that such drugs may be detrimental. Intravenous
administration of pooled human immunoglobulins has
been shown in several open-label trials to produce
remarkable resolution of toxic epidermal necrolysis,
presumably because of blockade of Fas ligand, which
is believed to be responsible for inducing epithelial cell
apoptosis. Because the lesions of toxic epidermal
necrolysis are analogous to those suffered by burn
patients, management of these patients in the burn unit
of the hospital is recommended.
ERYTHEMA MIGRANS (GEOGRAPHIC
TONGUE; BENIGN MIGRATORY
GLOSSITIS; WANDERING RASH OF
THE TONGUE; ERYTHEMA AREATA
MIGRANS; STOMATITIS
AREATA MIGRANS)
Erythema migrans is a common benign condition
that primarily affects the tongue. It is often detected on
routine examination of the oral mucosa. The lesion
occurs in 1% to 3% of the population. Females are
affected more frequently than males by a 2:1 ratio.
Patients may occasionally consult a health care profes-
sional if they happen to notice the unusual appearance
of their tongue or if the lingual mucosa becomes sensi-
tive to hot or spicy foods as a result of the process.
Even though erythema migrans has been docu-
mented for many years, the etiopathogenesis is still
unknown. Some investigators have suggested that ery-
thema migrans occurs with increased frequency in
atopic individuals; however, one recent large epidemi-
ologic study in the United States found no statistically
signiﬁcant association between erythema migrans and
a variety of conditions that had previously been postu-
lated either to cause or inﬂuence this process. Ery-
thema migrans was not seen as frequently in cigarette
smokers, while there seemed to be no signiﬁcant dif-
ferences in frequency related to age, sex, oral contra-
ceptive use, presence of allergies, diabetes mellitus, or
psychological or dermatologic conditions.
Fig. 16-81 Erythema multiforme. This medium-power
photomicrograph shows inﬂammation and intraepithelial
vesicle formation in the basilar portion of the epithelium.
Numerous necrotic eosinophilic keratinocytes are present in
the blister area.
Fig. 16-82 Erythema multiforme. This medium-power
photomicrograph shows the perivascular inﬂammatory
inﬁltrate, typically seen in erythema multiforme. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

780 ORAL AND MAXILLOFACIAL PATHOLOGY
CLINICAL FEATURES
The characteristic lesions of erythema migrans are
seen on the anterior two thirds of the dorsal tongue
mucosa. They appear as multiple, well-demarcated
zones of erythema (Figs. 16-83 and 16-84), concen-
trated at the tip and lateral borders of the tongue. This
erythema is due to atrophy of the ﬁliform papillae, and
these atrophic areas are typically surrounded at least
partially by a slightly elevated, yellow-white, serpen-
tine or scalloped border (Fig. 16-85). The patient who
is aware of the process is often able to describe the
lesions as appearing quickly in one area, healing within
a few days or weeks, then developing in a very different
area. Frequently, the lesion begins as a small white
patch, which then develops a central erythematous
atrophic zone and enlarges centrifugally. Often patients
with ﬁssured tongue (see page 13) are affected with
erythema migrans as well. Some patients may have
only a solitary lesion, but this is uncommon. The lesions
are usually asymptomatic, although a burning sensa-
tion or sensitivity to hot or spicy foods may be noted
when the lesions are active. Only rarely is the burning
sensation more constant and severe.
Very infrequently, erythema migrans may occur on
oral mucosal sites other than the tongue. In these
instances, the tongue is almost always affected; however,
other lesions develop on the buccal mucosa, on the
labial mucosa, and (less frequently) on the soft palate
(Figs. 16-86 and 16-87). These lesions typically produce
no symptoms and can be identiﬁed by a yellow-white
serpentine or scalloped border that surrounds an
erythematous zone. These features should prevent
confusion with such conditions as candidiasis or
erythroplakia.
Fig. 16-83 Erythema migrans. The erythematous, well-
demarcated areas of papillary atrophy are characteristic of
erythema migrans affecting the tongue (benign migratory
glossitis). Note the asymmetrical distribution and the
tendency to involve the lateral aspects of the tongue.
Fig. 16-84 Erythema migrans. Lingual mucosa of a
different patient than the one in Fig. 16-83. The lateral
distribution of the lesions is shown.
Fig. 16-85 Erythema migrans. Striking involvement of the
dorsal and lateral surfaces of the tongue.
Fig. 16-86 Erythema migrans. Lesions of the lower labial
mucosa. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 781
HISTOPATHOLOGIC FEATURES
If a biopsy specimen of the peripheral region of ery-
thema migrans is examined, a characteristic histo-
pathologic pattern is observed. Hyperparakeratosis,
spongiosis, acanthosis, and elongation of the epithelial
rete ridges are seen (Fig. 16-88). In addition, collec-
tions of neutrophils (Munro abscesses) are observed
within the epithelium (Fig. 16-89); lymphocytes and
neutrophils involve the lamina propria. The intense
neutrophilic inﬁltrate may be responsible for the
destruction of the superﬁcial portion of the epithelium,
thus producing an atrophic, reddened mucosa as the
lesion progresses. Because these histopathologic fea-
tures are reminiscent of psoriasis, this is called a pso-
riasiform mucositis. Despite the apparent lack of
association between dermatologic conditions and ery-
thema migrans in one recent report, another case-
control study of psoriatic patients showed that erythema
migrans occurred at a rate of about 10%; only 2.5% of
an age-matched and sex-matched population were
affected. A Brazilian study determined that both
patients with psoriasis and those with benign migratory
glossitis were more likely to have the same human
leukocyte antigen (HLA) group, namely HLA-Cw6.
Whether these ﬁndings mean that erythema migrans
represents oral psoriasis or that patients with psoriasis
are just more susceptible to erythema migrans is open
to debate.
TREATMENT AND PROGNOSIS
Generally no treatment is indicated for patients with
erythema migrans. Reassuring the patient that the con-
dition is completely benign is often all that is necessary.
Infrequently, patients may complain of tenderness or
a burning sensation that is so severe that it disrupts
their lifestyle. In such cases, topical corticosteroids,
such as ﬂuocinonide or betamethasone gel, may
provide relief when applied as a thin ﬁlm several times
a day to the lesional areas.
REACTIVE ARTHRITIS
(REITER’S SYNDROME)
Reactive arthritis represents a group of uncommon
diseases that most likely have an immunologically
mediated cause. Current evidence suggests that these
disorders may be triggered by any one of several infec-
tious agents in a genetically susceptible person. In
some instances, the arthritis will be accompanied by
Fig. 16-87 Erythema migrans. These palatal lesions show
well-demarcated erythematous areas surrounded by a white
border, similar to the process involving the tongue.
Fig. 16-88 Erythema migrans. This low-power
photomicrograph shows the elongation of the rete ridges
with parakeratosis and neutrophilic inﬁltration. Such features
are also common in psoriasis, which explains why this is
known as a psoriasiform mucositis.
Fig. 16-89 Erythema migrans. This medium-power
photomicrograph shows collections of neutrophils in the
superﬁcial spinous layer of the epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

782 ORAL AND MAXILLOFACIAL PATHOLOGY
mucocutaneous ﬁndings, including oral lesions. A
classic triad of signs has been described:
1. Nongonococcal urethritis
2. Arthritis
3. Conjunctivitis
However, most patients do not exhibit all three of
these signs. Although reactive arthritis with a mucocu-
taneous component is also known as Reiter syndrome,
some authors have advocated removing the Reiter
eponym because of Hans Reiter’s Nazi criminal activi-
ties during World War II and he was not the ﬁrst to
describe this syndrome.
It is interesting that reactive arthritis has been
reported with some frequency in patients infected with
the human immunodeﬁciency virus (HIV).
CLINICAL FEATURES
Reactive arthritis is particularly prevalent in young
adult men. According to most series, there is a male-to-
female ratio of 9:1. The majority (60% to 90%) of these
patients are positive for HLA-B27, a haplotype present
in only 4% to 8% of the population. The syndrome
usually develops 1 to 4 weeks after an episode of dys-
entery or venereal disease; in fact, two French physi-
cians published a description of this entity affecting
four postdysenteric soldiers 1 week before Reiter’s
paper appeared.
Urethritis is often the ﬁrst sign and is seen in both
affected males and females. Females may also have
inﬂammation of the uterine cervix. Conjunctivitis
usually appears concurrently with the urethritis, and
after several days, arthritis ensues. The arthritis usually
affects the joints of the lower extremities, although TMJ
involvement has been identiﬁed in one third of these
patients, typically as erosion of the condylar head. Skin
lesions often take the form of a characteristic lesion of
the glans penis (balanitis circinata). These lesions
develop in about 20% to 30% of patients with reactive
arthritis, and they appear as well-circumscribed ery-
thematous erosions with a scalloped, whitish linear
boundary.
The oral lesions, which occur in slightly less than
20% of patients with this disorder, are described in
various ways. Some reports mention painless erythem-
atous papules distributed on the buccal mucosa and
palate; other reports describe shallow, painless ulcers
that affect the tongue, buccal mucosa, palate, and
gingiva. Some authors have even implied that geo-
graphic tongue may be a component of reactive
arthritis, probably because geographic tongue bears a
superﬁcial resemblance to the lesions of balanitis
circinata.
The American Rheumatism Association has deﬁned
reactive arthritis based on the clinical ﬁndings of a
peripheral arthritis that lasts longer than 1 month in
conjunction with urethritis, cervicitis, or both.
HISTOPATHOLOGIC FEATURES
The histopathologic ﬁndings of the cutaneous lesions
in patients with reactive arthritis are frequently similar
to those found in patients with psoriasis, particularly
with respect to the presence of microabscesses within
the superﬁcial layers of the surface epithelium. Other
features in common with psoriasis include hyperpara-
keratosis with elongated, thin rete ridges.
TREATMENT AND PROGNOSIS
Some patients with reactive arthritis experience spon-
taneous resolution of their disease after 3 to 12 months,
but many others have chronic symptoms that may
wax and wane. Treatment may not be necessary for
the milder cases. Nonsteroidal antiinﬂammatory
drugs (NSAIDs) are initially used for managing arthri-
tis, and sulfasalazine may be helpful in resolving
cases that do not respond. Immunosuppressive agents,
including corticosteroids, azathioprine, and methotrex-
ate, are reserved for the most resistant cases if they are
not associated with HIV infection.
Physical therapy probably helps to reduce joint
ﬁbrosis associated with arthritis. About 10% to 25% of
patients with this disorder have severe disability,
usually from arthritis.
LICHEN PLANUS
Lichen planus is a relatively common, chronic derma-
tologic disease that often affects the oral mucosa. The
strange name of the condition was provided by the
British physician Erasmus Wilson, who ﬁrst described
it in 1869. Lichens are primitive plants composed of
symbiotic algae and fungi. The term planus is Latin for
ﬂat. Wilson probably thought that the skin lesions
looked similar enough to the lichens growing on rocks
to merit this designation. Even though the term lichen
planus suggests a ﬂat, fungal condition, current evi-
dence indicates that this is an immunologically medi-
ated mucocutaneous disorder.
A variety of medications may induce lesions that
can appear clinically very similar to the idiopathic
form of the condition; however, the term lichenoid
mucositis (or lichenoid dermatitis, depending on
the site involved) is probably a better name for the
drug-related alterations (see page 347). Similarly,
foreign material that becomes inadvertently em-
bedded in the gingiva may elicit a host response that
is termed lichenoid foreign body gingivitis (see page
160). Reports of hepatitis C infection associated with `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 783
oral lichen planus occasionally have appeared in the
literature, usually from the Mediterranean countries,
but this does not appear to be a signiﬁcant association
in the United States or Great Britain. More recent,
carefully controlled epidemiologic studies do not
appear to support an association of oral lichen planus
with hepatitis C. However, genetic inﬂuences presum-
ably may have an effect on the expression of lichen
planus in select populations.
The relationship of stress or anxiety to the develop-
ment of lichen planus is controversial, and most cited
cases appear to be anecdotal or lack appropriate con-
trols. Those studies that have applied psychologic ques-
tionnaires often ﬁnd increased levels of anxiety in these
patients; however, many patients who have been told
that they have lichen planus are aware that anxiety has
been linked to the disorder. Whether this awareness
may inﬂuence the manner in which they answer the
psychologic questionnaires could be debated. In one
study that used psychologic questionnaires to attempt
to resolve this question, patients with oral lichen planus
had no greater degree of stress in their lives than did
age-matched and sex-matched control patients. It
might be that stress has no bearing on the pathogenesis
of lichen planus; however, an alternative explanation
might be that those patients who have lichen planus
simply respond in this fashion to levels of stress that do
not induce lesions in other people.
CLINICAL FEATURES
Most patients with lichen planus are middle-aged
adults. It is rare for children to be affected. Women
predominate in most series of cases, usually by a 3:2
ratio over men. Approximately 1% of the population
may have cutaneous lichen planus. The prevalence of
oral lichen planus is between 0.1% and 2.2%.
The skin lesions of lichen planus have been classi-
cally described as purple, pruritic, polygonal papules
(Fig. 16-90). These usually affect the ﬂexor surfaces of
the extremities. Excoriations may not be visible, despite
the fact that the lesions itch, because it hurts the patient
when he or she scratches them.
Careful examination of the surface of the skin
papules reveals a ﬁne, lacelike network of white lines
(Wickham’s striae). Other sites of extraoral involve-
ment include the glans penis, the vulvar mucosa, and
the nails (Fig. 16-91). Essentially there are two forms
of oral lesions: reticular and erosive.
RETICULAR LICHEN PLANUS
Reticular lichen planus is much more common than
the erosive form, but the erosive form predominates in
several studies. This is probably because of referral bias
(because the erosive form is symptomatic and, there-
fore, the patient is more likely to be referred to an
academic center for evaluation). The reticular form
usually causes no symptoms and involves the posterior
buccal mucosa bilaterally (Figs. 16-92 and 16-93).
Other oral mucosal surfaces may also be involved
concurrently, such as the lateral and dorsal tongue,
the gingivae, the palate, and vermilion border (Fig.
16-94).
Reticular lichen planus is thus named because of its
characteristic pattern of interlacing white lines (also
referred to as Wickham’s striae); however, the white
lesions may appear as papules in some instances. These
lesions are typically not static but wax and wane over
weeks or months (Fig. 16-95). The reticular pattern
may not be as evident in some sites, such as the dorsal
tongue, where the lesions appear more as keratotic
plaques with atrophy of the papillae (Fig. 16-96). In
Fig. 16-90 Lichen planus. The cutaneous lesions on the
wrist appear as purple, polygonal papules. Careful
examination shows a network of ﬁne white lines (Wickham’s
striae) on the surface of the papules.
Fig. 16-91 Lichen planus. Dysplastic appearance of the
ﬁngernails. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

784 ORAL AND MAXILLOFACIAL PATHOLOGY
Fig. 16-92 Lichen planus. The interlacing white lines are
typical of reticular lichen planus involving the posterior
buccal mucosa, the most common site of oral involvement.
Fig. 16-93 Lichen planus. Diffuse papular and reticular
lesions of the right buccal mucosa.
Fig. 16-94 Lichen planus. Reticular lesions of the lower lip
vermilion.
A B
Fig. 16-95 Lichen planus. A, A middle-aged woman with mild reticular lichen planus of the
left buccal mucosa. B, Same patient 2 weeks later, showing exacerbation of the lesions. Such
waxing and waning is characteristic of lichen planus.
Fig. 16-96 Lichen planus. With involvement of the dorsal
tongue by reticular lichen planus, the characteristic
interlacing striae seen in the buccal mucosal lesions are
usually not present. Instead, smooth white plaques are
typically observed replacing the normal papillary surface of
the tongue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 785
sional tissue, because mucous membrane pemphigoid
(see page 771) and pemphigus vulgaris (see page 765)
may appear in a similar fashion.
If the erosive component is severe, epithelial separa-
tion from the underlying connective tissue may occur.
This results in the relatively rare presentation of
bullous lichen planus.
HISTOPATHOLOGIC FEATURES
The histopathologic features of lichen planus are char-
acteristic but may not be speciﬁc, because other condi-
tions, such as lichenoid drug reaction, lichenoid
amalgam reaction, oral graft-versus-host disease
(GVHD), lupus erythematosus (LE), chronic ulcer-
ative stomatitis, and oral mucosal cinnamon reac-
tion may also show a similar histopathologic pattern.
A B
Fig. 16-97 Lichen planus. Ulceration of the buccal mucosa
shows peripheral radiating keratotic striae, characteristic of
oral erosive lichen planus.
Fig. 16-98 Lichen planus. A, The dorsal surface of the tongue shows extensive ulceration
caused by erosive lichen planus. Note the ﬁne white streaks at the periphery of the
ulcerations. B, Same patient after systemic corticosteroid therapy. Much of the mucosa has
reepithelialized, with only focal ulcerations remaining.
Fig. 16-99 Lichen planus. Erosive lichen planus often
appears as a desquamative gingivitis, producing gingival
erythema and tenderness.
addition, superﬁcial mucoceles may develop within, or
adjacent to, mucosal areas that are involved by lichen
planus.
EROSIVE LICHEN PLANUS
Erosive lichen planus, although not as common as
the reticular form, is more signiﬁcant for the patient
because the lesions are usually symptomatic. Clini-
cally, there are atrophic, erythematous areas with
central ulceration of varying degrees. The periphery of
the atrophic regions is usually bordered by ﬁne, white
radiating striae (Figs. 16-97 and 16-98). Sometimes the
atrophy and ulceration are conﬁned to the gingival
mucosa, producing the reaction pattern called desqua-
mative gingivitis (see page 162) (Fig. 16-99). In such
cases, biopsy specimens should be obtained for light
microscopic and immunoﬂuorescent studies of perile- `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

786 ORAL AND MAXILLOFACIAL PATHOLOGY
Varying degrees of orthokeratosis and parakeratosis
may be present on the surface of the epithelium,
depending on whether the biopsy specimen is taken
from an erosive or reticular lesion.
The thickness of the spinous layer can also vary. The
rete ridges may be absent or hyperplastic, but they
classically have a pointed or “saw-toothed” shape (Fig.
16-100).
Destruction of the basal cell layer of the epithelium
(hydropic degeneration) is also evident. This is
accompanied by an intense, bandlike inﬁltrate of pre-
dominantly T lymphocytes immediately subjacent to
the epithelium (Fig. 16-101). Degenerating keratino-
cytes may be seen in the area of the epithelium and
connective tissue interface and have been termed
colloid, cytoid, hyaline, or Civatte bodies. No sig-
niﬁcant degree of epithelial atypia is expected in oral
lichen planus, although lesions having a superimposed
candidal infection may appear worrisome. These
should be reevaluated histopathologically after the
candidal infection is treated. On occasion, the chronic
inﬂammatory host response to the atypical cells of
epithelial dysplasia can appear virtually indistin-
guishable histopathologically from lichen planus, par-
ticularly in milder cases of epithelial dysplasia. Such
ambiguity may contribute to the controversy related
to the malignant transformation potential of lichen
planus.
A B
Fig. 16-100 Lichen planus. A, This low-power photomicrograph of an oral lesion shows
hyperkeratosis, saw-toothed rete ridges, and a bandlike inﬁltrate of lymphocytes immediately
subjacent to the epithelium. B, Higher-power view showing migration of lymphocytes into the
lower epithelium with interface degeneration of the basal cell layer.
A B
Fig. 16-101 Lichen planus. A, High-power photomicrograph of normal epithelium showing
an intact basal cell layer and no inﬂammation. B, High-power photomicrograph of lichen
planus showing degeneration of the basal epithelial layer and an intense lymphocytic inﬁltrate
in the superﬁcial lamina propria. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 787
The immunopathologic features of lichen planus are
nonspeciﬁc. Most lesions show the deposition of a
shaggy band of ﬁbrinogen at the basement membrane
zone.
DIAGNOSIS
The diagnosis of reticular lichen planus can often be
made based on the clinical ﬁndings alone. The interlac-
ing white striae appearing bilaterally on the posterior
buccal mucosa are virtually pathognomonic. Difﬁcul-
ties in diagnosis may arise if candidiasis is superim-
posed on the lesions because the organism may disturb
the characteristic reticular pattern of the lichen planus
(Fig. 16-102).
Erosive lichen planus is sometimes more challeng-
ing to diagnose (based on clinical features alone) than
the reticular form. If the typical radiating white striae
and erythematous, atrophic mucosa are present at the
periphery of well-demarcated ulcerations on the pos-
terior buccal mucosa bilaterally, then the diagnosis can
sometimes be rendered without the support of histo-
pathologic ﬁndings. However, a biopsy is often neces-
sary to rule out other ulcerative or erosive diseases,
such as lupus erythematosus or chronic ulcerative
stomatitis.
Specimens of isolated erosive lichenoid lesions, par-
ticularly those of the soft palate, the lateral and ventral
tongue, or the ﬂoor of the mouth, should be obtained
for biopsy to rule out premalignant changes or malig-
nancy. Another condition that may mimic an isolated
lesion of lichen planus, both clinically and histopatho-
logically, is a lichenoid reaction to dental amalgam
(see page 354).
TREATMENT AND PROGNOSIS
Reticular lichen planus typically produces no symp-
toms, and no treatment is needed. Occasionally,
affected patients may have superimposed candidiasis,
in which case they may complain of a burning sensa-
tion of the oral mucosa. Antifungal therapy is necessary
in such a case. Some investigators recommend annual
reevaluation of the reticular lesions of oral lichen
planus.
Erosive lichen planus is often bothersome because
of the open sores in the mouth. Because it is an immu-
nologically mediated condition, corticosteroids are
recommended. The lesions respond to systemic
corticosteroids, but such drastic therapy is usually not
necessary. One of the stronger topical corticosteroids
(e.g., ﬂuocinonide, betamethasone, clobetasol gel)
applied several times per day to the most symptomatic
areas is usually sufﬁcient to induce healing within 1
or 2 weeks. Some investigators have recommended
compounding corticosteroid ointments with an adhe-
sive methylcellulose base, but patient compliance
may be reduced because this material is difﬁcult to
apply. The patient should be warned that the condition
will undoubtedly ﬂare up again, in which case the
corticosteroids should be reapplied. In addition, the
possibility of iatrogenic candidiasis associated with
corticosteroid use should be monitored (Fig. 16-103).
Although the use of agents such as topical retinoids,
A B
Fig. 16-102 Lichen planus. A, These relatively nondescript white lesions affected the buccal
mucosa of a patient who had complained of a burning sensation. Histopathologic evaluation of
the lesion showed a lichenoid mucositis with superimposed candidiasis. B, Same patient 2
weeks after antifungal therapy. Once the mucosal reaction to the candidal organism was
eliminated, the characteristic white striae of reticular lichen planus were identiﬁed. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

788 ORAL AND MAXILLOFACIAL PATHOLOGY
tacrolimus, or cyclosporine has occasionally been
advocated for recalcitrant cases of erosive lichen
planus, reports of their efﬁcacy have been contradic-
tory. Furthermore, their side effects can be signiﬁcant,
and in the case of cyclosporine, the cost of the drug
may be prohibitive. Some investigators suggest that
patients with oral erosive lichen planus be evaluated
every 3 to 6 months, particularly if the lesions are not
typical.
The question of the malignant potential of lichen
planus, particularly the erosive form, is yet to be
resolved. Most cases of reported malignant transforma-
tion are rather poorly documented. Some of these
reported cases may not have been true lichen planus,
but rather they may have actually been dysplastic leu-
koplakias with a secondary lichenoid inﬂammatory
inﬁltrate that mimicked lichen planus (“lichenoid dys-
plasia”). In addition, the argument can be made that
because both lichen planus and squamous cell carci-
noma are not rare, some people may have both prob-
lems simultaneously, and the two processes may be
unrelated to one another. Conversely, some investiga-
tors say that the atrophic epithelium of lichen planus
may be more susceptible to the action of carcinogens,
resulting in an increased risk of malignant transforma-
tion. One study examined the molecular characteris-
tics of classic reticular lichen planus, comparing the
loss of heterozygosity at purported tumor suppressor
gene loci in these lesions with that of varying grades of
oral epithelial dysplasia, squamous cell carcinoma,
normal oral mucosa, and oral reactive lesions. The
molecular proﬁle of oral lichen planus more closely
resembled that of normal or reactive oral mucosa, a
ﬁnding that provides less support for the concept of
lichen planus being precancerous. Another study eval-
uated the malignant transformation rate of typical oral
lichen planus compared with oral “lichenoid” lesions.
The lichenoid lesions had some features of lichen
planus, but were not completely representative, either
clinically or histopathologically, of that disease. These
investigators found that there was no transformation of
characteristic lichen planus, although several of the
lichenoid lesions developed into squamous cell carci-
noma. Additional prospective clinical studies with
strict clinical and histopathologic criteria for the deﬁni-
tion of oral lichen planus will need to be performed to
resolve this question. If the potential for malignant
transformation exists, then it appears to be small. Most
of the reported cases have been conﬁned to patients
with either the erosive or so-called plaque-type form of
lichen planus.
CHRONIC ULCERATIVE STOMATITIS
Chronic ulcerative stomatitis is another immune-
mediated disorder that affects the oral mucosa. This
condition was initially described in 1989, and slightly
more than 40 cases have been reported. Although the
precise pathogenetic mechanisms are unknown, these
patients develop autoantibodies against a 70-kD
nuclear protein that is very similar to p63 and may play
a role in epithelial growth and differentiation.
A
B
C
Fig. 16-103 Lichen planus. A, This patient was diagnosed
with erosive lichen planus affecting the buccal mucosa and
was treated with topical corticosteroids. B, Same patient
2 weeks later. The creamy-white plaques of
pseudomembranous candidiasis have developed as a result of
the corticosteroid therapy. C, Same patient after antifungal
therapy. At this point, he was asymptomatic. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 789
The prevalence of this disease may be more common
than is realized. Because of its clinical similarity to
erosive lichen planus, it is possible that only a clinical
diagnosis is made when an affected patient is encoun-
tered, and a biopsy is not performed. Even if a biopsy
is done, the tissue is often submitted for routine light
microscopy alone, and the direct immunoﬂuorescence
studies that are required for its diagnosis are not
ordered. Distinction from lichen planus should be
made because chronic ulcerative stomatitis typically
does not respond as well to corticosteroid therapy, and
just as is the case with lupus erythematosus, chronic
ulcerative stomatitis often can be effectively treated
using antimalarial drugs.
CLINICAL FEATURES
Chronic ulcerative stomatitis usually affects adult
women, and the mean age at diagnosis is late in the
sixth decade of life. The condition may appear as des-
quamative gingivitis, although ulcerations or erosions
of the tongue or buccal mucosa are also quite common
(Fig. 16-104). The ulcers are generally surrounded by
patchy zones of erythema and streaky keratosis that
somewhat resemble lichen planus, although classic
striae formation is not evident. The ulcers heal without
scarring and often migrate around the oral mucosa. As
is typical with most immune-mediated conditions, the
severity of the oral lesions tends to wax and wane.
Fewer than 20% of affected patients will develop con-
current lichenoid skin lesions.
HISTOPATHOLOGIC FEATURES
Although the histopathologic features of chronic ulcer-
ative stomatitis are similar to those of lichen planus, the
epithelium is generally more atrophic and the inﬂam-
matory inﬁltrate usually contains signiﬁcant numbers
of plasma cells in addition to lymphocytes (Fig.
16-105). Artifactual epithelial separation from the
underlying connective tissue is not unusual.
DIAGNOSIS
The diagnosis of chronic ulcerative stomatitis is essen-
tially based on its characteristic immunopathologic
pattern. Although it may not be economically feasible
to do immunologic testing on every case of lichen
planus, this procedure should be considered for erosive
lichenoid lesions that do not have a characteristic
appearance or distribution, as well as for erosive lesions
that do not respond to topical corticosteroid therapy.
With direct immunoﬂuorescence studies, autoanti-
bodies (usually IgG) that are directed against the nuclei
of stratiﬁed squamous epithelial cells in the basal and
parabasal regions of the epithelium are detected (Fig.
16-106). Indirect immunoﬂuorescence studies are also
positive for these stratiﬁed epithelium-speciﬁc antinu-
clear antibodies (ANAs), and some investigators believe
that conﬁrmation of the diagnosis is necessary using
serum for indirect immunoﬂuorescence evaluation.
Other immune-mediated conditions (e.g., systemic
sclerosis and lupus erythematosus) may show ANA
deposition with direct immunoﬂuorescence; however,
nuclei throughout the entire thickness of the epithe-
lium are positive with those diseases.
TREATMENT AND PROGNOSIS
Unlike the lesions of erosive lichen planus, the lesions
associated with chronic ulcerative stomatitis may not
respond as well to topical or systemic corticosteroid
therapy. If the lesions are not adequately controlled
with corticosteroids, then management with hydroxy-
A B
Fig. 16-104 Chronic ulcerative stomatitis. A, White lesions with central erosion on the
buccal mucosa. B, Opposite buccal mucosa in the same patient. The lesions appear somewhat
lichenoid, although classic Wickham’s striae are not evident. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

790 ORAL AND MAXILLOFACIAL PATHOLOGY
chloroquine, an antimalarial drug, should be consid-
ered. Hydroxychloroquine therapy, however, requires
both periodic ophthalmologic evaluation to monitor
for drug-related retinopathy and periodic hematologic
evaluation.
GRAFT-VERSUS-HOST DISEASE
Graft-versus-host disease (GVHD) occurs mainly in
recipients of allogeneic bone marrow transplanta-
tion, a procedure performed on approximately 4000
patients in the United States each year. Such trans-
plants are performed at major medical centers to treat
life-threatening diseases of the blood or bone marrow,
such as leukemia, lymphoma, multiple myeloma, aplas-
tic anemia, thalassemia, sickle cell anemia, or dissemi-
nated metastatic disease. Cytotoxic drugs, radiation, or
both may be used to destroy the malignant cells, but
in the process the normal hematopoietic cells of
the patient are destroyed. To provide the patient with
an immune system, an HLA-matched donor must be
found. The donor supplies hematopoietic stem cells
obtained from bone marrow, peripheral blood, or
umbilical cord blood. These stem cells are transfused
into the patient, whose own hematopoietic and immune
cells have been destroyed. The transfused hematopoi-
etic cells make their way to the recipient’s bone marrow
and begin to reestablish normal function.
Unfortunately, the HLA match is not always exact,
and despite the use of immunomodulating and immu-
nosuppressive drugs, such as cyclosporine, methotrex-
ate, and prednisone, the engrafted cells often recognize
that they are not in their own environment. When this
happens, these cells start attacking what they perceive
as a foreign body. The result of this attack is GVHD,
and it can be quite devastating to the patient.
In recent years, oncologists have taken advantage of
this type of immunologic attack when treating leuke-
mia patients, and often a beneﬁcial “graft-versus-
leukemia” effect is seen when the donor cells interpret
the leukemic cells as being foreign. For older patients,
who tend to have more signiﬁcant side effects with
traditional bone marrow transplantation, the concept
of a “miniallograft” has been developed. Not all of the
patient’s white blood cells (WBCs) are destroyed in this
procedure, which is also known as nonmyeloablative allo-
genic hematopoietic cell transplantation, to allow the donor
cells to mount a more aggressive assault on the patient’s
leukemic cells.
Autologous stem cell transplantation has also
become an increasingly popular method of treatment
for some of these life-threatening diseases. Because
A B
Fig. 16-105 Chronic ulcerative stomatitis. A, Low-power photomicrograph showing
epithelial atrophy with a heavy chronic inﬂammatory cell inﬁltrate in the superﬁcial lamina
propria. B, High-power photomicrograph showing interface degeneration of the basilar
epithelium in association with the inﬂammation. Unlike lichen planus, this inﬁltrate includes
numerous plasma cells, as well as lymphocytes.
Fig. 16-106 Chronic ulcerative stomatitis. Direct
immunoﬂuorescence studies show presence of IgG in the
basal and parabasal epithelial nuclei. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 791
these cells are derived from the patient, there is no risk
of GVHD in this setting.
CLINICAL FEATURES
The systemic signs of GVHD are varied, depending on
the organ system involved and whether the problem is
acute or chronic. The severity of GVHD depends on
several factors, with milder disease seen in patients
who have a better histocompatibility match, are
younger, have received cord blood, and are female.
Acute GVHD is typically observed within the ﬁrst
few weeks after bone marrow transplantation. Although
acute GVHD has arbitrarily been deﬁned as occurring
within 100 days after the procedure, most investigators
make this diagnosis based on the clinical features
rather than a speciﬁc time point. The disease affects
about 50% of bone marrow transplant patients. The
skin lesions that develop may range from a mild rash
to a diffuse severe sloughing that resembles toxic epi-
dermal necrolysis (see page 777). These signs may be
accompanied by diarrhea, nausea, vomiting, abdomi-
nal pain, and liver dysfunction.
Chronic GVHD may represent a continuation of a
previously diagnosed case of acute GVHD, or it may
develop later than 100 days after bone marrow trans-
plantation, sometimes not appearing for several years
after the procedure. Chronic GVHD can be expected
to develop in 30% to 70% of bone marrow transplant
recipients, and it often mimics any one of a variety of
autoimmune conditions, such as systemic lupus ery-
thematosus (SLE), Sjögren syndrome, or primary biliary
cirrhosis. Skin involvement, which is the most common
manifestation, may resemble lichen planus or even sys-
temic sclerosis.
The oral mucosal manifestations of GVHD can also
vary, depending on the duration and severity of the
attack and the targeted oral tissues. Of patients with
acute GVHD, 33% to 75% will have oral involvement;
of patients with chronic GVHD, 80% or more will have
oral lesions. Sometimes the oral lesions of GVHD are
the only sign of the disorder. In most patients with oral
GVHD, there is a ﬁne, reticular network of white striae
that resembles oral lichen planus, although a more
diffuse pattern of pinpoint white papules has also been
described (Figs. 16-107 to 16-109). The tongue, the
labial mucosa, and the buccal mucosa are the oral
mucosal sites most frequently involved. Patients often
complain of a burning sensation of the oral mucosa,
and care must be taken not to overlook possible candi-
diasis. Atrophy of the oral mucosa may be present, and
this can contribute to the mucosal discomfort. Ulcer-
ations that are related to the chemotherapeutic condi-
tioning and neutropenic state of the patient often
develop during the ﬁrst 2 weeks after bone marrow
transplantation. Ulcers that persist longer than 2 weeks
Fig. 16-107 Graft-versus-host disease (GVHD). Conﬂuent,
interlacing white linear lesions of the vermilion zone
superﬁcially resemble oral lichen planus.
Fig. 16-108 Graft-versus-host disease (GVHD). Lichenoid
lesions of the left buccal mucosa.
Fig. 16-109 Graft-versus-host disease (GVHD).
Involvement of the tongue showing erosions and ulcerations
that resemble erosive lichen planus.
may represent acute GVHD, and these should be dif-
ferentiated from intraoral herpesvirus infection or bac-
terial infection. Bone marrow transplant patients have
a small but increased risk for the development of both
oral and cutaneous epithelial dysplasia and squamous `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

792 ORAL AND MAXILLOFACIAL PATHOLOGY
cell carcinoma. Demarcated white or red plaques of
the oral mucosa that do not have the characteristic
lichenoid features should be biopsied to rule out pre-
neoplastic or neoplastic changes (Fig. 16-110).
Xerostomia is also a common complaint. If the
patient is not taking drugs that dry the mouth, it is
likely that the immunologic response is destroying the
salivary gland tissue. Other evidence of salivary gland
involvement includes the development of small super-
ﬁcial mucoceles, particularly on the soft palate.
HISTOPATHOLOGIC FEATURES
The histopathologic features of GVHD resemble those
of oral lichen planus to a certain degree. Both lesions
display hyperorthokeratosis, short and pointed rete
ridges, and degeneration of the basal cell layer. The
inﬂammatory response in GVHD is usually not as
intense as in lichen planus. With advanced cases, an
abnormal deposition of collagen is present, similar to
the pattern in systemic sclerosis. Minor salivary gland
tissue usually shows periductal inﬂammation in the
early stages, with gradual acinar destruction and exten-
sive periductal ﬁbrosis appearing later.
DIAGNOSIS
The diagnosis of GVHD may be difﬁcult because of the
varied clinical manifestations. Such a diagnosis
is of great clinical signiﬁcance to the patient because
complications of the condition and its treatment
may be lethal. Although the diagnosis of GVHD is
based on the clinical and histopathologic ﬁndings, each
patient may have a different constellation of signs and
symptoms. Oral lesions appear to have value as a highly
predictive index of the presence of GVHD.
TREATMENT AND PROGNOSIS
The primary strategy for dealing with GVHD is to
reduce or prevent its occurrence. Careful tissue histo-
compatibility matching is performed, and the patient
is given prophylactic therapy with immunomodulatory
and immunosuppressive agents, such as prednisone in
combination with either cyclosporine or tacrolimus. If
GVHD develops, then the doses of these drugs may be
increased or similar pharmacologic agents, such as
mycophenolate mofetil, or azathioprine, may be added.
The drug thalidomide has shown some promise for
cases of chronic GVHD that have been resistant to
standard therapy.
Topical corticosteroids may facilitate the healing
of focal oral ulcerations associated with GVHD.
Topical anesthetic agents are administered to pro-
vide patient comfort while the lesions are present,
although narcotic analgesics may be required in
some cases. Several case reports have described the
efﬁcacy of topical tacrolimus for management of oral
ulceration caused by GVHD. The use of psoralen
and ultraviolet A (PUVA) therapy also has been shown
to improve the cutaneous and oral lesions of patients
with the lichenoid form of GVHD. If signiﬁcant
xerostomia is present in a dentulous patient, then
topical ﬂuorides should be used daily to prevent xero-
stomia-related caries. If signiﬁcant amounts of salivary
acinar tissue remain, then treatment with pilocarpine
hydrochloride or cevimeline hydrochloride may
improve the salivary ﬂow. Current recommendations
are to evaluate the oral status of patients before bone
marrow transplantation and eliminate any potential
sources of infection. Interestingly, one recent study
showed no differences in posttransplant infections or
survival between a group of patients who received
dental treatment before their transplant and a group
who did not.
In general, some degree of GVHD is expected in
most allogeneic bone marrow transplant recipients.
The prognosis depends on the extent to which the con-
dition progresses and whether or not it can be con-
trolled. The signiﬁcance of this complication is reﬂected
in the survival of more than 70% of patients with rela-
tively mild GVHD at 6 years posttransplant, compared
with approximately 15% of patients with severe
GVHD.
PSORIASIS
Psoriasis is a common chronic skin disease affecting
approximately 2% of people in the United States.
According to some estimates, roughly 6 million people
in this country have psoriasis, and up to 250,000 new
cases are diagnosed each year.
Fig. 16-110 Squamous cell carcinoma arising in graft-
versus-host disease (GVHD). Erythematous, ulcerated mass
arising on the lateral border of the tongue. Note the
surrounding mucosal erosions, which represent GVHD. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 793
Psoriasis is characterized by an increased prolifera-
tive activity of the cutaneous keratinocytes. Recent
advances in cell kinetics, immunology, and molecular
biology have increased the understanding of the etio-
pathogenesis of the keratinocyte proliferation in this
disorder. Although the triggering agent has yet to be
identiﬁed, activated T lymphocytes appear to orches-
trate a complex scenario that includes abnormal pro-
duction of cytokines, adhesion molecules, chemotactic
polypeptides, and growth factors. Genetic factors also
seem to play a role, because as many as one third of
these patients have affected relatives. Currently nine
different genetic loci have been identiﬁed that may be
related to the development of psoriasis. Yet, if one twin
in a set of identical twins has psoriasis, there is only
a 35% chance that the other twin will have it. This
suggests that genetic factors are not entirely responsi-
ble for the condition, and that one or more uniden-
tiﬁed environmental agents must inﬂuence its
pathogenesis.
CLINICAL FEATURES
Psoriasis often has its onset during the second or third
decade of life and tends to persist for years, with
periods of exacerbation and quiescence. Patients
often report that the lesions improve during the
summer and worsen during the winter, an observation
that may be related to lesional exposure to ultraviolet
(UV) light. The lesions are often symmetrically distrib-
uted in certain favored locations, such as the scalp,
elbows, and knees. The classic description is a well-
demarcated, erythematous plaque with a silvery scale
on its surface (Fig. 16-111). The lesions are often
asymptomatic, but it is not unusual for a patient to
complain of itching—in fact, the term psoriasis is
derived from the Greek word for itching. An unfortu-
nate complication affecting approximately 11% of
these patients is psoriatic arthritis, which may involve
the TMJ.
Oral lesions may occur in patients with psoriasis, but
they are distinctly uncommon. Because descriptions of
these lesions have ranged from white plaques to red
plaques to ulcerations, it is difﬁcult to determine the
true nature of intraoral psoriasis (Fig. 16-112). To
render a diagnosis of intraoral psoriasis, some investi-
gators say that the activity of the oral lesions should
parallel that of the cutaneous lesions. Some authors
refer to erythema migrans (see page 779) as intraoral
psoriasis, and the prevalence of erythema migrans in
psoriatic patients appears to be slightly greater than
that seen in the rest of the population. It is difﬁcult,
however, to prove a direct correlation of that common
mucosal alteration with psoriasis.
HISTOPATHOLOGIC FEATURES
Microscopically, psoriasis has a characteristic pattern.
The surface epithelium shows marked parakeratin pro-
duction, and the epithelial rete ridges are elongated
(Fig. 16-113). The connective tissue papillae, which
contain dilated capillaries, approach close to the epi-
thelial surface, and a perivascular chronic inﬂamma-
tory cell inﬁltrate is present. In addition, collections of
neutrophils (Munro abscesses), are seen within the
parakeratin layer.
With respect to oral lesions, good correlation with
skin disease activity should be seen in addition to the
characteristic histopathologic features, because other
intraoral lesions, such as erythema migrans and oral
mucosal cinnamon reaction (see page 352), exhibit a
psoriasiform microscopic appearance.
Fig. 16-111 Psoriasis. Characteristic cutaneous lesions on
the skin of the elbow. Note the erythematous plaques
surmounted by silvery keratotic scales.
Fig. 16-112 Psoriasis. This is an example of relatively rare
involvement of the oral mucosa by psoriasis. The
erythematous linear patches tended to ﬂare with the
patient’s cutaneous lesions. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

794 ORAL AND MAXILLOFACIAL PATHOLOGY
TREATMENT AND PROGNOSIS
The treatment of psoriasis depends on the severity of
the disease activity. For mild lesions, no treatment may
be necessary.
For moderate involvement, topical corticosteroids
are commonly prescribed in the United States. Coal tar
derivatives and keratolytic agents also may be used.
Other topical drugs that have proven effective include
calcipotriene, a vitamin D
3 analog, and tazarotene, a
retinoid (vitamin A) compound. Newer topical biologic
agents include the calcineurin inhibitors, tacrolimus
and pimecrolimus, although these are usually reserved
for recalcitrant lesions. Exposure to UV radiation may
also be helpful for mild to moderate disease.
For severe cases, psoralen and ultraviolet A (PUVA)
therapy or ultraviolet B (UVB) therapy may be needed.
Methotrexate or cyclosporine may also be used as sys-
temic treatments for severe disease; however, these
drugs have signiﬁcant side effects. Newer systemic bio-
logic agents that target speciﬁc disease-related compo-
nents include inﬂiximab and etanercept (directed
against tumor necrosis factor-α [TNF-α]) or alefacept
and efalizumab (directed against T-cell receptors).
Although the mortality rate is not increased in
patients with psoriasis, the condition often persists for
years despite therapy. Some studies have shown a
modest increase in the risk for cutaneous squamous
cell carcinoma in psoriasis patients, possibly related to
their PUVA or methotrexate therapy.
LUPUS ERYTHEMATOSUS
Lupus erythematosus (LE) is a classic example of an
immunologically mediated condition, and is the most
common of the so-called collagen vascular or connec-
tive tissue diseases in the United States, with more than
1.5 million people affected. It may exhibit any one of
several clinicopathologic forms.
Systemic lupus erythematosus (SLE) is a serious
multisystem disease with a variety of cutaneous and
oral manifestations. There is an increase in the activity
of the humoral limb (B lym phocytes) of the immune
system in conjunction with abnormal function of the T
lymphocytes. Although genetic factors probably play a
role in the pathogenesis of SLE, the precise cause is
unknown. Undoubtedly, interplay between genetic
and environmental factors occurs, for if SLE develops
in one monozygotic (identical) twin, then the other
twin has a 24% chance of having SLE as well. In con-
trast, if one dizygotic (fraternal) twin has SLE, then the
other twin has only a 2% chance of being affected.
Chronic cutaneous lupus erythematosus (CCLE)
may represent a different, but related, process. It pri-
marily affects the skin and oral mucosa, and the prog-
nosis is good.
Subacute cutaneous lupus erythematosus (SCLE)
is a third form of the disease, which has clinical fea-
tures intermediate between those of SLE and CCLE.
CLINICAL FEATURES
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE can be a very difﬁcult disease to diagnose in its
early stages because it often appears in a nonspeciﬁc,
vague fashion, frequently with periods of remission or
disease inactivity. Women are affected nearly 8 to 10
times more frequently than men. The average age at
diagnosis is 31 years. Common ﬁndings include fever,
weight loss, arthritis, fatigue, and general malaise. In
40% to 50% of affected patients, a characteristic rash,
having the pattern of a butterﬂy, develops over the
malar area and nose (Fig. 16-114), typically sparing
the nasolabial folds. Sunlight often makes the lesions
worse.
The kidneys are affected in approximately 40% to
50% of SLE patients. This complication may ultimately
lead to kidney failure; thus it is typically the most sig-
niﬁcant aspect of the disease.
Cardiac involvement is also common, with pericar-
ditis being the most frequent complication. At autopsy
nearly 50% of SLE patients display warty vegetations
affecting the heart valves (Libman-Sacks endocar-
ditis). Its signiﬁcance is debatable, although some
patients may develop superimposed subacute bacterial
endocarditis on these otherwise sterile outgrowths of
ﬁbrinoid material and connective tissue cells.
Oral lesions of SLE develop in 5% to 25% of these
patients, although some studies indicate prevalence as
high as 40%. The lesions usually affect the palate, buccal
mucosa, and gingivae. Sometimes they appear as
lichenoid areas, but they may also look nonspeciﬁc or
even somewhat granulomatous (Fig. 16-115). Involve-
Fig. 16-113 Psoriasis. Low-power photomicrograph
showing elongation of the rete ridges, hyperkeratosis, and
inﬂammation of the papillary dermis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 795
ment of the vermilion zone of the lower lip (lupus
cheilitis) is sometimes seen. Varying degrees of ulcer-
ation, pain, erythema, and hyperkeratosis may be
present. Other oral complaints such as xerostomia, sto-
matodynia, candidiasis, periodontal disease, and dys-
geusia have been described, but the direct association
of these problems with SLE remains to be proven.
Conﬁrming the diagnosis of SLE can often be difﬁ-
cult, particularly in the early stages. Criteria for making
the diagnosis of SLE have been established by the
American Rheumatism Association, and these include
both clinical and laboratory ﬁndings (Table 16-4).
CHRONIC CUTANEOUS LUPUS
ERYTHEMATOSUS
Patients with CCLE usually have few or no systemic
signs or symptoms, with lesions being limited to skin
or mucosal surfaces. The skin lesions of CCLE most
commonly present as discoid lupus erythematosus.
They begin as scaly, erythematous patches that are fre-
quently distributed on sun-exposed skin, especially in
the head and neck area (Fig. 16-116). Patients may
indicate that the lesions are exacerbated by sun expo-
sure. With time, the lesions may heal spontaneously in
one area, only to appear in another area. The healing
process usually results in cutaneous atrophy with scar-
ring and hypopigmentation or hyperpigmentation of
the resolving lesion. Conjunctival involvement by
CCLE has rarely been reported to cause cicatrizing
conjunctivitis, clinically similar to mucous membrane
pemphigoid.
In most cases the oral manifestations of CCLE
essentially appear clinically identical to the lesions
Fig. 16-114 Systemic lupus erythematosus (SLE). The
erythematous patches seen in the malar regions are a
characteristic sign.
Fig. 16-115 Systemic lupus erythematosus (SLE).
Irregularly shaped ulcerations of the buccal mucosa.
Table 16-4 Prevalence of Clinical and
Laboratory Manifestations of
Systemic Lupus Erythematosus
Findings Affected Patients (%)
SYSTEMIC SIGNS AND SYMP-
TOMS: FATIGUE, MALAISE,
FEVER, ANOREXIA, WEIGHT
LOSS
95%
MUSCULOSKELETAL SYMPTOMS 95%
Arthralgia/myalgia 95%
Nonerosive polyarthritis 60%
CUTANEOUS SIGNS 80%
Photosensitivity 70%
Malar rash 50%
Oral ulcers 40%
Discoid rash 20%
HEMATOLOGIC SIGNS 85%
Anemia (chronic disease) 70%
Leukopenia (<4000/μL) 65%
Lymphopenia (<1500/μL) 50%
Thrombocytopenia (<100,000/μL) 15%
Hemolytic anemia 10%
NEUROLOGIC SIGNS AND
SYMPTOMS
60%
Cognitive disorder 50%
Headache 25%
Seizures 20%
CARDIOPULMONARY SIGNS 60%
Pleurisy, pericarditis, effusions 30%-50%
Myocarditis, endocarditis 10%
RENAL SIGNS 30%-50%
Proteinuria >500 mg/24 hours,
cellular casts
30%-50%
Nephrotic syndrome 25%
End-stage renal disease 5%-10%
Adapted from Hahn BH: Systemic lupus erythematosus. In Kasper DL,
Braunwald E, Fanci AS et al, editors: Harrison’s principles of internal
medicine, ed 16, pp 1960-1967, New York, 2005, McGraw-Hill.
Reproduced with permission of The McGraw-Hill Companies. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

796 ORAL AND MAXILLOFACIAL PATHOLOGY
of erosive lichen planus. Unlike the oral lesions of
lichen planus, however, the oral lesions of CCLE
seldom occur in the absence of skin lesions. An ulcer-
ated or atrophic, erythematous central zone, sur-
rounded by white, ﬁne, radiating striae, characterizes
the oral lesion of CCLE (Figs. 16-117 and 16-118).
Sometimes the erythematous, atrophic central region
of a lesion may show a ﬁne stippling of white dots. As
with erosive lichen planus, the ulcerative and atrophic
oral lesions of CCLE may be painful, especially when
exposed to acidic or salty foods.
SUBACUTE CUTANEOUS LUPUS
ERYTHEMATOSUS
Patients with SCLE have clinical manifestations inter-
mediate between those of SLE and CCLE. The skin
lesions are the most prominent feature of this varia-
tion. They are characterized by photosensitivity and
are, therefore, generally present in sun-exposed areas.
These lesions do not show the induration and scarring
seen with the skin lesions of CCLE. Usually, the renal
or neurologic abnormalities associated with SLE
are not present either, with most patients having arthri-
tis or musculoskeletal problems. SCLE may be trig-
gered by any one of a variety of medications (see
page 347).
HISTOPATHOLOGIC FEATURES
The histopathologic features of the skin and oral lesions
of the various forms of LE show some features in
common but are different enough to warrant separate
discussions.
The skin lesions of CCLE are characterized by
hyperkeratosis, often displaying keratin packed into
the openings of hair follicles (“follicular plugging”). In
all forms of LE, degeneration of the basal cell layer is
frequently observed, and the underlying connective
tissue supports patchy to dense aggregates of chronic
inﬂammatory cells (Figs. 16-119 and 16-120). In the
deeper connective tissue, the inﬂammatory inﬁltrate
often surrounds the small blood vessels.
The oral lesions demonstrate hyperkeratosis, alter-
nating atrophy and thickening of the spinous cell layer,
degeneration of the basal cell layer, and subepithelial
lymphocytic inﬁltration. These features may also be
seen in oral lichen planus; however, the two conditions
can usually be distinguished by the presence in LE of
patchy deposits of a periodic acid-Schiff (PAS)-positive
material in the basement membrane zone, subepithe-
lial edema (sometimes to the point of vesicle forma-
tion), and a more diffuse, deep inﬂammatory inﬁltrate,
Fig. 16-116 Chronic cutaneous lupus erythematosus
(CCLE). The skin lesions are characterized by scaling, atrophy,
and pigmentary disturbances, which are most evident on
sun-exposed skin.
Fig. 16-117 Chronic cutaneous lupus erythematosus
(CCLE). Radiating keratotic striae surround erythematous
zones of the buccal mucosa. These features are similar to
those of erosive lichen planus.
Fig. 16-118 Chronic cutaneous lupus erythematosus
(CCLE). Oral involvement may also include relatively
nondescript erythematous patches, such as this one in the
palate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 797
often in a perivascular orientation. Some authorities,
however, feel that differentiating lichen planus from
LE is best done by direct immunoﬂuorescence studies
or histopathologic examination of the cutaneous
lesions.
DIAGNOSIS
In addition to the clinical and microscopic features, a
number of additional immunologic studies may be
helpful in making the diagnosis of LE.
Direct immunoﬂuorescence testing of lesional
tissue shows deposition of one or more immunoreac-
tants (usually IgM, IgG, or C3) in a shaggy or granular
band at the basement membrane zone. In addition,
direct immunoﬂuorescence testing of clinically normal
skin of SLE patients often shows a similar deposition
of IgG, IgM, or complement components. This ﬁnding
is known as a positive lupus band test. Although a
positive lupus band test is consistent with the diagnosis
of LE, it is now known that other conditions, such as
rheumatoid arthritis, Sjögren syndrome, and systemic
sclerosis, may also have similar positive ﬁndings. Fur-
thermore, some patients with LE may not have a posi-
tive lupus band test; therefore, this study must always
be interpreted in the context of other clinical signs.
Evaluation of serum obtained from a patient with
SLE shows various immunologic abnormalities.
Approximately 95% of these patients have antibodies
directed against multiple nuclear antigens (i.e., anti-
nuclear antibodies [ANAs]). Although this is a nonspe-
ciﬁc ﬁnding that may be seen in other autoimmune
diseases, as well as in otherwise healthy older individu-
als, it is nevertheless useful as a screening study. Fur-
thermore, if results are negative on multiple occasions,
then the diagnosis of SLE should probably be doubted.
Antibodies directed against double-stranded DNA are
noted in 70% of patients with SLE, and these are more
speciﬁc for the disease. Another 30% of patients show
antibodies directed against Sm, a protein that is com-
plexed with small nuclear RNA. This ﬁnding is very
speciﬁc for SLE.
A summary of selected immunologic ﬁndings in LE
is shown in Table 16-5.
TREATMENT AND PROGNOSIS
Patients with SLE should avoid excessive exposure to
sunlight because ultraviolet light may precipitate
disease activity. Mild active disease may be effectively
managed using nonsteroidal antiinﬂammatory drugs
(NSAIDs) combined with antimalarial drugs, such as
hydroxychloroquine. For more severe, acute episodes
that involve arthritis, pericarditis, thrombocytopenia,
or nephritis, systemic corticosteroids are generally
indicated; these may be combined with other immuno-
suppressive agents. If oral lesions are present, they typi-
cally respond to the systemic therapy.
As with SLE patients, patients with CCLE should
avoid excessive sunlight exposure. Because most of the
manifestations of CCLE are cutaneous, topical cortico-
steroids are often reasonably effective. For cases that
are resistant to topical therapy, systemic antimalarial
drugs or low-dose thalidomide may produce a response.
Topical corticosteroids are also helpful in treating the
oral lesions of CCLE.
Fig. 16-119 Lupus erythematosus (LE). Low-power
photomicrograph showing hyperparakeratosis with interface
mucositis and perivascular inﬂammation.
Fig. 16-120 Lupus erythematosus (LE). High-power
photomicrograph of the interface mucositis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

798 ORAL AND MAXILLOFACIAL PATHOLOGY
The prognosis for the patient with SLE is variable.
For patients undergoing treatment today, the 5-year
survival rate is approximately 82% to 90%; however, by
20 years, the survival rate falls to 63% to 75%. Ulti-
mately, the prognosis depends on which organs are
affected and how frequently the disease is reactivated.
The most common cause of death is renal failure;
however, chronic immunosuppression also predis-
poses these patients to increased mortality because of
infection and development of malignancy. For reasons
that are poorly understood, the prognosis is worse for
men than for women. In addition, blacks tend to fare
more poorly than whites.
The prognosis for patients with CCLE is consider-
ably better than that for patients with SLE, although
transformation to SLE may be seen in approximately
5% of CCLE patients. Usually, CCLE remains conﬁned
to the skin, but it may persist and be quite a nuisance.
For about 50% of CCLE patients, the problem eventu-
ally resolves after several years.
SYSTEMIC SCLEROSIS (PROGRESSIVE
SYSTEMIC SCLEROSIS; SCLERODERMA;
HIDE-BOUND DISEASE)
Systemic sclerosis is a relatively rare condition that
probably has an immunologically mediated pathogen-
esis. For reasons that are not understood, dense colla-
gen is deposited in the tissues of the body in extraordin-
ary amounts. Although its most dramatic effects are
seen in association with the skin, the disease is often
quite serious, with most organs of the body affected.
CLINICAL AND RADIOGRAPHIC
FEATURES
Systemic sclerosis affects approximately 19 persons
per million population each year. Women have the
condition three to ﬁve times more frequently than do
men. Most patients are adults. The onset of the disease
is generally insidious, with the cutaneous changes often
responsible for bringing the problem to the patient’s
attention.
Often one of the ﬁrst signs of the disease is Ray-
naud’s phenomenon, a vasoconstrictive event trig-
gered by emotional distress or exposure to cold.
Raynaud’s phenomenon (see CREST syndrome, on
page 801) is not speciﬁc for systemic sclerosis, however,
because it may be present in other immunologically
mediated diseases and in otherwise healthy people.
Resorption of the terminal phalanges (acro-osteoly-
sis) and ﬂexion contractures produce shortened,
clawlike ﬁngers (Fig. 16-121). The vascular events
and the abnormal collagen deposition contribute to
the production of ulcerations on the ﬁngertips (Fig.
16-122).
Table 16-5 Selected Abnormal Immunologic Findings in Lupus Erythematosus
Findings Frequency Signiﬁcance
Direct immunoﬂuorescence, lesional skinCCLE: 90%
SLE: 95%
May help distinguish among the various types of LE
Direct immunoﬂuorescence, normal skinCCLE: 0%
SLE: 25%-60%
Lupus band test
Antinuclear antibodies CCLE: 0%-10%
SLE: 95%
Very sensitive for SLE, but not very speciﬁc; not useful for
CCLE diagnosis
Antidouble-stranded DNA antibodies CCLE: 0%
SLE: 70%-80%
Speciﬁc for SLE; may indicate disease activity or kidney
involvement
Anti-Sm antibodies CCLE: 0%
SLE: 10%-30%
Speciﬁc for SLE
CCLE, Chronic cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; LE, lupus erythematosus.
Fig. 16-121 Systemic sclerosis. The tense, shiny
appearance of the skin is evident. Note that the ﬁngers are
ﬁxed in a clawlike position, with some showing shortening as
a result of acro-osteolysis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 799
The skin develops a diffuse, hard texture (sclero =
hard; derma = skin), and its surface is usually smooth.
Involvement of the facial skin by subcutaneous colla-
gen deposition results in the characteristic smooth,
taut, masklike facies (Fig. 16-123). Similarly, the nasal
alae become atrophied, resulting in a pinched appear-
ance to the nose, called a mouse facies.
Involvement of other organs may be subtle at ﬁrst,
but the results are more serious. Fibrosis of the lungs,
heart, kidneys, and gastrointestinal tract leads to organ
failure, typically within the ﬁrst 3 years after the diag-
nosis is made. Pulmonary ﬁbrosis is particularly sign-
iﬁcant, leading to pulmonary hypertension and heart
failure, a primary cause of death for these patients.
The oral manifestations occur in varying degrees.
Microstomia often develops as a result of collagen
deposition in the perioral tissues. This causes a limita-
tion of opening the mouth in nearly 70% of these
patients (Fig. 16-124). Characteristic furrows radiating
from the mouth produce a “purse string” appearance.
Loss of attached gingival mucosa and multiple areas of
gingival recession may occur in some patients. Dyspha-
gia often develops as a result of deposition of collagen
in the lingual and esophageal submucosa, producing a
ﬁrm, hypomobile (boardlike) tongue and an inelastic
esophagus, thus hindering swallowing. Xerostomia is
frequently identiﬁed in these patients, and the possibil-
ity of concurrent secondary Sjögren syndrome may
require consideration.
On dental radiographs, diffuse widening of the peri-
odontal ligament space is often present throughout the
dentition. The extent of the widening may vary, with
some examples being subtle and others quite dramatic
(Fig. 16-125). Varying degrees of resorption of the pos-
terior ramus of the mandible, the coronoid process, the
chin, and the condyle may be detected on panoramic
radiographs, affecting approximately 10% to 20% of
patients (Fig. 16-126). In theory, these areas are
resorbed because of the increased pressure associated
with the abnormal collagen production. Individual
tooth resorption has also been reported to occur at a
higher frequency in these patients.
A mild variant of this condition, called localized
scleroderma, usually affects only a solitary patch of
skin. Because these lesions often look like scars, the
Fig. 16-122 Systemic sclerosis. Ulcerations of the
ﬁngertips.
Fig. 16-123 Systemic sclerosis. The involvement of the
facial skin with abnormal collagen deposition produces a
masklike facies. Note the loss of the alae of the nose.
Fig. 16-124 Systemic sclerosis. Same patient as depicted
in Fig. 16-123. Because of the associated microstomia, this is
the patient’s maximal opening. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

800 ORAL AND MAXILLOFACIAL PATHOLOGY
name en coup de sabre (“strike of the sword”) is used to
describe them (Fig. 16-127). This problem is primarily
cosmetic and, unlike systemic sclerosis, it is rarely life
threatening.
HISTOPATHOLOGIC FEATURES
Microscopic examination of tissue involved by syste-
mic sclerosis shows diffuse deposition of dense colla-
gen within and around the normal structures (Fig.
16-128). This abnormal collagen replaces and destroys
the normal tissue, causing the loss of normal tissue
function.
Fig. 16-125 Systemic sclerosis. Diffuse widening of the
periodontal ligament space is often identiﬁed on evaluation
of periapical radiographs.
Fig. 16-126 Systemic sclerosis. Panoramic radiographic evaluation may show a
characteristic resorption of the ramus, coronoid process, or condyle.
Fig. 16-127 Localized scleroderma. The cutaneous
alteration on the patient’s forehead represents a limited form
of scleroderma called en coup de sabre, because the lesion
resembles a scar that might result from a cut with a sword.
DIAGNOSIS
During the early phases, it may be difﬁcult to make a
diagnosis of systemic sclerosis. Generally, the clinical
signs of stiffened skin texture along with the develop-
ment of Raynaud’s phenomenon are suggestive of the
diagnosis. A skin biopsy may be supportive of the diag-
noses if abundant collagen deposition is observed
microscopically.
Laboratory studies may be helpful to the diagno-
stic process if anticentromere antibodies or anti-Scl 70
(topoisomerase I) is detected. Antitopoisomerase I anti-
bodies are seen more often with systemic sclerosis; `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 801
anticentromere antibodies are usually associated with
more limited forms of scleroderma or CREST syn-
drome (see next topic). In addition, increasing levels
of endothelial cell autoantibodies appear to correlate
with disease severity.
TREATMENT AND PROGNOSIS
The management of systemic sclerosis is difﬁcult.
Unfortunately, many of the recommended treatments
have not been examined in controlled trials, and the
natural waxing and waning course of the disease
makes it difﬁcult to assess the effectiveness of a given
treatment in an open-label trial. Systemic medications,
such as penicillamine, are prescribed in an attempt to
inhibit collagen production. A recent double-blind
study, however, showed no difference in measured
patient outcomes with high-dose versus low-dose peni-
cillamine, suggesting that perhaps this medication
has limited efﬁcacy. Surprisingly, corticosteroids are
of little beneﬁt. Extracorporeal photochemotherapy
has shown some beneﬁcial effect on the skin lesions;
however, no improvement of the pulmonary function
tests is observed.
Other management strategies are directed at con-
trolling symptoms. Such techniques as esophageal dila-
tion are used, for example, to temporarily correct
the esophageal dysfunction and dysphagia. Calcium
channel blocking agents help to increase peripheral
blood ﬂow and lessen the symptoms of Raynaud’s phe-
nomenon, but many patients can reduce episodes by
keeping warm (especially their hands and feet) or by
stopping cigarette smoking. Angiotensin-converting
enzyme (ACE) inhibitors often effectively control
hypertension if kidney involvement is prominent.
From a dental standpoint, problems may develop
for patients who wear prostheses because of the micro-
stomia and inelasticity of the mouth. Collapsible dental
appliances with special hinges have been made to
facilitate the insertion and removal of dentures. Micro-
stomia and inelastic soft tissue also hamper the main-
tenance of good oral hygiene, and affected patients
have a decreased ability to manipulate a toothbrush as
a result of sclerotic changes in the ﬁngers and hands.
Surgical correction of open bite associated with condy-
lar resorption has been described. Infrequently, the
resorption of the mandible may become so great as to
cause a pathologic fracture.
The prognosis is poor, although the outlook is better
for patients with limited cutaneous involvement than
for those with diffuse involvement. If the heart is
affected, then the prognosis is particularly poor, but
most patients die because of pulmonary involvement.
Overall survival ﬁgures are difﬁcult to calculate be-
cause of a variety of factors, including the rarity of the
disease, the inherent variability of its natural course,
and the variation in treatments provided at medical
centers around the world. With current treatment
regimens, it is estimated that 10-year survival rates for
patients with limited cutaneous scleroderma approach
80% to 90%, whereas survival drops to 60% to 75% for
patients with diffuse systemic sclerosis.
CREST SYNDROME (ACROSCLEROSIS;
LIMITED SCLERODERMA)
CREST syndrome is an uncommon condition that
may be a relatively mild variant of systemic sclerosis.
The term CREST is an acronym for Calcinosis cutis,
Raynaud’s phenomenon, Esophageal dysfunction,
Sclerodactyly, and Telangiectasia.
CLINICAL FEATURES
As with systemic sclerosis, most patients with CREST
syndrome are women in the sixth or seventh decade of
life. The characteristic signs may not appear synchro-
nously but instead may develop sequentially over a
period of months to years.
Calcinosis cutis occurs in the form of movable,
nontender, subcutaneous nodules, 0.5 to 2.0 cm in size,
which are usually multiple (Fig. 16-129). Larger, more
numerous or superﬁcial calciﬁcations may occasion-
ally become bothersome and require removal.
Fig. 16-128 Systemic sclerosis. Medium-power
photomicrograph of an oral biopsy specimen. Diffuse
deposition of collagen is apparent throughout the lamina
propria. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

802 ORAL AND MAXILLOFACIAL PATHOLOGY
Raynaud’s phenomenon may be observed when a
person’s hands or feet are exposed to cold tempera-
tures. The initial clinical sign is a dramatic blanching
of the digits, which appear dead-white in color as a
result of severe vasospasm. A few minutes later, the
affected extremity takes on a bluish color because of
venous stasis. After warming, increased blood ﬂow
results in a dusky-red hue with the return of hyperemic
blood ﬂow. This may be accompanied by varying
degrees of throbbing pain.
Esophageal dysfunction, caused by abnormal col-
lagen deposition in the esophageal submucosa, may
not be noticeable in the early phases of CREST syn-
drome. Often the subtle initial signs of this problem
must be demonstrated by barium swallow radiologic
studies.
The sclerodactyly of CREST syndrome is rather
remarkable. The ﬁngers become stiff, and the skin
takes on a smooth, shiny appearance. Often the ﬁngers
undergo permanent ﬂexure, resulting in a characteris-
tic “claw” deformity (Fig. 16-130). As with systemic
sclerosis, this change is due to abnormal deposition of
collagen within the dermis in these areas.
The telangiectasias in this syndrome are similar to
those seen in hereditary hemorrhagic telangiectasia
(HHT) (see page 754). As with that condition, signiﬁ-
cant bleeding from the superﬁcial dilated capillaries
may occur. The facial skin and the vermilion zone of
the lips are commonly affected (Fig. 16-131).
HISTOPATHOLOGIC FEATURES
The histopathologic ﬁndings in CREST syndrome are
similar, although milder, to those seen in systemic
sclerosis. Superﬁcial dilated capillaries are observed
if a telangiectatic vessel is included in the biopsy
specimen.
DIAGNOSIS
Sometimes, HHT may be considered in the differential
diagnosis if the history is unclear and the other signs of
CREST syndrome are not yet evident. In these cases,
Fig. 16-129 CREST syndrome. The subcutaneous nodules
on this patient’s arm represent deposition of calcium salts
(calcinosis cutis). (Courtesy of Dr. Román Carlos.)
Fig. 16-130 CREST syndrome. Clawlike deformity
affecting the hands (sclerodactyly).
Fig. 16-131 CREST syndrome. The patient shows
numerous red facial macules representing telangiectatic
blood vessels. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 803
laboratory studies directed at identifying anticentro-
mere antibodies may be useful, because this test is rela-
tively speciﬁc for CREST syndrome.
TREATMENT AND PROGNOSIS
The treatment of patients with CREST syndrome is
essentially the same as that of those with systemic scle-
rosis. Because CREST syndrome usually is not as
severe, the treatment does not have to be as aggressive.
Although the prognosis for this condition is much
better than that for systemic sclerosis, patients should
be monitored for an increased risk of developing pul-
monary hypertension or primary biliary cirrhosis, gen-
erally more than 10 years after the initial diagnosis.
ACANTHOSIS NIGRICANS
Acanthosis nigricans is an acquired dermatologic
problem characterized by the development of a velvety,
brownish alteration of the skin. In some instances, this
unusual condition develops in conjunction with gastro-
intestinal cancer and is termed malignant acanthosis
nigricans. The cutaneous lesion itself is benign, yet it
is signiﬁcant because it represents a cutaneous marker
for internal malignancy. The cause of malignant acan-
thosis nigricans is unknown, although a cytokine-like
peptide capable of affecting the epidermal cells may be
produced by the malignancy.
Most cases, estimated to affect as many as 5% of
adults, are not associated with a malignancy and are
termed benign acanthosis nigricans. A clinically
similar form, pseudoacanthosis nigricans, may occur
in some obese people. Some benign forms of acantho-
sis nigricans may be inherited or may occur in associa-
tion with various endocrinopathies, such as diabetes
mellitus, Addison’s disease, hypothyroidism, and acro-
megaly. Furthermore, benign acanthosis nigricans may
occur with certain syndromes (e.g., Crouzon syndrome)
or drug ingestion (e.g., oral contraceptives, corticoste-
roids). These forms of the condition are typically associ-
ated with resistance of the tissues to the effects of
insulin, similar to the insulin resistance seen in non–
insulin-dependent diabetes mellitus (NIDDM). Even
though the affected individuals may not have overt dia-
betes mellitus, they often show increased levels of
insulin or an abnormal response to exogenously admin-
istered insulin.
CLINICAL FEATURES
The malignant form of acanthosis nigricans develops
in association with an internal malignancy, particularly
adenocarcinoma of the gastrointestinal tract. Approxi-
mately 20% of the cases of malignant acanthosis nigri-
cans are identiﬁed before the malignancy is found, but
most appear at about the same time as discovery of the
gastrointestinal tumor or thereafter.
Both forms of acanthosis nigricans affect the ﬂexural
areas of the skin predominantly, appearing as ﬁnely
papillary, hyperkeratotic, brownish patches that are
usually asymptomatic (Fig. 16-132). The texture of the
lesions has been variably described as either velvety or
leathery.
Oral lesions of acanthosis nigricans have also been
reported and may occur in 25% to 50% of affected
patients, especially those with the malignant form.
These lesions appear as diffuse, ﬁnely papillary areas
of mucosal alteration that most often involve the tongue
or lips, particularly the upper lip (Figs. 16-133 and
16-134). The buccal mucosa may also be affected.
The brownish pigmentation associated with the cuta-
neous lesions is usually not seen in oral acanthosis
nigricans.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the various forms of
acanthosis nigricans are essentially identical. The
epidermis exhibits hyperorthokeratosis and papilloma-
tosis. Usually, some degree of increased melanin depo-
Fig. 16-132 Acanthosis nigricans. The lesions are
characterized by numerous ﬁne, almost velvety, conﬂuent
papules. The lesions most often affect the ﬂexural areas, such
as the axilla depicted in this photograph. (From Hall JM, Moreland
A, Cox GJ et al: Oral acanthosis nigricans: report of a case and comparison
of oral and cutaneous pathology, Am J Dermatopathol 10:68-73, 1988.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

804 ORAL AND MAXILLOFACIAL PATHOLOGY
sition is noted, but the extent of acanthosis (thickening
of the spinous layer) is really rather mild. The oral
lesions have much more acanthosis, but show minimal
increased melanin pigmentation (Fig. 16-135).
TREATMENT AND PROGNOSIS
Although acanthosis nigricans itself is a harmless
process, the patient should be evaluated to ascertain
which form of the disease is present. Identiﬁcation and
treatment of the underlying malignancy obviously are
important for patients with the malignant type; unfor-
tunately, the prognosis for these individuals is very
poor. Interestingly, malignant acanthosis nigricans
may resolve when the cancer is treated. Keratolytic
agents may improve the appearance of the benign
forms.
BIBLIOGRAPHY
Ectodermal Dysplasia
Aswegan AL, Josephson KD, Mowbray R et al: Autosomal domi-
nant hypohidrotic ectodermal dysplasia in a large family, Am
J Med Genet 72:462-467, 1997.
Berg D, Weingold DH, Abson KG et al: Sweating in ectodermal
dysplasia syndromes, Arch Dermatol 126:1075-1079, 1990.
Bonilla ED, Guerra L, Luna O: Overdenture prosthesis for oral
rehabilitation of hypohidrotic ectodermal dysplasia: a case
report, Quintessence Int 28:657-665, 1997.
Cambiaghi S, Restano L, Paakkonen K et al: Clinical ﬁndings in
mosaic carriers of hypohidrotic ectodermal dysplasia, Arch
Dermatol 136:217-224, 2000.
Ho L, Williams MS, Spritz RA: A gene for autosomal dominant
hypohidrotic ectodermal dysplasia (EDA3) maps to chromo-
some 2q11-q13, Am J Hum Genet 62:1102-1106, 1998.
Itin PH, Fistarol SK: Ectodermal dysplasias, Am J Med Genet
131C:45-51, 2004.
Jorgenson RJ, Salinas CF, Dowben JS et al: A population study
on the density of palmar sweat pores, Birth Defects Orig Artic
Ser 24:51-63, 1988.
Kantaputra PN, Hamada T, Kumchai T et al: Heterozygous muta-
tion in the SAM domain of p63 underlies Rapp-Hodgkin
ectodermal dysplasia, J Dent Res 82:433-437, 2003.
Kearns G, Sharma A, Perrott D et al: Placement of endosseous
implants in children and adolescents with hereditary ecto-
dermal dysplasia, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 88:5-10, 1999.
Lamartine J: Towards a new classiﬁcation of ectodermal dyspla-
sias, Clin Exp Dermatol 28:351-355, 2003.
Levin LS: Dental and oral abnormalities in selected ectodermal
dysplasia syndromes, Birth Defects Orig Artic Ser 24:205-227,
1988.
Lo Muzio L, Bucci P, Carile F et al: Prosthetic rehabilitation of a
child affected from anhydrotic ectodermal dysplasia: a case
report, J Contemp Dent Pract 6:1-7, 2005.
Mills R, Montague M-L, Naysmith L: Ear, nose and throat mani-
festations of ectodermal dysplasia, J Laryngol Otol 118:406-
408, 2004.
Munoz F, Lestringant G, Sybert V et al: Deﬁnitive evidence for
an autosomal recessive form of hypohidrotic ectodermal dys-
Fig. 16-133 Acanthosis nigricans. The vermilion zone of
the lips is affected. (Courtesy of Dr. George Blozis.)
Fig. 16-134 Acanthosis nigricans. Same patient as
depicted in Fig. 16-133. Note involvement of the palatal
mucosa. (Courtesy of Dr. George Blozis.)
Fig. 16-135 Acanthosis nigricans. Medium-power
photomicrograph of an oral lesion showing papillomatosis,
mild hyperkeratosis, and acanthosis of the epithelium. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 805
plasia clinically indistinguishable from the more common
X-linked disorder, Am J Hum Genet 61:94-100, 1997.
Nordgarden H, Johannessen S, Storhaug K et al: Salivary gland
involvement in hypohidrotic ectodermal dysplasia, Oral Dis
4:152-154, 1998.
Shankly PE, Mackie IC, McCord FJ: The use of tricalcium phos-
phate to preserve alveolar bone in a patient with ectodermal
dysplasia: a case report, Spec Care Dentist 19:35-39, 1999.
Singh P, Warnakulasuriya S: Aplasia of submandibular salivary
glands associated with ectodermal dysplasia, J Oral Pathol Med
33:634-636, 2004.
White Sponge Nevus
Jorgenson RJ, Levin LS: White sponge nevus, Arch Dermatol
117:73-76, 1981.
Krajewska IA, Moore L, Brown JH: White sponge nevus present-
ing in the esophagus—case report and literature review,
Pathology 24:112-115, 1992.
Marcushamer M, King DL, McGuff S: White sponge nevus: case
report, Pediatr Dent 17:458-459, 1995.
Martelli H, Mourão-Pereira S, Martins-Rocha T et al:
White sponge nevus: report of a three-generation family, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 103:43-47,
2007.
Morris R, Gansler TS, Rudisill MT et al: White sponge nevus:
diagnosis by light microscopic and ultrastructural cytology,
Acta Cytol 32:357-361, 1988.
Richard G, De Laurenzi V, Didona B et al: Keratin 13 point
mutation underlies the hereditary mucosal disorder white
sponge nevus, Nat Genet 11:453-455, 1995.
Rugg EL, Magee GJ, Wilson NJ et al: Identiﬁcation of two novel
mutations in keratin 13 as the cause of white sponge naevus,
Oral Dis 5:321-324, 1999.
Rugg EL, McLean WHI, Allison WE et al: A mutation in the
mucosal keratin K4 is associated with oral white sponge
nevus, Nat Genet 11:450-452, 1995.
Terrinoni A, Candi E, Oddi S et al: A glutamine insertion in the
1A alpha helical domain of the keratin 4 gene in a familial
case of white sponge nevus, J Invest Dermatol 114:388-391,
2000.
Terrinoni A, Rugg EL, Lane EB et al: A novel mutation in the
keratin 13 gene causing oral white sponge nevus, J Dent Res
80:919-923, 2001.
Hereditary Benign Intraepithelial Dyskeratosis
McLean IW, Riddle PJ, Scruggs JH et al: Hereditary benign
intraepithelial dyskeratosis. A report of two cases from Texas,
J Ophthalmol 88:164-168, 1981.
Reed JW, Cashwell LF, Klintworth GK: Corneal manifestations
of hereditary benign intraepithelial dyskeratosis, Arch Oph-
thalmol 97:297-300, 1979.
Sadeghi EM, Witkop CJ: The presence of Candida albicans in
hereditary benign intraepithelial dyskeratosis: an ultrastruc-
tural observation, Oral Surg Oral Med Oral Pathol 48:342-346,
1979.
Shields CL, Shields JA, Eagle RC: Hereditary benign intraepithe-
lial dyskeratosis, Arch Ophthalmol 105:422-423, 1987.
Pachyonychia Congenita
Feinstein A, Friedman J, Schewach-Millet M: Pachyonychia con-
genita, J Am Acad Dermatol 19:705-711, 1988.
García-Rio I, Peñas PF, García-Díez A et al: A severe case of
pachyonychia congenital type I due to a novel praline muta-
tion in keratin 6a, Br J Dermatol 152:800-802, 2005.
Leachman SA, Kaspar RL, Fleckman P et al: Clinical and patho-
logical features of pachyonychia congenita, J Investig Dermatol
Symp Proc 10:3-17, 2005.
McLean WHI, Rugg EL, Lunny DP et al: Keratin 16 and keratin
17 mutations cause pachyonychia congenita, Nat Genet 9:273-
278, 1995.
Milstone LM, Fleckman P, Leachman SA et al: Treatment of
pachyonychia congenita, J Investig Dermatol Symp Proc 10:18-
20, 2005.
Pradeep AR, Nagaraja C: Pachyonychia congenita with unusual
dental ﬁndings: a case report, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 104:89-93, 2007.
Smith FJD, Liao H, Cassidy AJ et al: The genetic basis of pachyo-
nychia congenita, J Investig Dermatol Symp Proc 10:21-30,
2005.
Smith FJD, McKusick VA, Nielsen K et al: Cloning of
multiple keratin 16 genes facilitates prenatal diagnosis of
pachyonychia congenita type 1, Prenat Diag 19:941-946,
1999.
Stieglitz JB, Centerwall WR: Pachyonychia congenita
(Jadassohn-Lewandowsky syndrome): a seventeen member,
four-generation pedigree with unusual respiratory and dental
involvement, Am J Med Genet 14:21-28, 1983.
Dyskeratosis Congenita
Baykal C, Kavak A, Gülcan P et al: Dyskeratosis congenita associ-
ated with three malignancies, J Eur Acad Dermatol Venereol
17:216-218, 2003.
Davidovitch E, Eimerl D, Aker M et al: Dyskeratosis congenita:
dental management of a medically complex child, Pediatr
Dent 27:244-248, 2005.
Dokal I, Vulliamy T: Dyskeratosis congenita: its link to telomer-
ase and aplastic anemia, Blood Rev 17:217-225, 2003.
Elliot AM, Graham GE, Bernstein M et al: Dyskeratosis congen-
ita: an autosomal recessive variant, Am J Med Genet 83:178-
182, 1999.
Fernandes-Gomes M, Pinheiro de Abreu P, de Freitas-Banzi ÉC
et al: Interdisciplinary approach to treat dyskeratosis con-
genita associated with severe aplastic anemia: a case report,
Spec Care Dentist 26:81-85, 2006.
Ghavamzadeh A, Alimoghadam K, Nasseri P et al: Correction of
bone marrow failure in dyskeratosis congenita by bone
marrow transplantation, Bone Marrow Transplant 23:299-301,
1999.
Handley TPB, McCaul JA, Ogden GR: Dyskeratosis congenita,
Oral Oncol 42:331-336, 2006.
Handley TPB, Ogden GR: Dyskeratosis congenita: oral hyper-
keratosis in association with lichenoid reaction, J Oral Pathol
Med 35:508-512, 2006.
Hyodo M, Sadamoto A, Hinohira Y et al: Tongue cancer as a
complication of dyskeratosis congenita in a woman, Am J
Otolaryngol 20:405-407, 1999.
Kanegane H, Kasahara Y, Okamura Jet al: Identiﬁcation of
DKC1 gene mutations in Japanesepatients with X-linked
dyskeratosis congenita, Br J Haematol129:432-434, 2005.
Knight SW, Heiss NS, Vulliamy TJ et al: X-linked dyskeratosis
congenita is predominantly caused by missense mutations in
the DKC1 gene, Am J Hum Genet 65:50-58, 1999.
Marrone A, Mason PJ: Human genome and diseases: review.
Dyskeratosis congenita, Cell Mol Life Sci 60:507-517, 2003.
Mason PJ, Wilson DB, Bessler M: Dyskeratosis congenita—a
disease of dysfunctional telomere maintenance, Curr Mol Med
5:159-170, 2005.
Mitchell JR, Wood E, Collins K: A telomerase component is
defective in the human disease dyskeratosis congenita, Nature
402:551-555, 1999.
Tanaka A, Kumagai S, Nakagawa K et al: Cole-Engman syndrome
associated with leukoplakia of the tongue: a case report, J Oral
Maxillofac Surg 57:1138-1141, 1999. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

806 ORAL AND MAXILLOFACIAL PATHOLOGY
Vulliamy TJ, Marrone A, Knight SW et al: Mutations in dyskera-
tosis congenita: their impact on telomere length and the
diversity of clinical presentation, Blood 107:2680-2685,
2006.
Vulliamy T, Dokal I: Dyskeratosis congenita, Semin Hematol
43:157-166, 2006.
Xeroderma Pigmentosum
Benhamou S, Sarasin A: Variability in nucleotide excision repair
and cancer risk: a review, Mutat Res 462:149-158, 2000.
Cleaver JE: Common pathways for ultraviolet skin carcinogene-
sis in the repair and replication defective groups of xero-
derma pigmentosum, J Dermatol Sci 23:1-11, 2000.
Cleaver JE: Cancer in xeroderma pigmentosum and related dis-
orders of DNA repair, Nature Rev 5:564-573, 2005.
Goyal JL, Rao, VA, Srinivasan R et al: Oculocutaneous manifesta-
tions in xeroderma pigmentosa, Br J Ophthalmol 78:295-297,
1994.
Kraemer KH, Lee MM, Scotto J: Xeroderma pigmentosum: cuta-
neous, ocular, and neurologic abnormalities in 830 published
cases, Arch Dermatol 123:241-250, 1987.
Magnaldo T, Sarasin A: Xeroderma pigmentosum: from symp-
toms and genetics to gene-based skin therapy, Cells Tissues
Organs 177:189-198, 2004.
Park S, Dock M: Xeroderma pigmentosum: a case report, Pediatr
Dent 25:397-400, 2003.
Patton LL, Valdez IH: Xeroderma pigmentosum: review and
report of a case, Oral Surg Oral Med Oral Pathol 71:297-300,
1991.
van Steeg H, Kraemer KH: Xeroderma pigmentosum and the
role of UV-induced DNA damage in skin cancer, Mol Med
Today 5:86-94, 1999.
Hereditary Mucoepithelial Dysplasia
Boralevi F, Haftek M, Vabres P et al: Hereditary mucoepithelial
dysplasia: clinical, ultrastructural and genetic study of eight
patients and literature review, Br J Dermatol 153:310-318,
2005.
Rogers M, Kourt G, Cameron A: Hereditary mucoepithelial dys-
plasia, Pediatr Dermatol 11:133-138, 1994.
Scheman AJ, Ray DJ, Witkop CJ et al: Hereditary mucoepithelial
dysplasia: case report and review of the literature, J Am Acad
Dermatol 21:351-357, 1989.
Urban MD, Schosser R, Spohn W et al: New clinical aspects of
hereditary mucoepithelial dysplasia, Am J Med Genet 39:338-
341, 1991.
Witkop CJ, White JG, Sauk JJ et al: Clinical, histologic, cytologic
and ultrastructural characteristics of the oral lesions from
hereditary mucoepithelial dysplasia, Oral Surg Oral Med Oral
Pathol 46:645-657, 1978.
Incontinentia Pigmenti
Bentolila R, Rivera H, Sanchez-Quevedo MC: Incontinentia pig-
menti: a case report, Pediatr Dent 28:54-57, 2006.
Berlin AL, Paller AS, Chan LS: Incontinentia pigmenti: a review
and update on the molecular basis of pathophysiology, J Am
Acad Dermatol 47:169-187, 2002.
Bruckner AL: Incontinentia pigmenti: a window to the role of
NF-κB function, Semin Cutan Med Surg 23:116-124, 2004.
Emery MM, Siegfried EC, Stone MS et al: Incontinentia pigmenti:
transmission from father to daughter, J Am Acad Dermatol
29:368-372, 1993.
Faloyin M, Levitt J, Bercowitz E et al: All that is vesicular is not
herpes: incontinentia pigmenti masquerading as herpes
simplex virus in a newborn, Pediatrics 114:270-272, 2004.
Fusco F, Fimiani G, Tadini G et al: Clinical diagnosis of inconti-
nentia pigmenti in a cohort of male patients, J Am Acad Der-
matol 56:264-267, 2007.
Landy SJ, Donnai D: Incontinentia pigmenti (Bloch-Sulzberger
syndrome), J Med Genet 30:53-59, 1993.
Pacheco TR, Levy M, Collyer JC et al: Incontinentia pigmenti in
male patients, J Am Acad Dermatol 55:251-255, 2006.
Phan TA, Wargon O, Turner AM: Incontinentia pigmenti case
series: clinical spectrum of incontinentia pigmenti in 53
female patients and their relatives, Clin Exp Dermatol 30:474-
480, 2005.
Welbury TA, Welbury RR: Incontinentia pigmenti (Bloch-
Sulzberger syndrome): report of a case, ASDC J Dent Child
66:213-215, 1999.
Darier’s Disease
Adams AM, Macleod RI, Munro CS: Symptomatic and asymp-
tomatic salivary duct abnormalities in Darier’s disease: a
sialographic study, Dentomaxillofac Radiol 23:25-28, 1994.
Burge SM, Wilkinson JD: Darier-White disease: a review of the
clinical features in 163 patients, J Am Acad Dermatol 27:40-
50, 1992.
Cooper SM, Burge SM: Darier’s disease: epidemiology, patho-
physiology, and management, Am J Clin Dermatol 4:97-105,
2003.
Dhitavat J, Dode L, Leslie N et al: Mutations in the sarcoplasmic/
endoplasmic reticulum Ca
2+
ATPase isoform cause Darier’s
disease, J Invest Dermatol 121:486-489, 2003.
Foggia L, Hovnanian A: Calcium pump disorders of the skin, Am
J Med Genet 131C:20-31, 2004.
Frezzini C, Cedro M, Leao JC et al: Darier disease affecting the
gingival and oral mucosal surfaces, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 102:e29-e33, 2006.
Jalil AA, Zain RB, van der Waal I: Darier disease: a case report,
Br J Oral Maxillofac Surg 43:336-338, 2005.
Macleod RI, Munro CS: The incidence and distribution of oral
lesions in patients with Darier’s disease, Br Dent J 171:133-
136, 1991.
Munro CS: The phenotype of Darier’s disease: penetrance and
expressivity in adults and children, Br J Dermatol 127:126-
130, 1992.
Sakuntabhai A, Ruiz-Perez V, Carter S et al: Mutations in
ATP2A2, encoding a Ca
2+
pump, cause Darier’s disease, Nat
Genet 21:271-277, 1999.
Sehgal VN, Srivastava G: Darier’s (Darier-White) disease/kerato-
sis follicularis, Int J Dermatol 44:184-192, 2005.
Zeglaoui F, Zaraa I, Fazaa B et al: Dyskeratosis follicularis disease:
case reports and review of the literature, J Eur Acad Dermatol
Venereol 19:114-117, 2005.
Warty Dyskeratoma
Chau MNY, Radden BG: Oral warty dyskeratoma, J Oral Pathol
13:546-556, 1984.
Kaddu S, Dong H, Mayer G et al: Warty dyskeratoma—”follicular
dyskeratoma”: analysis of clinicopathologic features of a dis-
tinctive follicular adnexal neoplasm, J Am Acad Dermatol
47:423-428, 2002.
Kaugars GE, Lieb RJ, Abbey LM: Focal oral warty dyskeratoma,
Int J Dermatol 23:123-130, 1984.
Laskaris G, Sklavounou A: Warty dyskeratoma of the oral mucosa,
Br J Oral Maxillofac Surg 23:371-375, 1985.
Mesa ML, Lambert WC, Schneider LC et al: Oral warty dyskera-
toma, Cutis 33:293-296, 1984.
Peutz-Jeghers Syndrome
Giardiello FM, Trimbath JD: Peutz-Jeghers syndrome and man-
agement recommendations, Clin Gastroenterol Hepatol 4:408-
415, 2006.
Hearle N, Schumacher V, Menko FH et al: Frequency and spec-
trum of cancers in the Peutz-Jeghers syndrome, Clin Cancer
Res 12:3209-3215, 2006. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 807
Hemminki A: The molecular basis and clinical aspects of
Peutz-Jeghers syndrome, Cell Mol Life Sci 55:735-750,
1999.
Jenne DE, Reimann H, Nezu J-I et al: Peutz-Jeghers syndrome is
caused by mutations in a novel serine threonine kinase, Nat
Genet 18:38-43, 1998.
Le Meur N, Martin C, Saugier-Veber P et al: Complete germline
deletion of the STK11 gene in a family with Peutz-Jeghers
syndrome, Eur J Human Genet 12:415-418, 2004.
McGarrity TJ, Amos C: Peutz-Jeghers syndrome: clinicopathol-
ogy and molecular alterations, Cell Mol Life Sci 63:2135-2144,
2006.
McGarrity TJ, Kulin HE, Zaino RJ: Peutz-Jeghers syndrome, Am
J Gastroenterol 95:596-604, 2000.
Uno A, Hori Y: Disturbance of melanosome transfer in pig-
mented macules of Peutz-Jeghers syndrome. In Fitzpatrick
TB et al: Brown melanoderma, pp 173-178, Tokyo, 1986, Uni-
versity of Tokyo Press.
Westerman AM, Entius MM, de Baar E et al: Peutz-Jeghers syn-
drome: 78-year follow-up of the original family, Lancet
353:1211-1215, 1999.
Hereditary Hemorrhagic Telangiectasia
Abdalla SA, Letarte M: Hereditary haemorrhagic telangiectasia:
current views on genetics and mechanisms of disease, J Med
Genet 43:97-110, 2006.
Abdalla SA, Pece-Barbara N, Vera S et al: Analysis of ALK-1 and
endoglin in newborns from families with hereditary hemor-
rhagic telangiectasia type 2, Hum Mol Genet 9:1227-1237,
2000.
Bayrak-Toydemir P, McDonald J, Markewitz B et al: Genotype-
phenotype correlation in hereditary hemorrhagic telan-
giectasia: mutations and manifestations, Am J Med Genet
140A:463-470, 2006.
Begbie ME, Wallace GMF, Shovlin CL: Hereditary haemorrhagic
telangiectasia (Osler-Weber-Rendu syndrome): a view from
the 21st century, Postgrad Med J 79:18-24, 2003.
Bergler W, Götte K: Hereditary hemorrhagic telangiectasias: a
challenge for the clinician, Eur Arch Otorhinolaryngol 256:10-
15, 1999.
Braveman IM, Keh A, Jacobson BS: Ultrastructure and three-
dimensional organization of the telangiectases of hereditary
hemorrhagic telangiectasia, J Invest Dermatol 95:422-427,
1990.
Cymerman U, Vera S, Pece-Barbara N et al: Identiﬁcation of
hereditary hemorrhagic telangiectasia type 1 in newborns by
protein expression and mutation analysis of endoglin, Pediatr
Res 47:24-35, 2000.
Fiorella ML, Ross D, Henderson KJ et al: Outcome of septal der-
moplasty in patients with hereditary hemorrhagic telangiec-
tasia, Laryngoscope 115:301-305, 2005.
Guttmacher AE, Marchuk DA, White RI: Hereditary
hemorrhagic telangiectasia, N Engl J Med 333:918-924,
1995.
Hitchings AE, Lennox PA, Lund VJ et al: The effect of treatment
for epistaxis secondary to hereditary hemorrhagic telangiec-
tasia, Am J Rhinol 19:75-78, 2005.
Kjeldsen AD, Vase P, Green A: Hereditary haemorrhagic telan-
giectasia: a population-based study of prevalence and mortal-
ity in Danish patients, J Intern Med 245:31-39, 1999.
McAllister KA, Grogg KM, Johnson DW et al: Endoglin, a TGF-β
binding protein of endothelial cells, is the gene for hereditary
haemorrhagic telangiectasia type 1, Nat Genet 8:345-351,
1994.
Russi EW, Dazzi H, Gäumann N: Septic pulmonary embolism
due to periodontal disease in a patient with hereditary
hemorrhagic telangiectasia, Respiration 63:117-119, 1996.
Swanson DL, Dahl MV: Embolic abscesses in hereditary hemor-
rhagic telangiectasia, J Am Acad Dermatol 24:580-583,
1991.
Ehlers-Danlos Syndromes
Abel MD, Carrasco LR: Ehlers-Danlos syndrome: classiﬁcations,
oral manifestations, and dental considerations, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 102:582-590,
2006.
Beighton P, De Paepe A, Steinmann B et al: Ehlers-Danlos syn-
dromes: revised nosology, Villefranche, 1997, Am J Med Genet
77:31-37, 1998.
Burrows NP: The molecular genetics of the Ehlers-Danlos syn-
drome, Clin Exp Dermatol 24:99-106, 1999.
De Coster PJ, Malfait F, Martens LC et al: Unusual oral ﬁndings
in dermatosparaxis (Ehlers-Danlos syndrome type VIIC), J
Oral Pathol Med 32:568-570, 2003.
De Coster PJ, Martens LC, De Paepe A: Oral health in prevalent
types of Ehlers-Danlos syndromes, J Oral Pathol Med 34:298-
307, 2005.
Dyne KM, Vitellaro-Zuccarello L, Bacchella L et al: Ehlers-Danlos
syndrome type VIII: biochemical, stereological and immuno-
cytochemical studies on dermis from a child with clinical
signs of Ehlers-Danlos syndrome and a family history of pre-
mature loss of permanent teeth, Br J Dermatol 128:458-463,
1993.
Fridrich KL, Fridrich HH, Kempf KK et al: Dental implications
in Ehlers-Danlos syndrome: a case report, Oral Surg Oral Med
Oral Pathol 69:431-435, 1990.
Hartsﬁeld JK, Kousseff BG: Phenotypic overlap of Ehlers-Danlos
syndrome types IV and VIII, Am J Med Genet 37:465-470,
1990.
Malfait F, De Coster P, Hausser I et al: The natural history,
including orofacial features of three patients with Ehlers-
Danlos syndrome, dermatosparaxis type (EDS type VIIC), Am
J Med Genet 131A:18-28, 2004.
Norton LA, Assael LA: Orthodontic and temporomandibular
joint considerations in treatment of patients with Ehlers-
Danlos syndrome, Am J Orthod Dentofac Orthop 111:75-84,
1997.
Nuytinck L, Freund M, Lagae L et al: Classical Ehlers-Danlos
syndrome caused by a mutation in type I collagen, Am J Hum
Genet 66:1398-1402, 2000.
Pepin M, Schwarze U, Superti-Furga A et al: Clinical and genetic
features of Ehlers-Danlos syndrome type IV, the vascular
type, N Engl J Med 342:673-680, 2000.
Pope FM, Komorowska A, Lee KW et al: Ehlers Danlos syn-
drome type I with novel dental features, J Oral Pathol Med
21:418-421, 1992.
Rahman N, Dunstan M, Teare MD et al: Ehlers-Danlos syndrome
with severe early-onset periodontal disease (EDS-VIII) is a
distinct, heterogeneous disorder with one predisposition
gene at chromosome 12p13, Am J Hum Genet 73:198-204,
2003.
Sacks H, Zelig D, Schabes G: Recurrent temporomandibular
joint subluxation and facial ecchymosis leading to diagnosis
of Ehlers-Danlos syndrome: report of surgical management
and review of the literature, J Oral Maxillofac Surg 48:641-
647, 1990.
Yassin OM, Rihani FB: Multiple developmental dental anomalies
and hypermobility type Ehlers-Danlos syndrome, J Clin Pediatr
Dent 30:337-341, 2006.
Tuberous Sclerosis
Barron RP, Kainulainen VT, Forrest CR et al: Tuberous sclerosis:
clinicopathologic features and review of the literature, J Cra-
niomaxillofac Surg 30:361-366, 2002. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

808 ORAL AND MAXILLOFACIAL PATHOLOGY
Çelenk P, Alkan A, Canger EM et al: Fibrolipomatous hamar-
toma in a patient with tuberous sclerosis: report of a case, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 99:202-206,
2005.
Crino PB, Nathanson KL, Henske EP: The tuberous sclerosis
complex, N Engl J Med 355:1345-1356, 2006.
Damm DD, Tomich CE, White DK et al: Intraosseous ﬁbrous
lesions of the jaws. A manifestation of tuberous sclerosis, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 87:334-340,
1999.
Franz DN: Diagnosis and management of tuberous sclerosis
complex, Semin Pediatr Neurol 5:253-268, 1998.
Franz DN: Non-neurologic manifestations of tuberous sclerosis
complex, J Child Neurol 19:690-698, 2004.
Houser OW, Shepherd CW, Gomez MR: Imaging of intracranial
tuberous sclerosis, Ann N Y Acad Sci 615:81-93, 1991.
Hurst JS, Wilcoski S: Recognizing an index case of tuberous
sclerosis, Am Fam Physician 61:703-708, 710, 2000.
Hyman MH, Whittemore VH: National Institutes of Health con-
sensus conference: tuberous sclerosis complex, Arch Neurol
57:662-665, 2000.
Jones AC, Shyamsundar MM, Thomas MW et al: Comprehensive
mutation analysis of TSC1 and TSC2—and phenotypic corre-
lations in 150 families with tuberous sclerosis, Am J Hum
Genet 64:1305-1315, 1999.
Lendvay TS, Marshall FF: The tuberous sclerosis complex and its
highly variable manifestations, J Urol 169:1635-1642, 2003.
Lygidakis NA, Lindenhum RH: Oral ﬁbromatosis in tuberous
sclerosis, Oral Surg Oral Med Oral Pathol 68:725-728, 1989.
O’Callaghan FJ, Osborne JP: Advances in the understanding of
tuberous sclerosis, Arch Dis Child 83:140-142, 2000.
Roach ES, Sparagana SP: Diagnosis of tuberous sclerosis com-
plex, J Child Neurol 19:643-649, 2004.
Rosser T, Panigrahy A, McClintock W: The diverse clinical mani-
festations of tuberous sclerosis complex: a review, Semin
Pediatr Neurol 13:27-36, 2006.
Sampson JR, Attwood D, Al Mughery AS et al: Pitted enamel
hypoplasia in tuberous sclerosis, Clin Genet 42:50-52,
1992.
Shepherd CW, Gomez MR: Mortality in the Mayo Clinic tuber-
ous sclerosis complex study, Ann N Y Acad Sci 615:375-377,
1991.
Thomas D, Rapley J, Strathman R et al: Tuberous sclerosis with
gingival overgrowth, J Periodontol 63:713-717, 1992.
Multiple Hamartoma Syndrome
Albrecht S, Haber RM, Goodman JC et al: Cowden syndrome
and Lhermitte-Duclos disease, Cancer 70:869-876, 1992.
Bagan JV, Penarrocha M, Vera-Sempere F: Cowden syndrome:
clinical and pathological considerations in two new cases, J
Oral Maxillofac Surg 47:291-294, 1989.
Bonneau D, Longy M: Mutations of the human PTEN gene, Hum
Mutat 16:109-122, 2000.
Devlin MF, Barrie R, Ward-Booth RP: Cowden’s disease: a rare
but important manifestation of oral papillomatosis, Br J Oral
Maxillofac Surg 30:335-336, 1992.
Eng C: Genetics of Cowden syndrome: through the looking glass
of oncology (Review), Int J Oncol 12:701-710, 1998.
Hand JL, Rogers RS: Oral manifestations of genodermatoses, Der-
matol Clin 21:183-194, 2003.
Leão JC, Batista V, Guimarães PB et al: Cowden’s syndrome
affecting the mouth, gastrointestinal, and central nervous
system: a case report and review of the literature, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 99:569-572, 2005.
Mallory SB: Cowden syndrome (multiple hamartoma syndrome),
Dermatol Clin 13:27-31, 1995.
Merks JHM, de Vries LS, Zhou X-P et al: PTEN hamartoma tumor
syndrome: variability of an entity, J Med Genet 40:e111,
2003.
Mignogna MD, Lo Muzio L, Ruocco V et al: Early diagnosis
of multiple hamartoma and neoplasia syndrome (Cowden
disease). The role of the dentist, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 79:295-299, 1995.
Nelen MR, Padberg GW, Peeters EAJ et al: Localization of the
gene for Cowden disease to chromosome 10q22-23, Nat
Genet 13:114-116, 1996.
Pilarski R, Eng C: Will the real Cowden syndrome please stand
up (again)? Expanding mutational and clinical spectra of the
PTEN hamartoma tumour syndrome, J Med Genet 41:323-
326, 2004.
Porter S, Cawson R, Scully C et al: Multiple hamartoma syn-
drome presenting with oral lesions, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 82:295-301, 1996.
Schaffer JV, Kamino H, Witkiewicz A et al: Mucocutaneous neu-
romas: an underrecognized manifestation of PTEN hamar-
toma-tumor syndrome, Arch Dermatol 142:625-632, 2006.
Scheper MA, Nikitakis NG, Sarlani E et al: Cowden syndrome:
report of a case with immunohistochemical analysis and
review of the literature, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 101:625-631, 2006.
Takenoshita Y, Kubo S, Takeuchi T et al: Oral and facial lesions
in Cowden’s disease: report of two cases and a review of the
literature, J Oral Maxillofac Surg 51:682-687, 1993.
Wright DD, Whitney J: Multiple hamartoma syndrome
(Cowden’s syndrome): case report and literature review, Gen
Dent 54:417-419, 2006.
Epidermolysis Bullosa
Azrak B, Kaevel K, Hofmann L et al: Dystrophic epidermolysis
bullosa: oral ﬁndings and problems, Spec Care Dentist 26:111-
115, 2006.
Bello YM, Falabella AF, Schachner LA: Management of epider-
molysis bullosa in infants and children, Clin Dermatol 21:278-
282, 2003.
Brain JH, Paul BF, Assad DA: Periodontal plastic surgery in a
dystrophic epidermolysis bullosa patient: review and case
report, J Periodontol 70:1392-1396, 1999.
Bruckner-Tuderman L: Hereditary skin diseases of anchoring
ﬁbrils, J Dermatol Sci 20:122-133, 1999.
Çagirankaya LB, Hatipoglu MG, Hatipoglu H: Localized epider-
molysis bullosa simplex with generalized enamel hypoplasia
in a child, Pediatr Dermatol 23:167-168, 2006.
Das BB, Sahoo S: Dystrophic epidermolysis bullosa, J Perinatol
24:41-47, 2004.
De Benedittis M, Petruzzi M, Favia G et al: Oro-dental manifesta-
tions in Hallopeau-Siemens type recessive dystrophic epider-
molysis bullosa, Clin Exp Dermatol 29:128-132, 2004.
Dunnill MGS, Eady RAJ: The management of dystrophic epider-
molysis bullosa, Clin Exp Dermatol 20:179-188, 1995.
Fine J-D, Eady RAJ, Bauer EA et al: Revised classiﬁcation system
for inherited epidermolysis bullosa: report of the Second
International Consensus Meeting on diagnosis and classiﬁca-
tion of epidermolysis bullosa, J Am Acad Dermatol 42:1051-
1066, 2000.
Jonkman MF: Hereditary skin diseases of hemidesmosomes, J
Dermatol Sci 20:103-121, 1999.
Lin AN: Management of patients with epidermolysis bullosa, Der-
matol Clin 14:381-387, 1996.
Marinkovich MP: Update on inherited bullous dermatoses, Der-
matol Clin 17:473-485, 1999.
McAllister JC, Marinkovich MP: Advances in inherited epider-
molysis bullosa, Adv Dermatol 21:303-334, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
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Chapter 16 DERMATOLOGIC DISEASES 809
McGrath JA, O’Grady A, Mayou BJ et al: Mitten deformity
in severe generalized recessive dystrophic epidermolysis
bullosa: histological, immunoﬂuorescence, and ultrastruc-
tural study, J Cutan Pathol 19:385-389, 1992.
Momeni A, Pieper K: Junctional epidermolysis bullosa: a case
report, Int J Paediatr Dent 15:146-150, 2005.
Mullett F: A review of the management of the hand in dystrophic
epidermolysis bullosa, J Hand Ther 11:261-265, 1998.
Pai S, Marinkovich MP: Epidermolysis bullosa: new and emerg-
ing trends, Am J Clin Dermatol 3:371-380, 2002.
Pekiner FN, Yücelten D, Özbayrak S et al: Oral-clinical ﬁndings
and management of epidermolysis bullosa, J Clin Pediatr Dent
30:59-66, 2005.
Pulkkinen L, Uitto J: Mutation analysis and molecular
genetics of epidermolysis bullosa, Matrix Biol 18:29-42,
1999.
Serrano-Martínez MC, Bagán JV, Silvestre FJ et al: Oral lesions
in recessive dystrophic epidermolysis bullosa, Oral Dis 9:264-
268, 2003.
Silva LC, Cruz RA, Abou-Id LR et al: Clinical evaluation of
patients with epidermolysis bullosa: review of the literature
and case reports, Spec Care Dentist 24:22-27, 2004.
Uitto J: Molecular diagnostics of epidermolysis bullosa: novel
pathomechanisms and surprising genetics, Exp Dermatol
8:92-95, 1999.
Uitto J, Richard G: Progress in epidermolysis bullosa: genetic
classiﬁcation and clinical implications, Am J Med Genet
131C:61-74, 2004.
Uitto J, Richard G: Progress in epidermolysis bullosa: from
eponyms to molecular genetic classiﬁcation, Clin Dermatol
23:33-40, 2005.
Wright JT: Oral manifestations of epidermolysis bullosa. In Fine
J-D, Bauer EA, McGuire J et al, editors: Epidermolysis bullosa.
Clinical, epidemiologic, and laboratory advances and the ﬁndings
of the National Epidermolysis Bullosa Registry, pp 236-256,
Baltimore and London, 1999, The Johns Hopkins University
Press.
Pemphigus
Black M, Mignogna MD, Scully C: Pemphigus vulgaris, Oral Dis
11:119-130, 2005.
Brenner S, Bialy-Golan A, Ruocco V: Drug-induced pemphigus,
Clin Dermatol 16:393-397, 1998.
Bystryn J-C, Rudolph JL: Pemphigus, Lancet 366:61-73, 2005.
Bystryn J-C, Rudolph JL: IVIg treatment of pemphigus: how it
works and how to use it, J Invest Dermatol 125:1093-1098,
2005.
Calebotta A, Sáenz AM, González F et al: Pemphigus vulgaris:
beneﬁts of tetracycline as adjuvant therapy in a series of thir-
teen patients, Int J Dermatol 38:217-221, 1999.
Carson PJ, Hameed A, Ahmed AR: Inﬂuence of treatment on the
clinical course of pemphigus vulgaris, J Am Acad Dermatol
34:645-652, 1996.
Dabelsteen E: Molecular biological aspects of acquired bullous
diseases, Crit Rev Oral Biol Med 9:162-178, 1998.
Darling MR, Daley T: Blistering mucocutaneous diseases of the
oral mucosa—a review: Part 2. Pemphigus vulgaris, J Can Dent
Assoc 72:63-66, 2006.
Eisenberg E, Ballow M, Wolfe SH et al: Pemphigus-like mucosal
lesions: a side effect of penicillamine therapy, Oral Surg Oral
Med Oral Pathol 51:409-414, 1981.
El Tal AK, Posner MR, Spigelman Z et al: Rituximab: a monoclo-
nal antibody to CD20 used in the treatment of pemphigus
vulgaris, J Am Acad Dermatol 55:449-459, 2006.
Enk AH, Knop J: Mycophenolate is effective in the treatment of
pemphigus vulgaris, Arch Dermatol 135:54-56, 1999.
Harman KE, Seed PT, Gratian MJ et al: The severity of cutaneous
and oral pemphigus is related to desmoglein 1 and 3 antibody
levels, Br J Dermatol 144:775-780, 2001.
Herbst A, Bystryn JC: Patterns of remission in pemphigus vul-
garis, J Am Acad Dermatol 42:422-427, 2000.
Ioannides D, Chrysomallis F, Bystryn J-C: Ineffectiveness of
cyclosporine as an adjuvant to corticosteroids in the treat-
ment of pemphigus, Arch Dermatol 136:868-872, 2000.
Laforest C, Huilgol SC, Casson R et al: Autoimmune bullous
diseases: ocular manifestations and management, Drugs
65:1767-1779, 2005.
Laskaris G, Stouﬁ E: Oral pemphigus vulgaris in a 6-year-old girl,
Oral Surg Oral Med Oral Pathol 69:609-613, 1990.
Martel P, Joly P: Pemphigus: autoimmune diseases of
keratinocyte’s adhesion molecules, Clin Dermatol 19:662-
674, 2001.
Mignogna MD, Lo Muzio L, Mignogna RE et al: Oral pemphigus:
long term behaviour and clinical response to treatment with
deﬂazacort in sixteen cases, J Oral Pathol Med 29:145-152,
2000.
Mignogna MD, Lo Muzio L, Bucci E: Clinical features of
gingival pemphigus vulgaris, J Clin Periodontol 28:489-493,
2001.
Nousari HC, Anhalt GJ: Pemphigus and bullous pemphigoid,
Lancet 354:667-672, 1999.
Scully C, Challacombe SJ: Pemphigus vulgaris: update on etio-
pathogenesis, oral manifestations, and management, Crit Rev
Oral Biol Med 13:397-408, 2002.
Tóth GG, Jonkman MF: Therapy of pemphigus, Clin Dermatol
19:761-767, 2001.
Yeh SW, Sami N, Ahmed RA: Treatment of pemphigus vulgaris:
current and emerging options, Am J Clin Dermatol 6:327-342,
2005.
Paraneoplastic Pemphigus
Ahmed AR, Avram MM, Duncan LM: Case 23-2003: a 79-year-
old woman with gastric lymphoma and erosive mucosal and
cutaneous lesions, N Engl J Med 349:382-391, 2003.
Allen CM, Camisa C: Paraneoplastic pemphigus: a review of the
literature, Oral Dis 6:208-214, 2000.
Anhalt GJ: Paraneoplastic pemphigus, J Investig Dermatol Symp
Proc 9:29-33, 2004.
Anhalt GJ, Kim SC, Stanley JR et al: Paraneoplastic pemphigus:
an autoimmune mucocutaneous disease associated with neo-
plasia, N Engl J Med 323:1729-1735, 1990.
Billet SE, Grando SA, Pittelkow MR: Paraneoplastic autoimmune
multiorgan syndrome: review of the literature and support for
a cytotoxic role in pathogenesis, Autoimmunity 36:617-630,
2006.
Cummins DL, Mimouni D, Tzu J et al: Lichenoid paraneoplastic
pemphigus in the absence of detectable antibodies, J Am Acad
Dermatol 56:153-159, 2007.
Hashimoto T: Immunopathology of paraneoplastic pemphigus,
Clin Dermatol 19:675-682, 2001.
Helm TN, Camisa C, Valenzuela R et al: Paraneoplastic pemphi-
gus: a distinct autoimmune vesiculobullous disorder associ-
ated with neoplasia, Oral Surg Oral Med Oral Pathol 75:209-213,
1993.
Hoque SR, Black MM, Cliff S: Paraneoplastic pemphigus associ-
ated with CD20-positive follicular non-Hodgkin’s lymphoma
treated with rituximab: a third case resistant to rituximab
therapy, Clin Exp Dermatol 32:172-175, 2007.
Kaplan I, Hodak E, Ackerman L et al: Neoplasms associated with
paraneoplastic pemphigus: a review with emphasis on non-
hematologic malignancy and oral mucosal manifestations,
Oral Oncol 40:553-562, 2004. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

810 ORAL AND MAXILLOFACIAL PATHOLOGY
Laforest C, Huilgol SC, Casson R et al: Autoimmune bullous
diseases: ocular manifestations and management, Drugs
65:1767-1779, 2005.
Meyers SJ, Varley GA, Meisler DM et al: Conjunctival involve-
ment in paraneoplastic pemphigus, Am J Ophthalmol 114:621-
624, 1992.
Mimouni D, Anhalt GJ, Lazarova Z et al: Paraneoplastic pemphi-
gus in children and adolescents, Br J Dermatol 147:725-732,
2002.
Nousari HC, Deterding R, Wojtczack H et al: The mechanism of
respiratory failure in paraneoplastic pemphigus, N Engl J Med
340:1406-1410, 1999.
Nguyen VT, Ndoye A, Bassler KD et al: Classiﬁcation, clinical
manifestations, and immunopathological mechanisms of the
epithelial variant of paraneoplastic autoimmune multiorgan
syndrome: a reappraisal of paraneoplastic pemphigus, Arch
Dermatol 137:193-206, 2001.
Schmidt E, Hunzelmann N, Zillikens D et al: Rituximab in refrac-
tory autoimmune bullous diseases, Clin Exp Dermatol 31:503-
508, 2006.
Sklavounou A, Laskaris G: Paraneoplastic pemphigus: a review,
Oral Oncol 35:437-440, 1998.
Van Rossum MM, Verhaegen NTM, Jonkman MF et al: Follicular
non-Hodgkin’s lymphoma with refractory paraneoplastic
pemphigus: case report with review of novel treatment
modalities, Leuk Lymphoma 45:2327-2332, 2004.
Yokokura H, Demitsu T, Kakurai M et al: Paraneoplastic pem-
phigus mimicking erosive mucosal lichen planus associated
with primary hepatocellular carcinoma, J Dermatol 33:842-
845, 2006.
Cicatricial Pemphigoid
Ahmed AR, Colón JE: Comparison between intravenous immu-
noglobulin and conventional immunosuppressive therapy
regimens in patients with severe oral pemphigoid: effects on
disease progression in patients nonresponsive to dapsone
therapy, Arch Dermatol 137:1181-1189, 2001.
Ahmed M, Zein G, Khawaja F et al: Ocular cicatricial pemphi-
goid: pathogenesis, diagnosis and treatment, Prog Retin Eye
Res 23:579-592, 2004.
Bagan J, Muzio LL, Scully C: Mucous membrane pemphigoid,
Oral Dis 11:197-218, 2005.
Bhol KC, Goss L, Kumari S et al: Autoantibodies to human α6
integrin in patients with oral pemphigoid, J Dent Res 80:1711-
1715, 2001.
Calabresi V, Carrozzo M, Cozzani E et al: Oral pemphigoid auto-
antibodies preferentially target BP180 ectodomain, Clin
Immunol 122:207-213, 2007.
Casiglia J, Woo S-B, Ahmed AR: Oral involvement in autoim-
mune blistering diseases, Clin Dermatol 19:737-741, 2001.
Chaidemenos G: Tetracycline and niacinamide in the treatment
of blistering skin diseases, Clin Dermatol 19:781-785, 2001.
Chan LS: Mucous membrane pemphigoid, Clin Dermatol 19:703-
711, 2001.
Chan LS, Ahmed AR, Anhalt GJ et al: The ﬁrst international
consensus on mucous membrane pemphigoid: deﬁnition,
diagnostic criteria, pathogenic factors, medical treatment,
and prognostic indicators, Arch Dermatol 138:370-379,
2002.
Darling MR, Daley T: Blistering mucocutaneous diseases of the
oral mucosa—a review: Part 1. Mucous membrane pemphi-
goid, J Can Dent Assoc 71:851-854, 2005.
Egan CA, Lazarova Z, Darling TN et al: Anti-epiligrin cicatricial
pemphigoid: clinical ﬁndings, immunopathogenesis and sig-
niﬁcant associations, Medicine 82:177-186, 2003.
Egan CA, Taylor TB, Meyer LJ et al: The immunoglobulin A
antibody response in clinical subsets of mucous membrane
pemphigoid, Dermatology 198:330-335, 1999.
Ekong AS, Foster CS, Roque MR: Eye involvement in
autoimmune blistering diseases, Clin Dermatol 19:742-749,
2001.
Fatahzadeh M, Radfar L, Sirois DA: Dental care of patients with
autoimmune vesiculobullous diseases: case reports and litera-
ture review, Quintessence Int 37:777-787, 2006.
González-Moles MA, Scully C: Vesiculo-erosive oral mucosal
disease—management with topical corticosteroids: (1) funda-
mental principles and speciﬁc agents available, J Dent Res
84:294-301, 2005.
Grinspan D, Abulaﬁa J, Lanfranchi H: Angina bullosa hemor-
rhagica, Int J Dermatol 38:525-528, 1999.
Guiliani M, Favia GF, Lajolo C et al: Angina bullosa haemor-
rhagica: presentation of eight new cases and review of the
literature, Oral Dis 8:54-58, 2002.
Letko E, Bhol K, Anzaar F et al: Chronic cicatrizing conjunctivitis
in a patient with epidermolysis bullosa acquisita, Arch Oph-
thalmol 124:1615-1618, 2006.
Letko E, Miserocchi E, Daoud YJ et al: A nonrandomized com-
parison of the clinical outcome of ocular involvement in
patients with mucous membrane (cicatricial) pemphigoid
between conventional immunosuppressive and intravenous
immunoglobulin therapies, Clin Immunol 111:303-310,
2004.
Leverkus M, Schmidt E, Lazarova Z et al: Antiepiligrin cicatricial
pemphigoid. An underdiagnosed entity within the spectrum
of scarring autoimmune subepidermal bullous diseases? Arch
Dermatol 135:1091-1098, 1999.
Luke MC, Darling TN, Hsu R et al: Mucosal morbidity in patients
with epidermolysis bullosa acquisita, Arch Dermatol 135:954-
959, 1999.
O’Regan E, Bane A, Flint S et al: Linear IgA disease presenting
as desquamative gingivitis, Arch Otolaryngol Head Neck Surg
130:469-472, 2004.
Oyama N, Setterﬁeld JF, Powell AM et al: Bullous pemphigoid
antigen II (BP180) and its soluble extracellular domains are
major autoantigens in mucous membrane pemphigoid: the
pathogenic relevance to HLA class II alleles and disease
severity, Br J Dermatol 154:90-98, 2006.
Rashid KA, Gürcan HM, Ahmed AR: Antigen speciﬁcity in
subsets of mucous membrane pemphigoid, J Invest Dermatol
126:2631-2636, 2006.
Sacher C, Hunzelmann N: Cicatricial pemphigoid (mucous
membrane pemphigoid): current and emerging therapeutic
approaches, Am J Clin Dermatol 6:93-103, 2005.
Sami N, Bhol KC, Ahmed AR: Intravenous immunoglobulin
therapy in patients with multiple mucosal involvement in
mucous membrane pemphigoid, Clin Immunol 102:59-67,
2002.
Sánchez AR, Rogers III RS, Kupp LI et al: Desquamative gingivi-
tis associated with IgG/IgA pemphigoid presents a challeng-
ing diagnosis and treatment: a case report, J Periodontol
75:1714-1719, 2004.
Sapadin AN, Fleischmajer R: Tetracyclines: nonantibiotic prop-
erties and their clinical implications, J Am Acad Dermatol
54:258-265, 2006.
Scully C, Porter SR: The clinical spectrum of desquamative gin-
givitis, Sem Cutan Med Surg 16:308-313, 1997.
Setterﬁeld J, Shirlaw PJ, Kerr-Muir M et al: Mucous membrane
pemphigoid: a dual circulating antibody response with IgG
and IgA signiﬁes a more severe and persistent disease, Br J
Dermatol 138:602-610, 1998. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 811
Siegel MA, Anhalt GJ: Direct immunoﬂuorescence of detached
gingival epithelium for diagnosis of cicatricial pemphigoid:
report of ﬁve cases, Oral Surg Oral Med Oral Pathol 75:296-
302, 1993.
Sollecito TP, Parisi E: Mucous membrane pemphigoid, Dent Clin
North Am 49:91-106, 2005.
Stephenson P, Lamey P-J, Scully C et al: Angina bullosa haemor-
rhagica: clinical and laboratory features in 30 patients, Oral
Surg Oral Med Oral Pathol 63:560-565, 1987.
Thorne JE, Anhalt GJ, Jabs DA: Mucous membrane pemphigoid
and pseudopemphigoid, Ophthalmology 111:45-52, 2004.
Vincent SD, Lilly GE, Baker KA: Clinical, historic, and therapeu-
tic features of cicatricial pemphigoid: a literature review and
open therapeutic trial with corticosteroids, Oral Surg Oral Med
Oral Pathol 76:453-459, 1993.
Wojnarowska F, Kirtschig G, Khumalo N: Treatment of subepi-
dermal immunobullous diseases, Clin Dermatol 19:768-777,
2001.
Woodley DT, Chang C, Saadat P et al: Evidence that anti-type
VII collagen antibodies are pathogenic and responsible for
the clinical, histological, and immunological features of epi-
dermolysis bullosa acquisita, J Invest Dermatol 124:958-964,
2005.
Yamamoto K, Fujimoto M, Inoue M et al: Angina bullosa hemor-
rhagica of the soft palate: report of 11 cases and literature
review, J Oral Maxillofac Surg 64:1433-1436, 2006.
Bullous Pemphigoid
Anhalt GJ, Monison LH: Bullous and cicatricial pemphigoid, J
Autoimmun 4:17-35, 1991.
Korman NJ: Bullous pemphigoid. The latest in diagnosis, prog-
nosis, and therapy, Arch Dermatol 134:1137-1141, 1998.
Walsh SRA, Hogg D, Mydlarski PR: Bullous pemphigoid: from
bench to bedside, Drugs 65:905-926, 2005.
Williams DM: Vesiculo-bullous mucocutaneous disease: benign
mucous membrane and bullous pemphigoid, J Oral Pathol
Med 19:16-23, 1990.
Erythema Multiforme
Aslanzadeh J, Helm K, Espy MJ et al: Detection of HSV-speciﬁc
DNA in biopsy tissue of patients with erythema multiforme
by polymerase chain reaction, Br J Dermatol 126:19-23,
1992.
Auqier-Dunant A, Mockenhaupt M, Naldi L et al: Correlations
between clinical patterns and causes of erythema multiforme
majus, Stevens-Johnson syndrome, and toxic epidermal
necrolysis, Arch Dermatol 138:1019-1024, 2002.
Ayangco L, Rogers RS: Oral manifestations of erythema multi-
forme, Dermatol Clin 21:195-205, 2003.
Bastuji-Garin S, Rzany B, Stern RS et al: Clinical classiﬁcation of
cases of toxic epidermal necrolysis, Stevens-Johnson syn-
drome, and erythema multiforme, Arch Dermatol 129:92-96,
1993.
Chang Y-S, Huang F-C, Tseng S-H et al: Erythema multiforme,
Stevens-Johnson syndrome, and toxic epidermal necrolysis:
acute ocular manifestations, causes, and management, Cornea
26:1123-129, 2007.
Farthing P, Bagan J-V, Scully C: Erythema multiforme, Oral Dis
11:261-267, 2005.
French LE: Toxic epidermal necrolysis and Stevens Johnson syn-
drome: our current understanding, Allergol Int 55:9-16,
2006.
Garcia-Doval I, LeCleach L, Bocquet H et al: Toxic epidermal
necrolysis and Stevens-Johnson syndrome. Does early with-
drawal of causative drugs decrease the risk of death? Arch
Dermatol 136:323-327, 2000.
Kakourou T, Klontza D, Soteropoulou F et al: Corticosteroid
treatment of erythema multiforme major (Stevens-Johnson
syndrome) in children, Eur J Pediatr 156:90-93, 1997.
Lamoreux MR, Sternbach MR, Hsu WT: Erythema multiforme,
Am Fam Physician 74:1883-1888, 2006.
Lozada-Nur F, Cram D, Gorsky M: Clinical response to levami-
sole in thirty-nine patients with erythema multiforme: an
open prospective study, Oral Surg Oral Med Oral Pathol 74:294-
298, 1992.
Lyell A: Toxic epidermal necrolysis: an eruption resembling
scalding of the skin, Br J Dermatol 68:355-361, 1956.
Mittmann N, Chan B, Knowles S et al: Intravenous immuno-
globulin use in patients with toxic epidermal necrolysis and
Stevens-Johnson syndrome, Am J Clin Dermatol 7:359-368,
2006.
Paquet P, Piérard GE: Erythema multiforme and toxic epidermal
necrolysis: a comparative study, Am J Dermatopathol 19:127-
132, 1997.
Pereira FA, Mudgil AV, Rosmarin DM: Toxic epidermal necroly-
sis, J Am Acad Dermatol 56:181-200, 2007.
Schoﬁeld JK, Tatnail FM, Leigh IM: Recurrent erythema multi-
forme: clinical features and treatment in a large series of
patients, Br J Dermatol 128:542-545, 1993.
Shortt R, Gomez M, Mittman N et al: Intravenous immunoglobu-
lin does not improve outcome in toxic epidermal necrolysis,
J Burn Care Rehabil 25:246-255, 2004.
Singla R, Brodell RT: Erythema multiforme due to herpes simplex
virus: recurring target lesions are the clue to diagnosis, Post-
grad Med 106:151-154, 1999.
Stern RS: Improving the outcome of patients with toxic epider-
mal necrolysis and Stevens-Johnson syndrome, Arch Dermatol
136:410-411, 2000.
Trent J, Halem M, French L et al: Toxic epidermal necrolysis and
intravenous immunoglobulin: a review, Semin Cutan Med Surg
25:91-93, 2006.
Tripathi A, Ditto AM, Grammer LC et al: Corticosteroid therapy
in an additional 13 cases of Stevens-Johnson syndrome: a
total series of 67 cases, Allergy Asthma Proc 21:101-105,
2000.
Vanﬂeteren I, Van Gysel D, De Brandt C: Stevens-Johnson syn-
drome: a diagnostic challenge in the absence of skin lesions,
Pediatr Dermatol 20:52-56, 2003.
Viard I, Wehrli P, Bullani R et al: Inhibition of toxic epidermal
necrolysis by blockade of CD95 with human intravenous
immunoglobulin, Science 282:490-493, 1998.
Wilkins J, Morrison L, White CR: Oculocutaneous manifesta-
tions of the erythema multiforme/Stevens-Johnson syn-
drome/toxic epidermal necrolysis spectrum, Dermatol Clin
10:571-582, 1992.
Williams PM, Conklin RJ: Erythema multiforme: a review and
contrast from Stevens-Johnson syndrome/toxic epidermal
necrolysis, Dent Clin North Am 49:67-76, 2005.
Erythema Migrans
Espelid M, Bang G, Johannessen AC et al: Geographic stomatitis:
report of 6 cases, J Oral Pathol Med 20:425-428, 1991.
Gonzaga HFS, Torres EA, Alchorne MMA et al: Both psoriasis
and benign migratory glossitis are associated with HLA-Cw6,
Br J Dermatol 135:368-370, 1996.
Jainkittivong A, Langlais RP: Geographic tongue: clinical charac-
teristics of 188 cases, J Contemp Dent Pract 6:123-135,
2005.
Marks R, Radden BG: Geographic tongue: a clinico-pathological
review, Australas J Dermatol 22:75-79, 1981.
Morris LF, Phillips CM, Binnie WH et al: Oral lesions in patients
with psoriasis: a controlled study, Cutis 49:339-344, 1992. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

812 ORAL AND MAXILLOFACIAL PATHOLOGY
Shulman JD, Carpenter WM: Prevalence and risk factors associ-
ated with geographic tongue among US adults, Oral Dis
12:381-386, 2006.
Sigal MJ, Mock D: Symptomatic benign migratory glossitis: report
of two cases and literature review, Pediatr Dent 14:392-396,
1992.
Waltimo J: Geographic tongue during a year of oral contracep-
tive cycles, Br Dent J 171:94-96, 1991.
Zagari O: The prevalence and signiﬁcance of ﬁssured tongue and
geographical tongue in psoriatic patients, Clin Exp Dermatol
31:192-195, 2006.
Reactive Arthritis
Edwards L, Hartsen RC: Reiter’s syndrome of the vulva, Arch
Dermatol 128:811-814, 1992.
Kataria RK, Brent LH: Spondyloarthropathies, Am Fam Physician
69:2853-2860, 2004.
Keat A, Rowe I: Reiter’s syndrome and associated arthritides,
Rheum Dis Clin North Am 17:25-42, 1991.
Könönen M, Kovero O, Wenneberg B et al: Radiographic signs
in the temporomandibular joint in Reiter’s disease, J Orofac
Pain 16:143-147, 2002.
Lu DW, Katz KA: Declining use of the eponym “Reiter’s syn-
drome” in the medical literature, 1998-2003, J Am Acad Der-
matol 53:720-723, 2005.
Panush RS, Wallace DJ, Dorff EN et al: Retraction of the sugges-
tion to use the term “Reiter’s syndrome” sixty-ﬁve years later:
the legacy of Reiter, a war criminal, should not be eponymic
honor but rather condemnation (letter), Arthritis Rheum
56:693-694, 2007.
Rothe MJ, Kerdel FA: Reiter syndrome, Int J Dermatol 30:173-
180, 1991.
Schneider JM, Matthews JH, Graham BS: Reiter’s syndrome,
Cutis 71:198-200, 2003.
Lichen Planus
Al-Hashimi I, Schifter M, Lockhart PB et al: Oral lichen planus
and oral lichenoid lesions: diagnostic and therapeutic consid-
erations, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
103(suppl):S25e1-S25e12, January 2007 (Epub).
Belﬁore P, Di Fede O, Cabibi D et al: Prevalence of vulval lichen
planus in a cohort of women with oral lichen planus: an
interdisciplinary study, Br J Dermatol 155:994-998, 2006.
Borghelli RF, Pettinari IL, Chuchurru JA et al: Oral lichen planus
in patients with diabetes: an epidemiologic study, Oral Surg
Oral Med Oral Pathol 75:498-500, 1993.
Bornstein MM, Kalas L, Lemp S et al: Oral lichen planus and
malignant transformation: a retrospective follow-up study of
clinical and histopathologic data, Quintessence Int 37:261-
271, 2006.
Campana F, Sibaud V, Chauvel A et al: Recurrent superﬁcial
mucoceles associated with lichenoid disorders, J Oral Maxil-
lofac Surg 64:1830-1833, 2006.
Campisi G, Di Fede O, Craxì A et al: Oral lichen planus, hepatitis
C virus, and HIV: no association in a cohort study from an
area of high hepatitis C virus endemicity, J Am Acad Dermatol
51:364-370, 2004.
Carrozzo M, Francia di Celle P, Gandolfo S et al: Increased fre-
quency of HLA-DR6 allele in Italian patients with hepatitis C
virus-associated oral lichen planus, Br J Dermatol 144:803-
808, 2001.
DeRossi SS, Ciarrocca KN: Lichen planus, lichenoid drug reac-
tions, and lichenoid mucositis, Dent Clin North Am 49:77-89,
2005.
Eisen D: The clinical features, malignant potential, and systemic
associations of oral lichen planus: a study of 723 patients, J
Am Acad Dermatol 46:207-214, 2002.
Eisen D, Carrozzo M, Bagan-Sebastian J-V et al: Oral lichen
planus: clinical features and management, Oral Dis 11:338-
349, 2005.
Eisenberg E: Oral lichen planus: a benign lesion, J Oral Maxillofac
Surg 58:1278-1285, 2000.
Epstein JB, Wan LS, Gorsky M et al: Oral lichen planus: progress
in understanding its malignant potential and the implications
for clinical management, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 96:32-37, 2003.
Fatahzadeh M, Rinaggio J, Chiodo T: Squamous cell carcinoma
arising in an oral lichenoid lesion, J Am Dent Assoc 135:754-
759, 2004.
Firth NA, Rich AM, Radden BG et al: Assessment of the value of
immunoﬂuorescence microscopy in the diagnosis of oral
mucosal lichen planus, J Oral Pathol Med 19:295-297, 1990.
González-García A, Diniz-Freitas M, Gándara-Vila P et al: Triam-
cinolone acetonide mouth rinses for treatment of erosive oral
lichen planus: efﬁcacy and risk of fungal over-infection, Oral
Dis 12:559-565, 2006.
Gordon SC, Daley TD: Foreign body gingivitis. Clinical and
microscopic features of 61 cases, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 83:562-570,1997.
Harden D, Skelton H, Smith KJ: Lichen planus associated with
hepatitis C virus: no viral transcripts are found in the lichen
planus, and effective therapy for hepatitis C virus does not
clear lichen planus, J Am Acad Dermatol 49:847-852, 2003.
Hietanen J, Paasonen M-R, Kuhlefelt M et al: A retrospective
study of oral lichen planus patients with concurrent or sub-
sequent development of malignancy, Oral Oncol 35:278-282,
1999.
Holzberg M: Common nail disorders, Dermatol Clin 24:349-354,
2006.
Ingafou M, Leao JC, Porter SR et al: Oral lichen planus: a retro-
spective study of 690 British patients, Oral Dis 12:463-468,
2006.
Jainkittivong A, Kuvatanasuchati J, Pipattanagovit P et al: Candida
in oral lichen planus patients undergoing topical steroid
therapy, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
104:61-66, 2007.
Jungell P, Malmström M: Cyclosporin A mouthwash in the treat-
ment of oral lichen planus, Int J Oral Maxillofac Surg 25:60-62,
1996.
Kalmar JR: Diagnosis and management of oral lichen planus, J
Calif Dent Assoc 35:405-412, 2007.
Laeijendecker R, Tank B, Dekker SK et al: A comparison of treat-
ment of oral lichen planus with topical tacrolimus and triam-
cinolone acetonide ointment, Acta Derm Venereol 86:227-229,
2006.
Lodi G, Scully C, Carrozzo M et al: Current controversies in oral
lichen planus: report of an international consensus meeting.
Part 1. Viral infections and etiopathogenesis, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 100:40-51, 2005.
Lodi G, Scully C, Carrozzo M et al: Current controversies in oral
lichen planus: report of an international consensus meeting.
Part 2. Clinical management and malignant transformation,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100:164-
178, 2005.
Lozada-Nur FI, Sroussi HY: Tacrolimus powder in Orabase 0.1%
for the treatment of oral lichen planus and oral lichenoid
lesions: an open clinical trial, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 102:744-749, 2006.
Mattsson U, Jontell M, Holmstrup P: Oral lichen planus and
malignant transformation: is a recall of patients justiﬁed? Crit
Rev Oral Biol Med 13:390-396, 2002.
McCartan BE, McCreary CE: Oral lichenoid drug eruptions, Oral
Dis 3:58-63, 1997. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 813
Patel S, Yeoman CM, Murphy R: Oral lichen planus in child-
hood: a report of three cases, Int J Paediatr Dent 15:118-122,
2005.
Petruzzi M, De Benedittis M, Pastore L et al: Peno-gingival lichen
planus, J Periodontol 76:2293-2298, 2005.
Piboonniyom S, Treister N, Pitiphat W et al: Scoring system for
monitoring oral lichenoid lesions: a preliminary study, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 99:696-703,
2005.
Ramer MA, Altchek A, Deligdisch L et al: Lichen planus and the
vulvovaginal-gingival syndrome, J Periodontol 74:1385-1393,
2003.
Roosaar A, Yin L, Sandborgh-Englund G et al: On the natural
course of oral lichen lesions in a Swedish population-based
sample, J Oral Pathol Med 35:257-261, 2006.
Roy KM, Bagg J: Hepatitis C virus and oral disease: a critical
review, Oral Dis 5:270-277, 1999.
Setterﬁeld JF, Neill S, Shirlaw PJ et al: The vulvovaginal gingival
syndrome: a severe subgroup of lichen planus with charac-
teristic clinical features and a novel association with the class
II HLA DQB1*0201 allele, J Am Acad Dermatol 55:98-113,
2006.
Silverman S, Gorsky M, Lozada-Nur F et al: A prospective study
of ﬁndings and management in 214 patients with oral lichen
planus, Oral Surg Oral Med Oral Pathol 72:665-670, 1991.
Sugerman PB, Savage NW, Walsh LJ et al: The pathogenesis of
oral lichen planus, Crit Rev Oral Biol Med 13:350-365, 2002.
Thorne JE, Jabs DA, Nikolskaia OV et al: Lichen planus and cica-
trizing conjunctivitis: characterization of ﬁve cases, Am J Oph-
thalmol 136:239-243, 2003.
Thornhill MH, Sankar V, Xu X-J et al: The role of histopathologi-
cal characteristics in distinguishing amalgam-associated oral
lichenoid reactions and oral lichen planus, J Oral Pathol Med
35:233-240, 2006.
Tucker SC, Coulson IH: Lichen planus is not associated with
hepatitis C infection in patients from North West England,
Acta Derm Venereol 79:378-379, 1999.
Van der Meij EH, Mast H, van der Waal I: The possible prema-
lignant character of oral lichen planus and oral lichenoid
lesions: a prospective follow-up study of 192 patients, Oral
Oncol 43:742-748, 2007.
Van der Meij EH, Slootweg PJ, van der Wal JE et al: Interob-
server and intraobserver variability in the histologic assess-
ment of oral lichen planus, J Oral Pathol Med 28:274-277,
1999.
Van der Meij EH, van der Waal I: Lack of clinicopathologic cor-
relation in the diagnosis of oral lichen planus based on the
presently available diagnostic criteria and suggestions for
modiﬁcations, J Oral Pathol Med 32:507-512, 2003.
Voûte ABE, Schulten EAJM, Langendijk PNJ et al: Fluocinonide
in an adhesive base for treatment of oral lichen planus: a
double-blind, placebo-controlled clinical study, Oral Surg Oral
Med Oral Pathol 75:181-185, 1993.
Zakrzewska JM, Chan ES-Y, Thornhill MH: A systematic review
of placebo-controlled randomized clinical trials of treatments
used in oral lichen planus, Br J Dermatol 153:336-341,
2005.
Zhang LW, Michelsen C, Cheng X et al: Molecular analysis of
oral lichen planus. A premalignant lesion? Am J Pathol
151:323-327, 1997.
Chronic Ulcerative Stomatitis
Church LF, Schosser RH: Chronic ulcerative stomatitis associ-
ated with stratiﬁed epithelial speciﬁc antinuclear antibodies:
a case report of a newly described entity, Oral Surg Oral Med
Oral Pathol 73:579-582, 1992.
Jaremko WM, Beutner EH, Kumar V et al: Chronic ulcerative
stomatitis associated with a speciﬁc immunologic marker, J
Am Acad Dermatol 22:2115-2120, 1990.
Lee LA, Walsh P, Prater CA et al: Characterization of an autoan-
tigen associated with chronic ulcerative stomatitis: the CUSP
autoantigen is a member of the p53 family, J Invest Dermatol
113:146-151, 1999.
Lewis JE, Beutner EH: Chronic ulcerative stomatitis with strati-
ﬁed epithelium-speciﬁc antinuclear antibodies, Int J Dermatol
35:272-275, 1996.
Lorenzana ER, Rees TD, Glass M et al: Chronic ulcerative stoma-
titis: a case report, J Periodontol 71:104-111, 2000.
Solomon LW, Aguirre A, Neiders M et al: Chronic ulcerative
stomatitis: clinical, histopathologic, and immunopathologic
ﬁndings, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
96:718-726, 2003.
Wörle B, Wollenberg A, Schaller M et al: Chronic ulcerative
stomatitis, Br J Dermatol 137:262-265, 1997.
Graft-Versus-Host Disease
Abdelsayed RA, Sumner T, Allen CM et al: Oral precancerous
and malignant lesions associated with graft-versus-host
disease: report of 2 cases, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 93:75-80, 2002.
Alborghetti MR, Corrêa MEP, Adam RL et al: Late effect of
chronic graft-versus-host disease in minor salivary glands, J
Oral Pathol Med 34:486-493, 2005.
Bridge AT, Nelson RP, Schwartz JE et al: Histological evaluation
of acute mucocutaneous graft-versus-host disease in non-
myeloablative hematologic stem cell transplants with an
observation predicting an increased risk of progression to
chronic graft-versus-host disease, Am J Dermatopathol 29:1-6,
2007.
Centers for Disease Control: Guidelines for preventing opportu-
nistic infections among hematopoietic stem cell transplant
recipients, MMWR Morb Mortal Wkly Rep 49(RR-10):1-128,
2000.
Chao NJ, Schmidt GM, Niland JC et al: Cyclosporine, methotrex-
ate, and prednisone compared with cyclosporine and pred-
nisone for prophylaxis of acute graft-versus-host disease, N
Engl J Med 329:1225-1230, 1993.
Couriel D, Caldera H, Champlin R et al: Acute graft-versus-host
disease: pathophysiology, clinical manifestations, and man-
agement, Cancer 101:1936-1946, 2004.
Deeg HJ, Antin JH: The clinical spectrum of acute graft-versus-
host disease, Semin Hematol 43:24-31, 2006.
Demarosi F, Soligo D, Lodi G et al: Squamous cell carcinoma of
the oral cavity associated with graft versus host disease: report
of a case and review of the literature, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 100:63-69, 2005.
Easaw SJ, Lake DE, Beer M et al: Graft-versus-host disease.
Possible higher risk for African American patients, Cancer
78:1492-1497, 1996.
Eckardt A, Starke O, Stadler M et al: Severe oral chronic graft-
versus-host disease following allogeneic bone marrow trans-
plantation: highly effective treatment with topical tacrolimus,
Oral Oncol 40:811-814, 2004.
Euvrard S, Kanitakis J, Claudy A: Medical progress: skin cancers
after organ transplantation, N Engl J Med 348:1681-1691,
2003.
García-F-Villalta MJ, Pascual-López M, Elices M et al:
Superﬁcial mucoceles and lichenoid graft versus host disease:
report of three cases, Acta Derm Venereol 82:453-455,
2002.
Gilman AL, Serody J: Diagnosis and treatment of chronic graft-
versus-host disease, Semin Hematol 43:70-80, 2006. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

814 ORAL AND MAXILLOFACIAL PATHOLOGY
Goldman KE: Dental management of patients with bone marrow
and solid organ transplantation, Dent Clin North Am 50:659-
676, 2006.
Horwitz ME, Sullivan KM: Chronic graft-versus-host disease,
Blood Rev 20:15-27, 2006.
Johnson ML, Farmer ER: Graft-versus-host reactions in derma-
tology, J Am Acad Dermatol 38:369-392, 1998.
Lee SJ, Klein JP, Barrett AJ et al: Severity of chronic graft-versus-
host disease: association with treatment-related mortality and
relapse, Blood 100:406-414, 2002.
Melkos AB, Massenkeil G, Arnold R et al: Dental treatment
prior to stem cell transplantation and its inﬂuence on the
posttransplantation outcome, Clin Oral Invest 7:113-115,
2003.
Nagler RM, Nagler A: Pilocarpine hydrochloride relieves xero-
stomia in chronic graft-versus-host disease: a sialometrical
study, Bone Marrow Transplant 23:1007-1011, 1999.
Nagler RM, Nagler A: Salivary gland involvement in graft-versus-
host disease: the underlying mechanism and implicated treat-
ment, Isr Med Assoc J 6:167-172, 2004.
Pérez-Simón JA, Sánchez-Abarca I, Díez-Campelo M et al:
Chronic graft-versus-host disease: pathogenesis and clinical
management, Drugs 66:1041-1057, 2006.
Rocha V, Wagner JE, Sobocinski KA et al: Graft-versus-host
disease in children who have received a cord-blood or bone
marrow transplant from an HLA-identical sibling, N Engl J
Med 342:1846-1854, 2000.
Rodu B, Gockerman JP: Oral manifestations of the chronic graft-
v-host reaction, JAMA 249:504-507, 1983.
Sánchez AR, Sheridan PJ, Rogers RS: Successful treatment of
oral lichen planus-like chronic graft-versus-host disease with
topical tacrolimus: a case report, J Periodontol 75:613-619,
2004.
Sato M, Tokuda N, Fukumoto T et al: Immunohistopathological
study of the oral lichenoid lesions of chronic GVHD, J Oral
Pathol Med 35:33-36, 2006.
Schubert MM, Williams BE, Lloid ME et al: Clinical assessment
scale for the rating of oral mucosal changes associated with
bone marrow transplantation: development of an oral muco-
sitis index, Cancer 69:2469-2477, 1992.
Sedghizadeh PP, Allen CM, Anderson KE et al: Oral graft-versus-
host disease and programmed cell death: pathogenetic and
clinical correlates, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 97:491-498, 2004.
Shulman HM, Kleiner D, Lee SJ et al: Histopathologic diagnosis
of chronic graft-versus-host disease: National Institutes of
Health consensus development project on criteria for clinical
trials in chronic graft-versus-host disease: II. Pathology
working group report, Biol Blood Marrow Transplant 12:31-47,
2006.
Soares AB, Faria PR, Magna LA et al: Chronic GVHD in minor
salivary glands and oral mucosa: histopathological and immu-
nohistochemical evaluation of 25 patients, J Oral Pathol Med
34:368-373, 2005.
Szeto CH, Shek TWH, Lie AKW et al: Squamous cell carcinoma
of the tongue complicating chronic oral mucosal graft-versus-
host disease after allogeneic hematopoietic stem cell trans-
plantation, Am J Hematol 77:200-202, 2004.
Thomas ED: Bone marrow transplantation: a review, Semin
Hematol 36 (suppl7):95-103, 1999.
Treister NS, Woo S-B, O’Holleran EW et al: Oral chronic graft-
versus-host disease in pediatric patients after hematopoietic
stem cell transplantation, Biol Blood Marrow Transplant 11:721-
731, 2005.
Vogelsang GB: Acute and chronic graft-versus-host disease, Curr
Opin Oncol 5:276-281, 1993.
Woo S-B, Lee SJ, Schubert MM: Graft-vs-host disease, Crit Rev
Oral Biol Med 8:201-216, 1997.
Woo S-B, Sonis ST, Monopoli MM et al: A longitudinal study of
oral ulcerative mucositis in bone marrow transplant recipi-
ents, Cancer 72:1612-1617, 1993.
Psoriasis
Bruce AJ, Rogers RS: Oral psoriasis, Dermatol Clin 21:99-104,
2003.
Camisa C: Psoriasis: a clinical update on diagnosis and new
therapies, Cleve Clin J Med 67:105-106, 109-113, 117-119,
2000.
Doffy DL, Spelman LS, Martin NG: Psoriasis in Australian twins,
J Am Acad Dermatol 29:428-434, 1993.
Eastman JR, Goldblatt LI: Psoriasis: palatal manifestations and
physiologic considerations, J Periodontol 54:736-739, 1983.
Gelfand JM, Gladman DD, Mease PJ et al: Epidemiology of pso-
riatic arthritis in the population of the United States, J Am
Acad Dermatol 53:573, 2005.
Lowes MA, Bowcock AM, Krueger JG: Pathogenesis and therapy
of psoriasis, Nature 445:866-873, 2007.
Myers WA, Gottlieb AB, Mease P: Psoriasis and psoriatic arthri-
tis: clinical features and disease mechanisms, Clin Dermatol
24:438-447, 2006.
Richardson LJ, Kratochvil FJ, Zieper MB: Unusual palatal presen-
tation of oral psoriasis, J Can Dent Assoc 66:80-82, 2000.
Smith CH, Barker JNWN: Psoriasis and its management, Br Med
J 333:380-384, 2006.
Stern RS, Laird N: The carcinogenic risk of treatments for severe
psoriasis, Cancer 73:2759-2764, 1994.
Younai FS, Phelan JA: Oral mucositis with features of psoriasis:
report of a case and review of the literature, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 84:61-67, 1997.
Lupus Erythematosus
Brennan MT, Valerin MA, Napeñas JJ et al: Oral manifestations
of patients with lupus erythematosus, Dent Clin North Am
49:127-141, 2005.
Burge SM, Frith PA, Millard PR et al: Mucosal involvement in
systemic and chronic cutaneous lupus erythematosus, Br J
Dermatol 121:727-741, 1989.
Callen JP: Oral manifestations of collagen vascular disease, Semin
Cutan Med Surg 16:323-327, 1997.
Cervera R, Khamashta MA, Font J et al: Morbidity and mortality
in systemic lupus erythematosus during a 5-year period, Medi-
cine (Baltimore) 78:167-175, 1999.
Deapen D, Escalante A, Weinrib L et al: A revised estimate of
twin concordance in systemic lupus erythematosus, Arthritis
Rheum 35:311-318, 1992.
D’Cruz DP: Systemic lupus erythematosus, Br Med J 332:890-
894, 2006.
D’Cruz DP, Khamashta MA, Hughes GRV: Systemic lupus ery-
thematosus, Lancet 369:587-596, 2007
De Rossi SS, Glick M: Lupus erythematosus: considerations for
dentistry, J Am Dent Assoc 129:330-339, 1998.
Doria A, Iaccarino L, Ghirardello A et al: Long-term prognosis
and causes of death in systemic lupus erythematosus, Am J
Med 119:700-706, 2006.
Duong DJ, Spigel GT, Moxley RT et al: American experience with
low-dose thalidomide therapy for severe cutaneous lupus ery-
thematosus, Arch Dermatol 135:1079-1087, 1999.
Fabbri P, Cardinali C, Giomi B et al: Cutaneous lupus erythema-
tosus: diagnosis and management, Am J Clin Dermatol 4:449-
465, 2003.
Ginzler EM, Dooley MA, Aranow C et al: Mycophenolate mofetil
or intravenous cyclophosphamide for lupus nephritis, N Engl
J Med 353:2219-2228, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 16 DERMATOLOGIC DISEASES 815
Hahn BH: Systemic lupus erythematosus. In Kasper DL, Braun-
wald E, Fauci AS et al: Harrison’s principles of internal medicine,
ed 16, pp 1960-1967, New York, 2005, McGraw-Hill.
Rhodus NL, Johnson DK: The prevalence of oral manifestations
of systemic lupus erythematosus, Quintessence Int 21:461-
465, 1990.
Rothﬁeld N, Sontheimer RD, Bernstein M: Lupus erythematosus:
systemic and cutaneous manifestations, Clin Dermatol 24:348-
362, 2006.
Tebbe B: Clinical course and prognosis of cutaneous lupus ery-
thematosus, Clin Dermatol 22:121-124, 2004.
Thorne JE, Jabs DA, Nikolskaia O et al: Discoid lupus erythema-
tosus and cicatrizing conjunctivitis: clinicopathologic study of
two cases, Ocul Immunol Inﬂamm 10:287-292, 2002.
Velthuis PJ, Kater L, Baart de la Faille H: Direct immunoﬂuores-
cence patterns in clinically healthy skin of patients with col-
lagen diseases, Clin Dermatol 10:423-430, 1993.
Werth VP: Clinical manifestations of cutaneous lupus erythema-
tosus, Autoimmun Rev 4:296-302, 2005.
Systemic Sclerosis
Chung L, Lin J, Furst DE et al: Systemic and localized sclero-
derma, Clin Dermatol 24:374-392, 2006.
Demir Y, Karaaslan T, Aktepe F et al: Linear scleroderma “en
coup de sabre” of the cheek, J Oral Maxillofac Surg 61:1091-
1094, 2003.
Eversole LR, Jacobsen PL, Stone CE: Oral and gingival changes
in systemic sclerosis (scleroderma), J Periodontol 55:175-178,
1984.
Generini S, Fiori G, Moggi-Pignone A et al: Systemic sclerosis: a
clinical overview, Adv Exp Med Biol 455:73-83, 1999.
Gonzales TS, Coleman GC: Periodontal manifestations of colla-
gen vascular disorders, Periodontol 2000 21:94-105, 1999.
Haers PE, Sailer HF: Mandibular resorption due to systemic
sclerosis: case report of surgical correction of a secondary
open bite deformity, Int J Oral Maxillofac Surg 24:261-267,
1995.
Ioannidis JPA, Vlachoyiannopoulos PG, Haidich A-B et al: Mor-
tality in systemic sclerosis: an international meta-analysis of
individual patient data, Am J Med 118:2-10, 2005.
Knobler RM, French LE, Kim Y et al: A randomized, double-
blind, placebo-controlled trial of photopheresis in systemic
sclerosis, J Am Acad Dermatol 54:793-799, 2006.
Marmary Y, Glaiss R, Pisanty S: Scleroderma: oral manifesta-
tions, Oral Surg Oral Med Oral Pathol 52:32-37, 1981.
Medsger TA: Natural history of systemic sclerosis and the assess-
ment of disease activity, severity, functional status, and psy-
chologic well-being, Rheum Dis Clin North Am 29:255-273,
2003.
Naylor WP: Oral management of the scleroderma patient, J Am
Dent Assoc 105:814-817, 1982.
Ong VH, Brough G, Denton CP: Management of systemic scle-
rosis, Clin Med 5:214-219, 2005.
Rook AH, Freundlich B, Jegasothy BV et al: Treatment of
systemic sclerosis with extracorporeal photochemotherapy:
results of a multicenter trial, Arch Dermatol 128:337-346,
1992.
Rout PGJ, Hamburger J, Potts AJC: Orofacial radiological mani-
festations of systemic sclerosis, Dentomaxillofac Radiol 25:193-
196, 1996.
Salojin KV, Tonquèze ML, Saraux A et al: Antiendothelial cell
antibodies: useful markers of systemic sclerosis, Am J Med
102:178-185, 1997.
Spackman GK: Scleroderma: what the general dentist should
know, Gen Dent 47:576-579, 1999.
Wollheim FA: Classiﬁcation of systemic sclerosis. Visions and
reality, Rheumatol 44:1212-1216, 2005.
Yenisey M, Külünk T, Kurt S¸ et al: A prosthodontics management
alternative for scleroderma patients, J Oral Rehabil 32:696-
700, 2005.
CREST Syndrome
Chamberlain AJ, Walker NPJ: Successful palliation and signiﬁ-
cant remission of cutaneous calcinosis in CREST syndrome
with carbon dioxide laser, Dermatol Surg 968-970, 2003.
Paley M, McLoughlin P: Oral problems associated with CREST
syndrome: a case report, Br Dent J 175:295-296, 1993.
Sparsa A, Lesaux N, Kessler E et al: Treatment of cutaneous cal-
cinosis in CREST syndrome by extracorporeal shock wave
lithotripsy, J Am Acad Dermatol 53:S263-S265, 2005.
Stanford TW, Peterson J, Machen RL: CREST syndrome and
periodontal surgery: a case report, J Periodontol 70:536-541,
1999.
Ueda M, Abe Y, Fujiwara H et al: Prominent telangiectasia asso-
ciated with marked bleeding in CREST syndrome, J Dermatol
20:180-184, 1993.
Acanthosis Nigricans
Cairo F, Rubino I, Rotundo R et al: Oral acanthosis nigricans as
a marker of internal malignancy. A case report, J Periodontol
72:1271-1275, 2001.
Hall JM, Moreland A, Cox GJ et al: Oral acanthosis nigricans:
report of a case and comparison of oral and cutaneous pathol-
ogy, Am J Dermatopathol 10:68-73, 1988.
McGuinness J, Greer K: Malignant acanthosis nigricans and tripe
palms associated with pancreatic adenocarcinoma, Cutis
78:37-40, 2006.
Mostoﬁ RS, Hayden NP, Soltani K: Oral malignant acanthosis
nigricans, Oral Surg Oral Med Oral Pathol 56:372-374,
1983.
Pentenero M, Carrozzo M, Pagano M et al: Oral acanthosis
nigricans, tripe palms and sign of Leser-Trélat in a patient
with gastric adenocarcinoma, Int J Dermatol 43:530-532,
2004.
Ramirez-Amador V, Esquivel-Pedraza L, Caballero-Mendoza E
et al: Oral manifestations as a hallmark of malignant acantho-
sis nigricans, J Oral Pathol Med 28:278-281, 1999.
Schwartz RA: Acanthosis nigricans, J Am Acad Dermatol 31:1-19,
1994.
Scully C, Barrett WA, Gilkes J et al: Oral acanthosis nigricans,
the sign of Leser-Trélat and cholangiocarcinoma, Br J Derma-
tol 145:505-526, 2001.
Stuart CA, Driscoll MS, Lundquist KF et al: Acanthosis nigricans,
J Basic Clin Physiol Pharmacol 9:407-418, 1998. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

816
17
Oral Manifestations of
Systemic Diseases
CHAPTER OUTLINE
Mucopolysaccharidosis
Lipid Reticuloendothelioses
Gaucher Disease
Niemann-Pick Disease
Tay-Sachs Disease
Lipoid Proteinosis
Jaundice
Amyloidosis
Vitamin Deﬁciency
Vitamin A
Thiamin
Riboﬂavin
Niacin
Pyridoxine
Vitamin C
Vitamin D
Vitamin E
Vitamin K
Iron-Deﬁciency Anemia
Plummer-Vinson Syndrome
Pernicious Anemia
Pituitary Dwarﬁsm
Gigantism
Acromegaly
Hypothyroidism
Hyperthyroidism
Hypoparathyroidism
Pseudohypoparathyroidism
Hyperparathyroidism
Hypercortisolism
Addison’s Disease
Diabetes Mellitus
Hypophosphatasia
Vitamin D–Resistant Rickets
Crohn’s Disease
Pyostomatitis Vegetans
Uremic Stomatitis
MUCOPOLYSACCHARIDOSIS
The mucopolysaccharidoses are a heterogeneous
group of metabolic disorders that are usually inherited
in an autosomal recessive fashion. These disorders are
all characterized by the lack of any one of several
normal enzymes needed to process the important
intercellular substances known as glycosaminoglycans.
These substances used to be known as mucopolysaccha-
rides, thus the term mucopolysaccharidosis. Examples of
glycosaminoglycans include the following:
● Heparan sulfate
● Dermatan sulfate
● Keratan sulfate
● Chondroitin sulfate
The type of mucopolysaccharidosis that is seen clini-
cally depends on which of these substrates lacks its
particular enzyme. The mucopolysaccharidoses as a
group occur with a frequency of approximately 1 in
15,000 to 29,000 live births, although some types are
much less common. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 817
CLINICAL AND RADIOGRAPHIC
FEATURES
The clinical features of the mucopolysaccharidoses
vary, depending on the particular syndrome that is
examined (Table 17-1). Furthermore, affected patients
with a particular type of this disorder often exhibit a
wide range of severity of involvement. Most types of
mucopolysaccharidosis display some degree of mental
retardation. Often the facial features of affected patients
are somewhat coarse, with heavy browridges (Fig.
17-1), and there are other skeletal changes, such as stiff
joints. Cloudy degeneration of the corneas, a problem
that frequently leads to blindness, is seen in several
forms of mucopolysaccharidosis.
The oral manifestations vary according to the par-
ticular type of mucopolysaccharidosis. Most types show
some degree of macroglossia. Gingival hyperplasia
may be present, particularly in the anterior regions, as
a result of the drying and irritating effects of mouth
Table 17-1 Features of Selected Mucopolysaccharidosis Syndromes
TypeEponym InheritanceEnzyme Deﬁciency Stored SubstrateClinical Features
I-H Hurler AR α-L-Iduronidase HS and DS Appears in infancy;
cloudy corneas,
growth retardation,
reduced intelligence,
coronary artery
disease; rarely live
10 years
I-S Scheie AR α-L-Iduronidase HS and DS Onset in late
childhood; cloudy
corneas, normal
intelligence, aortic
regurgitation; survive
to adulthood
II Hunter X-Linked R Iduronate-2-sulfatase HS and DS Appears at 1 to 2 years
of age; clear corneas,
reduced intelligence,
growth retardation,
stiff joints
III-ASanﬁlippo-A AR Sulfamidase HS Appears at 4 to 6 years
of age; clear corneas,
reduced intelligence,
mild skeletal
changes; death in
adolescence
III-BSanﬁlippo-B AR α-N-acetylglucosaminidase HS Generally same as
Sanﬁlippo-A
IV-AMorquio-A AR Galactosamine-6-sulfatase KS, CS, GalNAc6SAppears at 1 to 2 years
of age; cloudy
corneas, normal
intelligence, lax
joints; may survive
to middle age
IV-BMorquio-B AR β-galactosidase KS Generally similar to
Morquio-A
VI Maroteaux-LamyAR N-acetylgalactosamine-4-sulfataseDS, CS, GalNAc4S,
GalNAc4, 6dis
Appears at 2 to 6 years
of age; cloudy
corneas, normal
intelligence, growth
retardation, stiff
joints; may survive
to adulthood
AR, Autosomal recessive; CS, chondroitin sulfate; dis, disulfate; DS, dermatan sulfate; GalNAc, N-acetylgalactosamine; HS, heparan sulfate; KS, keratan
sulfate; R, recessive; S, sulfate. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

818 ORAL AND MAXILLOFACIAL PATHOLOGY
levels of glycosaminoglycans in the urine, as well as
deﬁciencies of the speciﬁc enzymes in the patient’s
leukocytes and ﬁbroblasts.
TREATMENT AND PROGNOSIS
No satisfactory systemic treatment of the mucopolysac-
charidoses exists at this time. Several forms of muco-
polysaccharidosis are associated with a markedly
reduced life span and with mental retardation. Attempts
to improve the survival and quality of life of these
patients using allogeneic bone marrow transplantation
have met with some success. Unfortunately, not all
aspects of the disease are corrected, and the com-
plications associated with transplantation must be
addressed. Such complications are associated with a
15% to 20% mortality rate. Enzyme replacement therapy
currently is available for mucopolysaccharidosis I.
Initiation of the enzyme, laronidase, early in the
patient’s life appears to improve signiﬁcantly many of
the aspects of the disease, although complete resolu-
tion does not occur. Enzyme replacement strategies are
also being developed for several of the other forms of
this condition. Because of the rarity of these conditions
and the expense of developing the treatments, the
annual cost for such therapy typically exceeds
$340,000. Genetic counseling is indicated for the
parents and siblings of a patient affected by one of the
mucopolysaccharidosis syndromes. Prenatal diagnosis
is available for family planning as well.
Management of the dental problems of these patients
is essentially no different from that of other patients.
However, several factors may have to be taken into
account:
●Degree of mental retardation (if any)
●Presence or absence of a seizure disorder
●Degree of joint stiffening
●Extent of other related medical problems
Depending on which of these factors is present and
the extent of involvement, dental care may warrant
sedation, hospitalization, or general anesthesia of the
patient for optimal results. General anesthesia and
sedation may be challenging, however, because of
excess amounts of pharyngeal tissues that often produce
a smaller than normal airway. In severely affected
patients, general anesthesia probably should be consid-
ered only in life-threatening situations.
LIPID RETICULOENDOTHELIOSES
The lipid reticuloendothelioses are a relatively
rare group of inherited disorders. These include the
following conditions:
● Gaucher disease
● Niemann-Pick disease
● Tay-Sachs disease
Fig. 17-1 Mucopolysaccharidosis. This patient affected by
Hunter syndrome exhibits the characteristic facial features of
this disorder.
A B
Fig. 17-2 Mucopolysaccharidosis. Radiographic
examination of the dentition of a child affected by Hunter
syndrome typically shows radiolucencies (arrows) associated
with the crowns of unerupted teeth.
breathing. The dental changes include thin enamel
with pointed cusps on the posterior teeth, although this
seems to be a feature unique to mucopolysaccharidosis
type IVA. Other dental manifestations include numer-
ous impacted teeth with prominent follicular spaces
(Fig. 17-2), possibly caused by the accumulation of
glycosaminoglycans in the follicular connective tissue.
Some investigators have reported the occurrence
of multiple impacted teeth that are congregated in
a single large follicle, forming a rosette pattern
radiographically.
Although the clinical ﬁndings may suggest that a
patient is affected by one of the mucopolysaccharido-
ses, the diagnosis is conﬁrmed by ﬁnding elevated `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 819
These conditions are seen with increased frequency
in patients with Ashkenazi Jewish heritage. Affected
patients lack certain enzymes necessary for processing
speciﬁc lipids, and this results in an accumulation of
the lipids within a variety of cells. Because of this accu-
mulation, it appeared that cells were attempting to
store these substances; therefore, the term storage
disease was commonly used for these disorders.
In Gaucher disease (the most common of the retic-
uloendothelioses), a lack of glucocerebrosidase results
in the accumulation of glucosylceramide, particularly
within the lysosomes of cells of the macrophage and
monocyte lineage. Three types of Gaucher disease
are now recognized: type 1 (nonneuronopathic) is
seen primarily in the Ashkenazi Jewish population,
and types 2 and 3 (neuronopathic) have a panethnic
distribution.
Niemann-Pick disease is characterized by a deﬁ-
ciency of acid sphingomyelinase, resulting in the accu-
mulation of sphingomyelin, also within the lysosomes
of macrophages.
Tay-Sachs disease is caused by a lack of β-hexosa-
minidase A, which results in the accumulation of
a ganglioside, principally within the lysosomes of
neurons.
All these disorders are inherited as autosomal
recessive traits. When the genetic mutation known
to cause Gaucher disease was evaluated for the
Ashkenazi Jewish population, researchers found that
approximately 1 in 10 persons carried the defective
gene. Most of the persons identiﬁed as having the
gene, however, were heterozygous and, therefore,
asymptomatic.
CLINICAL AND RADIOGRAPHIC
FEATURES
GAUCHER DISEASE
The clinical features of Gaucher disease are generally
the result of the effects of the abnormal storage of
glucosylceramide. Macrophages laden with this gluco-
cerebroside are typically rendered relatively nonfunc-
tional, and they tend to accumulate within the bone
marrow of the affected patient. This accumulation dis-
places the normal hematopoietic cells and produces
anemia and thrombocytopenia. In addition, these
patients are susceptible to bone infarctions. The result-
ing bone pain is often the presenting complaint. Char-
acteristic Erlenmeyer ﬂask deformities of the long bones,
particularly of the femur, are often identiﬁed. Accumu-
lations of the macrophages in the spleen and liver
result in visceral enlargement. Many affected patients
show a signiﬁcant degree of growth retardation. Neu-
rologic deterioration occurs in patients with the less
common types 2 and 3 Gaucher disease. Jaw lesions
typically appear as ill-deﬁned radiolucencies that
usually affect the mandible without causing devitaliza-
tion of the teeth or resorption of the lamina dura.
Decreased salivary ﬂow has been documented for
patients with Gaucher disease compared with an age-
and sex-matched population, although this decrease
may not be clinically signiﬁcant.
NIEMANN-PICK DISEASE
Niemann-Pick disease occurs as three different types,
each associated with a different clinical expression and
prognosis. Types A and B are caused by a deﬁciency of
acid sphingomyelinase, whereas type C is primarily the
result of mutation of NPC-1, a gene involved with cho-
lesterol processing. Types A and C have neu ronopathic
features, characterized by psychomotor retardation,
dementia, spasticity, and hepatosplenomegaly, with
death occurring during the ﬁrst or second decade of
life. Type B patients normally survive into adulthood
and exhibit visceral signs, primarily hepatospleno-
megaly, and sometimes pulmonary involvement.
TAY-SACHS DISEASE
Tay-Sachs disease may have a wide clinical range
because the condition is genetically heterogeneous.
Some forms are mild, with patients surviving into adult-
hood. In the severe infantile form, however, rapidly
progressive neuronal degeneration develops shortly
after birth. Signs and symptoms include blindness,
developmental retardation, and intractable seizures.
Death usually occurs by 3 to 5 years of age.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of an osseous lesion of
Gaucher disease shows sheets of lipid-engorged mac-
rophages (Gaucher cells) exhibiting abundant bluish
cytoplasm, which has a ﬁne texture resembling wrin-
kled silk. In Niemann-Pick disease, the characteristic
cell seen on examination of a bone marrow aspirate is
the “sea blue” histiocyte.
TREATMENT AND PROGNOSIS
GAUCHER DISEASE
For patients with a mild expression of Gaucher disease,
no treatment may be necessary. For more severe forms
of Gaucher disease, enzyme replacement therapy
with macrophage-targeted glucocerebrosidase (imiglu-
cerase for injection) is used; however, this is quite
expensive, often costing more than $200,000 per year
for treatment. After 9 to 12 months of therapy, patients
exhibit improvement in the status of their anemia, a
decrease in plasma glucocerebroside levels, and a
decrease in hepatosplenomegaly. Resolution of the
radiographic bone changes takes place over a longer `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

820 ORAL AND MAXILLOFACIAL PATHOLOGY
period. Children treated with this regimen may show
signiﬁcant gain in height. Unfortunately enzyme
replacement therapy has shown minimal effect on the
neuronopathic Gaucher disease types 2 and 3. Bone
marrow transplantation has also been attempted;
however, the problems inherent in graft-versus-host
disease (GVHD) are still present with that form of
therapy, and thus it is not recommended. A case-control
study showed that adults with Gaucher disease have an
increased risk for hematologic malignancies, particu-
larly lymphoma and multiple myeloma. Genetic coun-
seling should be provided to all affected patients.
NIEMANN-PICK AND TAY-SACHS DISEASE
The neuronopathic forms of Niemann-Pick disease and
the infantile form of Tay-Sachs disease are associated
with a poor prognosis. Genetic counseling should be
provided for affected families. Molecular markers of
these disorders have been developed to identify carri-
ers. Such identiﬁcation allows earlier intervention in
terms of counseling, and targeted population screening
for the gene that causes Tay-Sachs disease has resulted
in a marked decrease in affected patients during the
past 3 decades.
LIPOID PROTEINOSIS
(HYALINOSIS CUTIS ET MUCOSAE;
URBACH-WIETHE SYNDROME)
A rare condition, lipoid proteinosis is inherited as an
autosomal recessive trait. It is characterized by the
deposition of a waxy material in the dermis and sub-
mucosal connective tissue of affected patients. The ear-
liest thorough description of lipoid proteinosis was
by Urbach and Wiethe in 1929, and more than 300
patients, most of whom are of European background,
have been reported to date. Mutations of the ECM1
gene, which encodes a glycoprotein known as extracel-
lular matrix protein 1, have recently been identiﬁed as
the cause for this condition.
CLINICAL FEATURES
The laryngeal mucosa and vocal cords are usually the
sites that are initially affected by lipoid proteinosis.
Therefore, the ﬁrst sign of the disease may be one of
the following:
●An inability of the infant to make a crying sound
●A hoarse cry in infancy
●The development of a hoarse voice during early
childhood
The vocal cords become thickened as the accumula-
tion of an amorphous material begins to affect the
laryngeal mucosa. This inﬁltrative mucosal process
may also involve the pharynx, esophagus, tonsils, vulva,
and rectum. Skin lesions also develop early in
life, appearing as thickened, yellowish, waxy papules;
plaques; or nodules that often affect the face, particu-
larly the lips and the margins of the eyelids (Fig. 17-3).
Some lesions may begin as dark-crusted vesicles that
heal as atrophic hyperpigmented patches.
Eventually, most patients exhibit a thickened, fur-
rowed appearance of the skin. Other areas of the skin
that may be involved include the neck, palms, axillae,
elbows, scrotum, knees, and digits. In those areas sub-
jected to chronic trauma, a hyperkeratotic, verrucous
surface often develops. In addition to the cutaneous
manifestations, symmetrical intracranial calciﬁcations
of the medial temporal lobes have been identiﬁed in
approximately 70% of affected patients. These lesions
are usually asymptomatic, although a few patients with
such calciﬁcations have been reported to have a seizure
disorder.
The oral mucosal abnormalities typically become
evident in the second decade of life. The tongue, labial
mucosa, and buccal mucosa become nodular, diffusely
enlarged, and thickened because of inﬁltration with
waxy, yellow-white plaques and nodules (Fig. 17-4).
The dorsal tongue papillae are eventually destroyed,
and the tongue develops a smooth surface. The accu-
mulation of the amorphous material within the tongue
may result in its being bound to the ﬂoor of the mouth.
Therefore, the patient may not be able to protrude the
tongue. Gingival enlargement appears to be an infre-
quent ﬁnding.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of an early lesion of lipoid proteino-
sis typically reveals the deposition of a lamellar mate-
rial around the blood vessels, nerves, hair follicles, and
sweat glands. This material stains positively with the
Fig. 17-3 Lipoid proteinosis. Thickened papules are
present along the margin of the eyelid. (Courtesy of Dr. Maria
Copete.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 821
periodic acid-Schiff (PAS) method and is not digested
by diastase. The location of this material, its staining
properties, and the presence of increased laminin, type
IV collagen, and type V collagen suggest a basement
membrane origin.
A biopsy specimen of a lesion in its later stages
usually shows not only the lamellar material but also
deposition of an amorphous substance within the
dermal connective tissue (Fig. 17-5).
TREATMENT AND PROGNOSIS
Generally, no speciﬁc treatment is available for lipoid
proteinosis other than genetic counseling. In rare
instances, the inﬁltration of the laryngeal mucosa may
produce difﬁcult breathing for some infants, in which
case debulking of the mucosal lesions may be neces-
sary. Most patients with lipoid proteinosis have a
normal life span. Certainly, however, the vocal hoarse-
ness and the appearance of the skin may inﬂuence the
quality of life for affected patients.
JAUNDICE (ICTERUS)
Jaundice is a condition characterized by excess biliru-
bin in the bloodstream. The bilirubin accumulates in
the tissues, which results in a yellowish discoloration
of the skin and mucosa. To understand jaundice, it is
important to know something about the metabolism of
bilirubin. Most bilirubin is derived from the break-
down of hemoglobin, the oxygen-carrying pigment of
erythrocytes. The average life span of an erythrocyte in
the circulation is 120 days. After this time, it undergoes
physiologic breakdown. The hemoglobin is degraded
and processed by the cells of the reticuloendothelial
system, and bilirubin is liberated into the bloodstream
in an unconjugated state. In the liver, bilirubin is taken
up by the hepatocytes and conjugated with glucuronic
acid, which produces conjugated bilirubin, a soluble
product that can be excreted in the bile.
There are numerous causes for increased serum
levels of bilirubin; some are physiologic, and many are
pathologic. Therefore, the presence of jaundice is not
a speciﬁc sign and generally necessitates physical
examination and laboratory studies to determine the
precise cause. The basic disturbances associated with
increased bilirubin levels include an increased produc-
tion of bilirubin. This occurs when the red blood cells
(RBCs) are being broken down at such a rapid rate that
the liver cannot keep pace with processing. This break-
down is seen in such conditions as autoimmune
hemolytic anemia or sickle cell anemia.
Fig. 17-4 Lipoid proteinosis. The upper labial mucosa
exhibits yellow-white, nodular thickening. (Courtesy of Dr. Maria
Copete.)
A B
Fig. 17-5 Lipoid proteinosis. A, This medium-power photomicrograph shows perivascular
deposition of a lamellar, acellular material. B, The periodic acid-Schiff (PAS) method is used to
stain and highlight the perivascular deposits. (Courtesy of Dr. Maria Copete.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

822 ORAL AND MAXILLOFACIAL PATHOLOGY
In addition, the liver may not be functioning cor-
rectly, resulting in decreased uptake of the bilirubin
from the circulation or decreased conjugation of bili-
rubin in the liver cells. Jaundice is frequently present
at birth as a result of the low level of activity of the
enzyme system that conjugates bilirubin. Defects in
this enzyme system may also be seen with certain
inherited problems, one of the more common of which
is Gilbert syndrome. This innocuous condition is
often detected on routine examination, and it is esti-
mated to affect up to 5% of people in the United States.
Because most of these examples of jaundice occur with
impaired processing of bilirubin, laboratory studies
usually show unconjugated bilirubin in the serum.
The presence of conjugated bilirubinemia in jaun-
dice can usually be explained by the reduced excretion
of bilirubin into the bile ducts. This can be the result of
swelling of the hepatocytes (resulting in an occlusion
of the bile canaliculi) or hepatocyte necrosis, with dis-
ruption of the bile canaliculi and liberation of conju-
gated bilirubin. Thus liver function may be disturbed
because of any one of a variety of infections (e.g.,
viruses) or toxins (e.g., alcohol). Occlusion of the bile
duct from gallstones, stricture, or cancer can also force
conjugated bilirubin into the bloodstream.
CLINICAL FEATURES
The patient affected by jaundice exhibits a diffuse,
uniform, yellowish discoloration of the skin and
mucosa. The color varies in intensity, depending on the
serum level of bilirubin and the anatomic site. Because
elastin ﬁbers have an afﬁnity for bilirubin, tissues
that have a high content of elastin, including the
sclera, lingual frenum, and soft palate, are prominently
affected. The sclera of the eye is often the ﬁrst site at
which the yellow color is noted (Fig. 17-6). The yellow
discoloration caused by hypercarotenemia (resulting
from excess ingestion of carotene, a vitamin-A precur-
sor found in yellow vegetables and fruits) may be con-
fused with jaundice, but the sclera is not involved in
that condition.
Other signs and symptoms associated with jaundice
vary with the underlying cause of the hyperbilirubin-
emia. For example, patients with viral hepatitis usually
have a fever, abdominal pain, anorexia, and fatigue. The
patient with jaundice typically requires a complete
medical evaluation to determine the precise cause of
the condition so that proper therapy can be instituted.
TREATMENT AND PROGNOSIS
The treatment and prognosis of the patient with jaun-
dice vary with the cause. The jaundice that is com-
monly noted at birth often resolves spontaneously;
however, if the infant is placed under special lights,
then the clearing will occur more quickly because con-
jugation of the bilirubin molecule is triggered by expo-
sure to blue light. If the episode of jaundice is due to
signiﬁcant liver damage, as may be seen with viral
hepatitis B or hepatotoxic chemical injury, then the
prognosis will vary, depending on the extent of liver
damage. The prognosis for patients with jaundice sec-
ondary to liver damage associated with metastatic
malignancy is poor.
AMYLOIDOSIS
Amyloidosis represents a heterogeneous group of
conditions characterized by the deposition of an extra-
cellular proteinaceous substance called amyloid.
Virchow coined the term amyloid in the middle of the
nineteenth century because he believed it to be a
starchlike material (amyl = starch; oid = resembling).
We now understand that amyloid can be formed in a
variety of settings, each with its own speciﬁc type of
amyloid protein. Many of these amyloid proteins have
been identiﬁed precisely with respect to their bio-
chemical composition, and ideally an attempt should
be made to categorize the type of amyloid speciﬁcally
when this diagnosis is made. The various amyloid pro-
teins are designated with an A, to indicate amyloid,
followed by an abbreviation for the speciﬁc amyloid
protein. For example, AL would identify amyloid com-
posed of immunoglobulin light (L) chain molecules.
Although amyloid may have several sources, all types
of amyloid have the common feature of a β-pleated
sheet molecular conﬁguration, which can be seen with
x-ray diffraction crystallographic analysis. Because of
this similarity of molecular structure, the different
types of amyloid have similar staining patterns with
special stains.
Fig. 17-6 Jaundice. The yellow color of the sclera
represents a common ﬁnding. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 823
Amyloidosis can produce a variety of effects, depend-
ing on the organ of involvement and the extent to
which the amyloid is deposited. With limited cutane-
ous forms of amyloidosis, virtually no effect on survival
is seen. With some forms of systemic amyloidosis,
however, death may occur within a few years of the
diagnosis as a result of cardiac or renal failure. Further-
more, the presence of amyloid may be associated with
other problems, such as multiple myeloma or chronic
infections.
CLINICAL FEATURES
Several classiﬁcations of amyloidosis have been pro-
posed in the past decade, each evolving as the knowl-
edge of this unusual condition increases. None of the
classiﬁcations is completely satisfactory, although in
recent years, the biochemical makeup of these proteins
has ﬁgured more prominently in most classiﬁcations.
This discussion attempts to be as concise and direct as
possible. Essentially, amyloidosis may be divided into
organ-limited and systemic forms from a clinical
standpoint.
ORGAN-LIMITED AMYLOIDOSIS
Although organ-limited amyloidosis may occur in a
variety of organs, it has rarely been reported in the oral
soft tissues. An example of a limited form of amyloido-
sis is the amyloid nodule, which appears as a solitary,
otherwise asymptomatic, submucosal deposit. Most of
the organ-limited forms of amyloidosis consist of aggre-
gates of immunoglobulin light chains, which in some
cases are produced by a focal collection of monoclonal
plasma cells. By deﬁnition, such amyloid deposits are
not associated with any systemic alteration.
SYSTEMIC AMYLOIDOSIS
Systemic amyloidosis may occur in several forms:
● Primary
● Myeloma associated
● Secondary
● Hemodialysis associated
● Heredofamilial
PRIMARY AND MYELOMA-ASSOCIATED AMYLOIDOSIS
The primary and myeloma-associated forms of amyloi-
dosis usually affect older adults (average age, 65 years),
and a slight male predilection is present. These types
of amyloidosis are caused by deposition of light chain
molecules (thus the designation AL), with most cases
being idiopathic, although approximately 15% to 20%
are associated with multiple myeloma. The initial signs
and symptoms may be nonspeciﬁc, often resulting in a
delayed diagnosis. Fatigue, weight loss, paresthesia,
hoarseness, edema, and orthostatic hypotension are
among the ﬁrst indications of this disease process.
Eventually, carpal tunnel syndrome, mucocutaneous
lesions, hepatomegaly, and macroglossia develop as a
result of the deposition of the amyloid protein. The skin
lesions appear as smooth-surfaced, ﬁrm, waxy papules
and plaques. These most commonly affect the eyelid
region (Fig. 17-7), the retroauricular region, the neck,
and the lips. The lesions are often associated with pete-
chiae and ecchymoses. Macroglossia has been reported
in 10% to 40% of these patients and may appear as
diffuse or nodular enlargement of the tongue (Fig.
17-8). Sometimes oral amyloid nodules show ulceration
and submucosal hemorrhage overlying the lesions.
Infrequently, patients may complain of dry eyes or dry
mouth, which is secondary to amyloid inﬁltration and
destruction of the lacrimal and salivary glands. When
signiﬁcant blood vessel inﬁltration has occurred, clau-
dication of the jaw musculature may be noticed.
SECONDARY AMYLOIDOSIS
Secondary amyloidosis is so named because it charac-
teristically develops as a result of a chronic inﬂamma-
tory process, such as long-standing osteomyelitis,
tuberculosis, or sarcoidosis. Cleavage fragments of a
circulating acute-phase reactant protein appear to
comprise this type of amyloidosis, which is thus desig-
nated AA. The heart is usually not affected as in other
forms of amyloidosis. Liver, kidney, spleen, and adrenal
involvement are typical, however. With the advent of
modern antibiotic therapy, this form of amyloidosis has
become much less common in the United States.
HEMODIALYSIS-ASSOCIATED AMYLOIDOSIS
Patients who have undergone long-term renal dialysis
also are susceptible to amyloidosis, although in this
case the amyloid protein has been identiﬁed as
β
2-microglobulin, and this type of amyloidosis is
Fig. 17-7 Amyloidosis. This patient exhibits a ﬁrm, waxy
nodular lesion in the periocular region, a ﬁnding that is
characteristic of this condition. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

824 ORAL AND MAXILLOFACIAL PATHOLOGY
designated as Aβ
2M. β
2-Microglobulin is a normally
occurring protein that is not removed by the dialysis
procedure, and it accumulates in the plasma. Eventu-
ally, it forms deposits, particularly in the bones and
joints. Often, carpal tunnel syndrome occurs, as well as
cervical spine pain and dysfunction. Tongue involve-
ment has been reported.
HEREDOFAMILIAL AMYLOIDOSIS
Heredofamilial amyloidosis is an uncommon but sig-
niﬁcant form of the disease. Several kindred have been
identiﬁed in Swedish, Portuguese, and Japanese popu-
lations, and most types are inherited as autosomal
dominant traits. An autosomal recessive form, known
as familial Mediterranean fever, has also been described.
Several of these conditions appear as polyneuropathies,
although other manifestations, such as cardiomyopa-
thy, cardiac arrhythmias, congestive heart failure, and
renal failure, eventually develop as the amyloid deposi-
tion continues.
HISTOPATHOLOGIC FEATURES
Biopsy of rectal mucosa has classically been used to
conﬁrm a diagnosis of primary or myeloma-associated
amyloidosis, with up to 80% of such biopsy specimens
being positive. Aspiration biopsy of abdominal subcu-
taneous fat is a simpler procedure, however, and the
sensitivity of this technique has been reported to range
from 55% to 75%. Alternative tissue sources, however,
are the gingiva and labial salivary glands. Histopatho-
logic examination of gingival tissue that has been
affected by amyloidosis shows extracellular deposition
in the submucosal connective tissue of an amorphous,
eosinophilic material, which may be arranged in a peri-
vascular orientation or may be diffusely present
throughout the tissue (Fig. 17-9). Relatively low sensi-
tivity has been reported for gingival biopsies, whereas
labial salivary gland tissue shows deposition of amyloid
in a periductal or perivascular location in more than
80% of the cases.
A standard means of identifying amyloid uses the
dye, Congo red, which has an afﬁnity for the abnormal
protein. In tissue sections stained with Congo red, the
amyloid appears red. When the tissue is viewed with
polarized light, it exhibits an apple-green birefrin-
gence (Fig. 17-10). Microscopic sections stained with
crystal violet reveal a characteristic metachromasia;
this normally purple dye appears more reddish when
Fig. 17-8 Amyloidosis. Same patient as depicted in Fig.
17-7. Note amyloid nodules of lateral tongue, some of which
are ulcerated. The patient’s amyloidosis was the result of
previously undiagnosed multiple myeloma.
Fig. 17-9 Amyloidosis. This medium-power
photomicrograph shows the eosinophilic, acellular deposits
that are characteristic of amyloid deposition.
Fig. 17-10 Amyloidosis. High-power photomicrograph of a
Congo red–stained section, demonstrating characteristic
apple-green birefringence when viewed with polarized light.
(Courtesy of Dr. John Kalmar.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 825
it reacts with amyloid. Staining with thioﬂavine T, a
ﬂuorescent dye, also gives positive results if amyloid
is present. Ultrastructurally, amyloid is seen as a col-
lection of 7.5- to 10-nm diameter, nonbranching,
linear ﬁbrils.
DIAGNOSIS
Once the histopathologic diagnosis of amyloidosis has
been made, the patient must be evaluated medically to
determine the type of amyloidosis that is present. This
often entails a workup that includes serum immuno-
electrophoresis to determine whether a monoclonal
gammopathy exists so that multiple myeloma can be
ruled out. Immunohistochemical studies are proving to
be very useful in distinguishing the speciﬁc type of
amyloid protein. Family history and physical examina-
tion ﬁndings are also important.
TREATMENT AND PROGNOSIS
In most instances, no effective therapy is available for
amyloidosis. Surgical debulking of amyloid deposition
in the tongue has met with limited success. Selected
forms of amyloidosis may respond to treatment, or at
least their progression may be slowed, depending on
the underlying cause. In cases of secondary amyloido-
sis associated with an infectious agent, treatment of the
infection and reduction of the inﬂammation often
result in clinical improvement. Renal transplantation
may arrest the progression of the bone lesions in hemo-
dialysis-associated amyloidosis, but this procedure
apparently does not reverse the process. Liver trans-
plantation can improve the prognosis of several forms
of inherited amyloidosis, particularly the transthyretin
variant. Familial Mediterranean fever may respond to
systemic colchicine therapy. Genetic counseling is also
appropriate for patients affected by the inherited forms
of amyloidosis. Treatment of primary amyloidosis (AL)
with colchicine, prednisone, and melphalan appears to
improve the prognosis of patients who do not have
cardiac or renal involvement, although the outlook is
guarded to poor in most instances. Most patients die of
cardiac failure, arrhythmia, or renal disease within
months to a few years after the diagnosis.
VITAMIN DEFICIENCY
In the United States today, signiﬁcant vitamin deﬁcien-
cies are not common. Patients with malabsorption syn-
dromes or eating disorders, persons who follow “fad
diets,” and alcoholics are the groups most commonly
affected.
Vitamin A (retinol) is essential for the maintenance
of vision, and it also plays a role in growth and tissue
differentiation. Vitamin A can be obtained directly
from dietary sources, such as organ meats (particularly
liver), or the body can synthesize it from β-carotene,
which is abundant in red and yellow vegetables.
Vitamin B
1 (thiamin) acts as a coenzyme for several
metabolic reactions and is thought to maintain the
proper functioning of neurons. Thiamin is found in
many animal and vegetable food sources.
Vitamin B
2 (riboﬂavin) is necessary for cellular oxi-
dation-reduction reactions. Foods that contain sig-
n iﬁcant amounts of riboﬂavin include milk, green
vegetables, lean meat, ﬁsh, legumes, and eggs.
Vitamin B
3 (niacin) acts as a coenzyme for oxidation-
reduction reactions. Rich sources include food from
animal sources, especially lean meat and liver, milk,
eggs, whole grains, peanuts, yeast, and cereal bran
or germ.
Vitamin B
6 (pyridoxine) serves as a cofactor associ-
ated with enzymes that participate in amino acid syn-
thesis. It is found in many animal and vegetable food
sources.
Vitamin C (ascorbic acid) is necessary for the proper
synthesis of collagen. This vitamin is present in a wide
variety of vegetables and fruits, although it is particu-
larly abundant in citrus fruits.
Vitamin D, which is now considered to be a hormone,
can be synthesized in adequate amounts within the
epidermis if the skin is exposed to a moderate degree
of sunlight. Most milk and processed cereal is fortiﬁed
with vitamin D in the United States today, however.
Appropriate levels of vitamin D and its active me-
tabolites are necessary for calcium absorption from
the gut.
Vitamin E (α-tocopherol) is a fat-soluble vitamin that
is widely stored throughout the body. It probably func-
tions as an antioxidant. Vegetable oils, meats, nuts,
cereal grains, and fresh greens and vegetables are good
sources of vitamin E.
Vitamin K is a fat-soluble vitamin found in a wide
variety of green vegetables, as well as milk, butter, and
liver; intestinal bacteria also produce it. This vitamin is
necessary for the proper synthesis of various proteins,
including the clotting factors II, VII, IX, and X.
CLINICAL FEATURES
VITAMIN A
A severe deﬁciency of vitamin A during infancy may
result in blindness. The early changes associated with
a lack of this vitamin later in life include an inability of
the eye to adapt to reduced light conditions (i.e., night
blindness). With more severe, prolonged deﬁciency,
dryness of the skin and conjunctiva develop, and the
ocular changes may progress to ulceration of the
cornea, leading to blindness. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

826 ORAL AND MAXILLOFACIAL PATHOLOGY
THIAMIN
A deﬁciency of thiamin results in a condition called
beriberi, a problem that is relatively uncommon in the
Western world except in alcoholics or other individu-
als who do not receive a balanced diet. Thiamin deﬁ-
ciency has also been documented in patients who have
had gastric bypass surgery for weight control, presum-
ably because an adequate amount of the vitamin is not
obtained in the diet. The condition became prevalent
in southeast Asia when the practice of removing the
outer husks of the rice grain by machine was intro-
duced. Because these outer husks contained nearly all
of the thiamin, people who subsisted on the “polished”
rice became deﬁcient in this vitamin. The disorder is
manifested by cardiovascular problems (e.g., periph-
eral vasodilation, heart failure, edema) and neurologic
problems (including peripheral neuropathy and Wer-
nicke’s encephalopathy). Patients with Wernicke’s
encephalopathy experience vomiting, nystagmus, and
progressive mental deterioration, which may lead to
coma and death.
RIBOFLAVIN
A diet that is chronically deﬁcient in riboﬂavin causes
a number of oral alterations, including glossitis, angular
cheilitis, sore throat, and swelling and erythema of the
oral mucosa. A normocytic, normochromic anemia
may be present, and seborrheic dermatitis may affect
the skin.
NIACIN
A deﬁciency of niacin causes a condition known as
pellagra, a term derived from the Italian words pelle
agra, meaning rough skin. This condition may occur in
populations that use maize as a principal component
of their diets, because corn is a poor source of niacin.
Pellagra was once common in the southeastern United
States and may still be seen in some parts of the world.
The classic systemic signs and symptoms include the
triad of dermatitis, dementia, and diarrhea. The derma-
titis is distributed symmetrically; sun-exposed areas,
such as the face, neck, and forearms, are affected most
severely (Fig. 17-11). The oral manifestations have
been described as stomatitis and glossitis, with the
tongue appearing red, smooth, and raw. Without cor-
rection of the niacin deﬁciency, the disease may evolve
and persist over a period of years, eventually leading to
death.
PYRIDOXINE
A deﬁciency of pyridoxine is unusual because of its
widespread occurrence in a variety of foods. A number
of drugs, such as the antituberculosis drug isoniazid,
act as pyridoxine antagonists; therefore, patients who
receive these medications may have a deﬁciency state.
Because the vitamin plays a role in neuronal function,
patients may show weakness, dizziness, or seizure dis-
orders. Cheilitis and glossitis, reported in people with
pellagra, are also reported in patients with pyridoxine
deﬁciency.
VITAMIN C
A deﬁciency of vitamin C is known as scurvy, and its
occurrence in the United States is usually limited to
people whose diets lack fresh fruits and vegetables.
Commonly affected groups include inner-city infants
(whose diets often consist entirely of milk) and older
edentulous men, particularly those who live alone.
The clinical signs of scurvy are typically related to
inadequate collagen synthesis. For example, weakened
vascular walls may result in widespread petechial hem-
orrhage and ecchymosis. Similarly, wound healing is
delayed, and recently healed wounds may break down.
In childhood, painful subperiosteal hemorrhages may
occur.
The oral manifestations are well documented and
include generalized gingival swelling with spontane-
ous hemorrhage, ulceration, tooth mobility, and
increased severity of periodontal infection and peri-
odontal bone loss. The gingival lesions have been
termed scorbutic gingivitis (Fig. 17-12). If untreated,
scurvy may ultimately lead to death, often as a result of
intracranial hemorrhage.
Fig. 17-11 Pellagra. The skin on the foot is rough and
hyperpigmented, except for a central band that was
protected from sunlight by a sandal strap. (Courtesy of Dr. Sylvie
Brener.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 827
VITAMIN D
A deﬁciency of vitamin D during infancy results in a
condition called rickets; adults who are deﬁcient in
this vitamin develop osteomalacia. With the vitamin-
D supplementation of milk and cereal, rickets is a rela-
tively uncommon disease today in the United States. In
past centuries, however, rickets was often seen, partic-
ularly in the temperate zones of the world, which often
do not receive adequate sunlight to ensure physiologic
levels of vitamin D. Even today in the United States,
children who are dark skinned and do not receive
adequate sun exposure, as well as solely breast-fed
infants, remain at risk for developing rickets. Nutri-
tional rickets remains a problem in many developing
countries, although the condition is thought to be asso-
ciated more with calcium deﬁciency than vitamin-D
deﬁciency.
Clinical manifestations of rickets include irritability,
growth retardation, and prominence of the costochon-
dral junctions (rachitic rosary). As the child ages and
begins to put weight on the long bones of the legs, sig-
niﬁcant bowing results because of the poor mineraliza-
tion of the skeleton.
A similar pattern of poorly mineralized bone is seen
in osteomalacia in adults. Bone normally undergoes
continuous remodeling and turnover, and the osteoid
that is produced during this process does not have suf-
ﬁcient calcium to mineralize completely. Thus a weak,
fragile bone structure results. Patients affected by
osteomalacia frequently complain of diffuse skeletal
pain, and their bones are susceptible to fracture with
relatively minor injury.
VITAMIN E
A deﬁciency of vitamin E is rare and occurs primarily
in children who suffer from chronic cholestatic liver
disease. These patients have severe malabsorption of
all fat-soluble vitamins, but particularly vitamin E. Mul-
tiple neurologic signs develop as a result of abnormali-
ties in the central nervous system (CNS) and peripheral
nervous system.
VITAMIN K
A deﬁciency of vitamin K may be seen in patients with
malabsorption syndromes or in those whose intestinal
microﬂora has been eliminated by long-term, broad-
spectrum antibiotic use. Oral anticoagulants in the
dicumarol family also inhibit the normal enzymatic
activity of vitamin K. A deﬁciency or inhibition of syn-
thesis of vitamin K leads to a coagulopathy because of
the inadequate synthesis of prothrombin and other
clotting factors. Intraorally, this coagulopathy is most
often manifested by gingival bleeding. If the coagulopa-
thy is not corrected, death may result from uncon-
trolled systemic hemorrhage.
TREATMENT AND PROGNOSIS
Replacement therapy is indicated for vitamin deﬁcien-
cies. However, such deﬁciencies are uncommon,
except for the situations described earlier. In fact,
vitamin excess is perhaps more likely to be encoun-
tered in the United States today because so many
people self-medicate with unnecessary and potentially
harmful vitamin supplements. For example, excess
vitamin A may cause abdominal pain, vomiting, head-
ache, joint pain, and exostoses, whereas excess vitamin
C may induce the formation of additional kidney stones
in individuals with a history of nephrolithiasis.
IRON-DEFICIENCY ANEMIA
Iron-deﬁciency anemia is the most common cause of
anemia in the United States and throughout the world.
This form of anemia develops when the amount of iron
available to the body cannot keep pace with the need
for iron in the production of red blood cells (RBCs).
This type of anemia develops under four conditions:
1. Excessive blood loss
2. Increased demand for RBCs
3. Decreased intake of iron
4. Decreased absorption of iron
It is estimated that 20% of women of childbearing
age in the United States are iron deﬁcient as a result
of the chronic blood loss associated with excessive
menstrual ﬂow (menorrhagia). Similarly, 2% of adult
men are iron deﬁcient because of chronic blood loss,
usually associated with gastrointestinal disease, such as
peptic ulcer disease, diverticulosis, hiatal hernia, or
malignancy.
Fig. 17-12 Scurvy. Hemorrhagic gingival enlargement
(scorbutic gingivitis) because of capillary fragility. (Courtesy of
Dr. James Hargan.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

828 ORAL AND MAXILLOFACIAL PATHOLOGY
An increased demand for erythrocyte production
occurs during childhood growth spurts and during
pregnancy. A decreased intake of iron may be seen
during infancy when the diet consists of relatively iron-
poor foods, such as cereals and milk. Likewise, the diets
of older people may be deﬁcient if their dental condi-
tion prohibits them from eating the proper foods or if
they cannot afford iron-rich foods, such as meats and
vegetables. In the developing world, intestinal para-
sites (especially hookworms) are a common cause of
iron deﬁciency in children and pregnant women.
Decreased absorption is a much less common
problem; however, it can be seen in patients who have
had a complete gastrectomy or who have celiac sprue,
a condition that results in severe chronic diarrhea
because of sensitivity to the plant protein, gluten.
CLINICAL FEATURES
Patients with iron-deﬁciency anemia that is severe
enough to cause symptoms may complain of fatigue,
easy tiring, palpitations, lightheadedness, and lack of
energy. Oral manifestations include angular cheilitis
and atrophic glossitis or generalized oral mucosal
atrophy. The glossitis has been described as a diffuse
or patchy atrophy of the dorsal tongue papillae, often
accompanied by tenderness or a burning sensation.
Such ﬁndings are also evident in oral candidiasis, and
some investigators have suggested that iron deﬁciency
predisposes the patient to candidal infection, which
results in the changes seen at the corners of the mouth
and on the tongue. Such lesions are rarely seen in the
United States, perhaps because the anemia is usually
detected relatively early before the oral mucosal
changes have had a chance to develop.
LABORATORY FINDINGS
The diagnosis should be established by means of a
complete blood count with RBC indices because
many other conditions, such as hypothyroidism, other
anemias, or chronic depression, may elicit similar sys-
temic clinical complaints. The laboratory evaluation
characteristically shows hypochromic microcytic RBCs
in addition to reduced numbers of erythrocytes. Addi-
tional supporting evidence for iron deﬁciency includes
the ﬁndings of low serum iron levels and ferritin con-
centration together with elevated total iron-binding
capacity.
TREATMENT AND PROGNOSIS
Therapy for most cases of iron-deﬁciency anemia con-
sists of dietary iron supplementation by means of oral
ferrous sulfate. For patients with malabsorption prob-
lems, parenteral iron may be given periodically. The
response to therapy is usually prompt, with red cell
parameters returning to normal within 1 to 2 months.
The underlying cause of the anemia should be identi-
ﬁed so that it may be addressed, if feasible.
PLUMMER-VINSON SYNDROME
(PATERSON-KELLY SYNDROME;
SIDEROPENIC DYSPHAGIA)
Plummer-Vinson syndrome is a rare condition char-
acterized by iron-deﬁciency anemia, seen in conjunc-
tion with glossitis and dysphagia. Its incidence in
developed countries has been declining, probably as a
result of the improved nutritional status of the popula-
tions. The condition is signiﬁcant in that it has been
associated with a high frequency of both oral and
esophageal squamous cell carcinoma; therefore, it is
considered a premalignant process.
CLINICAL AND RADIOGRAPHIC
FEATURES
Most reported patients with Plummer-Vinson syn-
drome have been women of Scandinavian or Northern
European background, between 30 and 50 years of
age. Patients typically complain of a burning sensation
associated with the tongue and oral mucosa. Some-
times this discomfort is so severe that dentures cannot
be worn. Angular cheilitis is often present and may be
severe (Fig. 17-13). Marked atrophy of the lingual
papillae, which produces a smooth, red appearance of
the dorsal tongue, is seen clinically (Fig. 17-14).
Patients also frequently complain of difﬁculty in
swallowing (dysphagia) or pain on swallowing. An
evaluation with endoscopy or esophageal barium con-
trast radiographic studies usually shows the presence
Fig. 17-13 Plummer-Vinson syndrome. Patients often
show angular cheilitis. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 829
of abnormal bands of tissue in the esophagus, called
esophageal webs. Another sign is an alteration of the
growth pattern of the nails, which results in a spoon-
shaped conﬁguration (koilonychia). The nails may
also be brittle.
Symptoms of anemia may prompt patients with
Plummer-Vinson syndrome to seek medical care.
Fatigue, shortness of breath, and weakness are charac-
teristic symptoms.
LABORATORY FINDINGS
Hematologic studies show a hypochromic microcytic
anemia that is consistent with an iron-deﬁciency
anemia.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of involved mucosa from a patient
with Plummer-Vinson syndrome typically shows epi-
thelial atrophy with varying degrees of submucosal
chronic inﬂammation. In advanced cases, evidence of
epithelial atypia or dysplasia may be seen.
TREATMENT AND PROGNOSIS
Treatment of Plummer-Vinson syndrome is primarily
directed at correcting the iron-deﬁciency anemia by
means of dietary iron supplementation. This therapy
usually resolves the anemia, relieves the glossodynia,
and may reduce the severity of the esophageal symp-
toms. Occasionally, esophageal dilation is necessary to
help improve the symptoms of dysphagia. Patients with
Plummer-Vinson syndrome should be evaluated
periodically for oral, hypopharyngeal, and esophageal
cancer because a 5% to 50% prevalence of upper aerodi-
gestive tract malignancy has been reported in affected
persons.
PERNICIOUS ANEMIA
Pernicious anemia is an uncommon condition that
occurs with greatest frequency among older patients of
Northern European heritage, although recent studies
have identiﬁed the disease in black and Hispanic popu-
lations as well. The disease is a megaloblastic anemia
caused by poor absorption of cobalamin (vitamin B
12,
extrinsic factor). Intrinsic factor, which is produced by
the parietal cells of the stomach lining, is needed for
vitamin-B
12 absorption. Normally, when cobalamin is
ingested, it binds to intrinsic factor in the duodenum.
Because the lining cells of the intestine preferentially
take up the cobalamin-intrinsic factor complex, signiﬁ-
cant amounts of the vitamin cannot be absorbed unless
both components are present.
In the case of pernicious anemia, most patients lack
intrinsic factor because of an autoimmune destruction
of the parietal cells of the stomach, and this results in
decreased absorption of cobalamin. Antibodies directed
against intrinsic factor are also found in the serum of
these patients. Vitamin B
12 deﬁciency may occur for
other reasons, and although the resulting signs and
symptoms may be identical to those of pernicious
anemia, these should be considered as distinctly differ-
ent deﬁciency disorders. For example, a decreased
ability to absorb cobalamin may also occur after gas-
trointestinal bypass operations. In addition, because
cobalamin is primarily derived from animal sources,
some strict vegetarians (vegans) may develop vitamin
B
12 deﬁciency. In older patients, gastritis associated
with Helicobacter pylori infection can result in decreased
vitamin B
12 absorption.
Because cobalamin is necessary for normal nucleic
acid synthesis, anything that disrupts the absorption of
the vitamin causes problems, especially for cells that
are multiplying rapidly and, therefore, synthesizing
large amounts of nucleic acids. The cells that are the
most mitotically active are affected to the greatest
degree, especially the hematopoietic cells and the gas-
trointestinal lining epithelial cells.
CLINICAL FEATURES
With respect to systemic complaints, patients with per-
nicious anemia often report fatigue, weakness, short-
ness of breath, headache, and feeling faint. Such
symptoms are associated with most anemias and prob-
ably reﬂect the reduced oxygen-carrying capacity
of the blood. In addition, many patients report
Fig. 17-14 Plummer-Vinson syndrome. The diffuse
papillary atrophy of the dorsal tongue is characteristic of the
oral changes. (From Neville BW, Damm DD, White DK: Color atlas of
clinical oral pathology, ed 2, Philadelphia, 1999, Lippincott Williams &
Wilkins.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

830 ORAL AND MAXILLOFACIAL PATHOLOGY
paresthesia, tingling, or numbness of the extremities.
Difﬁculty in walking and diminished vibratory and
positional sense may be present. Psychiatric symptoms
of memory loss, irritability, depression, and dementia
have also been described.
Oral symptoms often consist of a burning sensation
of the tongue, lips, buccal mucosa, or other mucosal
sites. Clinical examination may show focal patchy areas
of oral mucosal erythema and atrophy (Fig. 17-15), or
the process may be more diffuse, depending on the
severity and duration of the condition. The tongue may
be affected in as many as 50% to 60% of patients with
pernicious anemia, but it may not show as much
involvement as other areas of the oral mucosa in some
instances. The atrophy and erythema may be easier to
appreciate on the dorsal tongue than at other sites,
however.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of an erythematous
portion of the oral mucosa shows marked epithelial
atrophy with loss of rete ridges, an increased nuclear-
to-cytoplasmic ratio, and prominent nucleoli (Fig.
17-16). This pattern can be misinterpreted as epithelial
dysplasia at times, although the nuclei in pernicious
anemia typically are pale staining and show peripheral
chromatin clumping. A patchy diffuse chronic inﬂam-
matory cell inﬁltrate is usually noted in the underlying
connective tissue.
LABORATORY FINDINGS
Hematologic evaluation of vitamin B
12 deﬁciency
shows a macrocytic anemia and reduced serum cobal-
amin levels. The Schilling test for pernicious anemia
has been used to determine the pathogenesis of the
cobalamin deﬁciency by comparing absorption and
excretion rates of radiolabeled cobalamin. However,
this study is rather complicated to perform, and it
appears to be falling out of favor. The presence of
serum antibodies directed against intrinsic factor is
quite speciﬁc for pernicious anemia.
TREATMENT AND PROGNOSIS
Once the diagnosis of pernicious anemia is established,
treatment traditionally has consisted of monthly intra-
muscular injections of cyanocobalamin. The condition
responds rapidly once therapy is initiated, with reports
of clearing of oral lesions within 5 days. High-dose oral
cobalamin therapy has also been shown to be an equally
A B
Fig. 17-15 Pernicious anemia. A, The dorsal tongue shows erythema and atrophy. B, After
therapy with vitamin B12, the mucosal alteration resolved.
Fig. 17-16 Pernicious anemia. This medium-power
photomicrograph shows epithelial atrophy and atypia with
chronic inﬂammation of the underlying connective tissue.
These features are characteristic of a megaloblastic anemia,
such as pernicious anemia. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 831
effective treatment, however, with advantages being its
cost-effectiveness and the elimination of painful injec-
tions. One study has conﬁrmed an increased risk of
malignancy, particularly gastric carcinoma, a compli-
cation that affects between 1% and 2% of pernicious
anemia patients.
PITUITARY DWARFISM
Pituitary dwarﬁsm is a relatively rare condition that
results from either the diminished production of
growth hormone by the anterior pituitary gland or a
reduced capacity of the tissues to respond to growth
hormone. Affected patients are typically much shorter
than normal, although their body proportions are gen-
erally appropriate.
Several conditions may cause short stature, and a
careful evaluation of the patient must be performed to
rule out other possible causes, such as the following:
1.Intrinsic defects in the patient’s tissues (e.g.,
certain skeletal dysplasias, chromosomal abnor-
malities, idiopathic short stature)
2.Alterations in the environment of the growing
tissues (e.g., malnutrition, hypothyroidism, diabe-
tes mellitus)
If a lack of growth hormone is detected, the cause
should be determined. Sometimes the fault lies with
the pituitary gland itself (e.g., aplasia, hypoplasia). In
other instances, the problem may be related to destruc-
tion of the pituitary or hypothalamus by tumors, thera-
peutic radiation, or infection.
If the hypothalamus is affected, a deﬁciency in
growth hormone–releasing hormone, which is pro-
duced by the hypothalamus, results in a deﬁciency of
growth hormone. Often deﬁciencies in other hor-
mones, such as thyroid hormone and cortisol, are also
detected in patients with primary pituitary or hypotha-
lamic disorders.
Some patients exhibit normal or even elevated levels
of growth hormone, yet still show little evidence of
growth. These individuals usually have inherited an
autosomal recessive trait, resulting in abnormal and
reduced growth hormone receptors on the patients’
cells. Thus normal growth cannot proceed.
CLINICAL FEATURES
Perhaps the most striking feature of pituitary dwarﬁsm
is the remarkably short stature of the affected patient.
Sometimes this is not noticed until the early years of
childhood, but a review of the patient’s growth history
should show a consistent pattern of failure to achieve
the minimal height on the standard growth chart. Often
the patient’s height may be as much as three standard
deviations below normal for a given age. Unlike the
body proportions in many of the dysmorphic syn-
dromes and skeletal dysplasias, the body proportions
of patients affected by a lack of growth hormone are
usually normal. One possible exception is the size of
the skull, which is usually within normal limits. Because
the facial skeleton does not keep pace with the skull,
however, the face of an affected patient may appear
smaller than it should be. Mental status is generally
within normal limits.
The maxilla and mandible of affected patients are
smaller than normal, and the teeth show a delayed
pattern of eruption. The delay ranges from 1 to 3 years
for teeth that normally erupt during the ﬁrst decade of
life and from 3 to 10 years for teeth that normally erupt
in the second decade of life. Often the shedding of
deciduous teeth is delayed by several years, and the
development of the roots of the permanent teeth also
appears to be delayed. A lack of development of the
third molars seems to be a common ﬁnding. The size
of the teeth is usually reduced in proportion to the
other anatomic structures.
LABORATORY FINDINGS
Radioimmunoassay for human growth hormone shows
levels that are markedly below normal.
TREATMENT AND PROGNOSIS
Replacement therapy with human growth hormone is
the treatment of choice for patients with pituitary
dwarﬁsm if the disorder is detected before closure of
the epiphyseal growth plates. In the past, growth
hormone was extracted from cadaveric pituitary glands;
today, genetically engineered human growth hormone
is produced with recombinant DNA technology. For
patients with a growth hormone deﬁciency caused
by a hypothalamic defect, treatment with growth
hormone–releasing hormone is appropriate. If patients
are identiﬁed and treated at an early age, they can be
expected to achieve a relatively normal height. The
craniofacial bone structure also assumes a less child-
like pattern. Evaluation of a series of patients who had
been treated for long periods with growth hormone
determined that up to half developed acromegalic fea-
tures, including larger feet and a larger mandible. For
patients who lack growth hormone receptors, no treat-
ment is available.
GIGANTISM
Gigantism is a rare condition caused by an increased
production of growth hormone, usually related to a
functional pituitary adenoma. The increased produc-
tion of growth hormone takes place before closure of `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

832 ORAL AND MAXILLOFACIAL PATHOLOGY
the epiphyseal plates, and the affected person grows at
a much more rapid pace, becoming abnormally tall.
Although the average height of the population of the
United States has been gradually increasing during the
past several decades, individuals who exceed the mean
height by more than three standard deviations may be
considered candidates for endocrinologic evalua-
tion. Familial examples of gigantism have also been
described.
CLINICAL AND RADIOGRAPHIC
FEATURES
Patients with gigantism usually show markedly accel-
erated growth during childhood, irrespective of normal
growth spurts. Radiographic evaluation of the skull
often shows an enlarged sella as a result of the pres-
ence of a pituitary adenoma. The adenoma may result
in hormonal deﬁciencies, such as hypothyroidism
and hypoadrenocorticism, if the remaining normal
pituitary gland tissue is compressed and destroyed.
McCune-Albright syndrome (polyostotic ﬁbrous dys-
plasia and café au lait pigmentation with associated
endocrinologic disturbances) (see page 636) may
account for as many as 20% of the cases of gigantism.
If the condition remains uncorrected for a prolonged
period, extreme height (more than 7 feet tall) will be
achieved, and enlargement of the facial soft tissues, the
mandible, and the hands and feet will become appar-
ent. These changes often resemble those seen in acro-
megaly (discussed later). Another oral ﬁnding is true
generalized macrodontia.
TREATMENT AND PROGNOSIS
Appropriate management of gigantism involves the
surgical removal of the functioning pituitary ade-
noma, usually by a transsphenoidal approach. Radia-
tion therapy may also be used.
The life span of patients with gigantism is usually
markedly reduced. Complications associated with
hypertension, peripheral neuropathy, osteoporosis,
and pulmonary disease contribute to increased mor-
bidity and mortality.
ACROMEGALY
Acromegaly is an uncommon condition characterized
by the excess production of growth hormone after
closure of the epiphyseal plates in the affected patient.
Usually, this increase in growth hormone is due to a
functional pituitary adenoma. The incidence is esti-
mated to be approximately three to ﬁve new cases diag-
nosed per million population per year. The prevalence
is believed to be 66 affected patients per million.
CLINICAL AND RADIOGRAPHIC
FEATURES
Because most patients with acromegaly have a pitu-
itary adenoma, symptoms related directly to the space-
occupying mass of the tumor may be present. These
symptoms include headaches, visual disturbances,
and other signs of a brain tumor. Sometimes pressure
atrophy of the residual normal pituitary by the adenoma
results in diminished production of other pituitary hor-
mones and causes other indirect endocrine problems.
The direct effects of increased levels of growth hormone
include a variety of problems, such as hypertension,
heart disease, hyperhidrosis, arthritis, and peripheral
neuropathy.
Renewed growth in the small bones of the hands
and feet (Fig. 17-17) and in the membranous bones of
the skull and jaws is typically observed. Patients may
complain of gloves or hats becoming “too small.” The
soft tissue is also often affected, producing a coarse
facial appearance (Fig. 17-18). Hypertrophy of the soft
palatal tissues may cause or accentuate sleep apnea.
Because these signs and symptoms are slow to develop
and are vague at the onset, an average time of nearly 9
years elapses from the onset of symptoms to the diag-
nosis of disease. The average age at diagnosis is 42
years, and no sex predilection is seen.
From a dental perspective, these patients have man-
dibular prognathism as a result of the increased growth
of the mandible (Fig. 17-19), which may cause aperto-
gnathia (anterior open bite). Growth of the jaws also
may cause spacing of the teeth, resulting in diastema
formation. Soft tissue growth often produces uniform
macroglossia in affected patients.
Fig. 17-17 Acromegaly. Enlargement of the bones of the
hands. (Courtesy of Dr. William Bruce.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 833
LABORATORY FINDINGS AND DIAGNOSIS
If acromegaly is suspected, measurement of serum
growth hormone levels is done after giving the patient
a measured quantity of glucose orally. Normally, this
glucose challenge will reduce the production of growth
hormone, but if the patient has acromegaly, growth
hormone will not be suppressed. Usually magnetic
resonance imaging (MRI) will identify the pituitary
adenoma that is responsible for inappropriate growth
hormone secretion.
TREATMENT AND PROGNOSIS
The treatment of a patient with acromegaly is typically
directed at the removal of the pituitary tumor mass and
the return of the growth hormone levels to normal. The
most effective treatment with the least associated
morbidity is surgical excision by a transsphenoidal
approach. The prognosis for such a procedure is good,
although a mortality rate of approximately 1% is still
expected. The condition is usually controlled with this
procedure, but patients with larger tumors and mark-
edly elevated growth hormone levels are less likely to
be controlled.
Radiation therapy may be used in some instances,
but the return of the growth hormone levels to normal
is not as rapid or as predictable as with surgery. Because
some patients also experience hypopituitarism caused
by radiation effects on the rest of the gland, some
centers may offer radiation therapy as treatment only
when surgery fails or is too risky. Pharmacotherapy
with one of the somatostatin analogues (e.g., octreotide,
lanreotide, vapreotide) helps to control acromegaly if
surgical treatment is unsuccessful or if surgery is con-
traindicated. A growth hormone receptor–blocking
agent, pegvisomant, has also been developed and may
be used in conjunction with one of the somatostatin
analogues or by itself if the patient cannot tolerate the
somatostatin analogue. Pegvisomant is injected daily
and acts in the peripheral tissues to inhibit the action
of growth hormone. These drugs are also used as an
adjunct to radiation therapy during the prolonged
period that is sometimes necessary for that treatment
to take effect.
The prognosis for untreated patients is guarded,
with an increased mortality rate compared with that of
the general population. Hypertension, diabetes melli-
tus, coronary artery disease, congestive heart failure,
respiratory disease, and colon cancer are seen with
increased frequency in acromegalic patients, and each
of these contributes to the increased mortality rate.
Although treatment of the patient with acromegaly
helps to control many of the other complicating prob-
lems and improves the prognosis, the life span of these
patients still is shortened.
Fig. 17-18 Acromegaly. This patient shows the typical
coarse facial features. (Courtesy of Dr. William Bruce.)
Fig. 17-19 Acromegaly. This lateral skull ﬁlm shows the
dramatic degree of mandibular enlargement that may occur. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

834 ORAL AND MAXILLOFACIAL PATHOLOGY
HYPOTHYROIDISM (CRETINISM;
MYXEDEMA)
Hypothyroidism is a condition that is characterized
by decreased levels of thyroid hormone. When this
decrease occurs during infancy, the resulting clinical
problem is known as cretinism. If an adult has mark-
edly decreased thyroid hormone levels for a prolonged
period, then deposition of a glycosaminoglycan ground
substance is seen in the subcutaneous tissues, produc-
ing a nonpitting edema. Some call this severe form of
hypothyroidism myxedema; others use the terms myx-
edema and hypothyroidism interchangeably.
Hypothyroidism may be classiﬁed as either primary
or secondary. In primary hypothyroidism, the thyroid
gland itself is in some way abnormal; in secondary
hypothyroidism, the pituitary gland does not produce
an adequate amount of thyroid-stimulating hormone
(TSH), which is necessary for the appropriate release
of thyroid hormone. Secondary hypothyroidism, for
example, often develops after radiation therapy for
brain tumors, resulting in unavoidable radiation
damage to the pituitary gland. Most cases, however,
represent the primary form of the disease.
Screening for this disorder is routinely carried out
at birth, and the prevalence of congenital hypothyroid-
ism in North America is approximately 1 in 4000
births. Usually, this is due to hypoplasia or agenesis of
the thyroid gland. In other areas of the world, hypothy-
roidism in infancy is usually due to a lack of dietary
iodine. In adults, hypothyroidism is often caused by
autoimmune destruction of the thyroid gland (known
as Hashimoto’s thyroiditis) or iatrogenic factors, such
as radioactive iodine therapy or surgery for the treat-
ment of hyperthyroidism. Because thyroid hormone is
necessary for normal cellular metabolism, many of the
clinical signs and symptoms of hypothyroidism can
be related to the decreased metabolic rate in these
patients.
CLINICAL FEATURES
The most common features of hypothyroidism include
such signs and symptoms as lethargy, dry and coarse
skin, swelling of the face (Fig. 17-20) and extremities,
huskiness of the voice, constipation, weakness, and
fatigue. The heart rate is usually slowed (bradycardia).
Reduced body temperature (hypothermia) may be
present, and the skin often feels cool and dry to the
touch. In the infant, these signs may not be readily
apparent, and the failure to grow normally may be the
ﬁrst indication of the disease.
With respect to the oral ﬁndings, the lips may appear
thickened because of the accumulation of glycosami-
noglycans. Diffuse enlargement of the tongue occurs
A B
Fig. 17-20 Hypothyroidism. A, The facial appearance of this 9-year-old child is due to the
accumulation of tissue edema secondary to severe hypothyroidism. B, Same patient after 1
year of thyroid hormone replacement therapy. Note the eruption of the maxillary permanent
teeth. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 835
for the same reason (Fig. 17-21). If the condition devel-
ops during childhood, the teeth may fail to erupt,
although tooth formation may not be impaired (Figs.
17-22 and 17-23).
LABORATORY FINDINGS
The diagnosis is made by assaying the free thyroxine
(T
4) levels. If these levels are low, then TSH levels are
measured to determine whether primary or secondary
hypothyroidism is present. With primary thyroid
disease, TSH levels are elevated. With secondary
disease caused by pituitary dysfunction, TSH levels are
normal or borderline.
TREATMENT AND PROGNOSIS
Thyroid replacement therapy, usually with levothyrox-
ine, is indicated for conﬁrmed cases of hypothyroidism.
The prognosis is generally good for adult patients. If the
condition is recognized within a reasonable time, the
prognosis is also good for children. If the condition is
not identiﬁed in a timely manner, however, permanent
damage to the central nervous system may occur, result-
ing in mental retardation. For affected children, thyroid
hormone replacement therapy often results in a dra-
matic resolution of the condition (see Fig. 17-20).
HYPERTHYROIDISM
(THYROTOXICOSIS; GRAVES’
DISEASE)
Hyperthyroidism is a condition caused by excess pro-
duction of thyroid hormone. This excess production
results in a state of markedly increased metabolism in
the affected patient. Most cases (60% to 90%) are due
to Graves’ disease, a condition that was initially
described in the early nineteenth century. It is thought
to be triggered by autoantibodies that are directed
against receptors for thyroid-stimulating hormone
(TSH) on the surface of the thyroid cells. When the
autoantibodies bind to these receptors, they seem to
stimulate the thyroid cells to release inappropriate
thyroid hormone.
Other causes of hyperthyroidism include hyperplas-
tic thyroid tissue and thyroid tumors, both benign
and malignant, which secrete inappropriate thyroid
hormone. Similarly, a pituitary adenoma may produce
TSH, which can then stimulate the thyroid to secrete
excess thyroid hormone.
CLINICAL FEATURES
Graves’ disease is ﬁve to 10 times more common in
women than in men and is seen with some frequency.
It affects almost 2% of the adult female population.
Fig. 17-21 Hypothyroidism. The enlarged tongue
(macroglossia) is secondary to edema associated with adult
hypothyroidism (myxedema). (Courtesy of Dr. George Blozis.)
Fig. 17-22 Hypothyroidism. Photograph of the same
patient depicted in Fig. 17-20 before hormone replacement
therapy. Note the retained deciduous teeth, for which the
patient was initially referred.
Fig. 17-23 Hypothyroidism. Panoramic radiograph of the
same patient in Figs. 17-20 and 17-22. Note the unerupted,
yet fully developed permanent dentition. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

836 ORAL AND MAXILLOFACIAL PATHOLOGY
Graves’ disease is most commonly diagnosed in patients
during the third and fourth decades of life.
Most patients with Graves’ disease exhibit diffuse
thyroid enlargement. Many of the signs and symptoms
of hyperthyroidism can be attributed to an increased
metabolic rate caused by the excess thyroid hormone.
Patients usually complain about nervousness, heart
palpitations, heat intolerance, emotional lability, and
muscle weakness. The following are often noted during
the clinical evaluation:
●Weight loss despite increased appetite
● Tachycardia
● Excessive perspiration
●Widened pulse pressure (increased systolic and
decreased diastolic pressures)
●Warm, smooth skin
● Tremor
Ocular involvement, which develops in 20% to 40%
of affected patients, is perhaps the most striking feature
of this disease. In the early stages of hyperthyroidism,
patients have a characteristic stare with eyelid retrac-
tion and lid lag. With some forms of Graves’ disease,
protrusion of the eyes (exophthalmos or proptosis)
develops (Fig. 17-24). This bulging of the eyes is due to
an accumulation of glycosaminoglycans in the retro-
orbital connective tissues.
LABORATORY FINDINGS
The diagnosis of hyperthyroidism is made by assaying
free T
4 (thyroxine) and TSH levels in the serum. In
affected patients, the T
4 levels should be elevated and
the TSH concentration is typically depressed.
HISTOPATHOLOGIC FEATURES
Diffuse enlargement and hypercellularity of the thy-
roid gland are seen in patients with Graves’ disease,
typically with hyperplastic thyroid epithelium and
little apparent colloid production. Lymphocytic
inﬁltration of the glandular parenchyma is also often
noted.
TREATMENT AND PROGNOSIS
In the United States, radioactive iodine (
131
I) is the
most commonly used form of therapy for adult patients
with Graves’ disease. The thyroid gland normally takes
up iodine from the bloodstream because this element
is a critical component of thyroid hormone. When
radioactive iodine is given to a patient with Graves’
disease, the thyroid gland quickly removes it from the
bloodstream and sequesters the radioactive material
within the glandular tissue. The radioactivity then
destroys the hyperactive thyroid tissue, bringing the
thyroid hormone levels back to normal. Most of the
radiation is received during the ﬁrst few weeks because
the half-life of
131
I is short.
Other techniques include drug therapy with agents
that block the normal use of iodine by the thyroid
gland, and this form of therapy is initially favored in
most European centers. The two widely used drugs are
propylthiouracil and methimazole. At times, they are
used before the radioactive iodine therapy. Sometimes
they may be administered chronically in the hope that
a remission may be induced. In addition, a portion of
the thyroid gland may be removed surgically, thereby
reducing thyroid hormone production.
Drug therapy alone is often unsuccessful in control-
ling hyperthyroidism. Unfortunately, with radioactive
iodine and surgery, the risk of hypothyroidism is rela-
tively great, although thyroid hormone replacement
therapy can be instituted, if needed.
In a patient with uncontrolled hyperthyroidism, a
deﬁnite risk exists with respect to an inappropriate
release of large amounts of thyroid hormone at one
time, resulting in a condition called a thyroid storm.
A thyroid storm may be precipitated by infection, psy-
chologic trauma, or stress. Clinically, patients may
have delirium, convulsions, an elevated tempera-
ture (up to 106° F), and tachycardia (sometimes more
than 140 beats/minute). Such individuals should be
hospitalized immediately because the mortality rate
associated with thyroid storm is 20% to 50%. The
clinician should be aware of the potential for this
problem, and patients with hyperthyroidism should
ideally have the condition under control before dental
treatment.
Fig. 17-24 Hyperthyroidism. The prominent eyes are
characteristic of the exophthalmos associated with Graves’
disease. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 837
HYPOPARATHYROIDISM
Calcium levels in extracellular tissues are normally
regulated by parathyroid hormone (PTH) (parathor-
mone) in conjunction with vitamin D. If calcium levels
drop below a certain point, then the release of PTH is
stimulated. The hormone then acts directly on the
kidney and the osteoclasts of the bone to restore the
calcium to normal levels. In the kidney, calcium reab-
sorption is promoted, phosphate excretion is enhanced,
and the production of vitamin D is stimulated, which
increases the absorption of calcium from the gut.
Osteoclasts are activated to resorb bone and thus liber-
ate calcium.
If a reduced amount of PTH is produced, the rela-
tively rare condition known as hypoparathyroidism
results. Usually, hypoparathyroidism is due to inadver-
tent surgical removal of the parathyroid glands when
the thyroid gland is excised for other reasons, but
sometimes it is the result of autoimmune destruction
of the parathyroid tissue. Rare syndromes, such as
DiGeorge syndrome and the autoimmune poly-
endocrinopathy-candidiasis-ectodermal dystrophy
syndrome (endocrine-candidiasis syndrome), may
be associated with hypoparathyroidism.
CLINICAL FEATURES
With the loss of parathyroid function, the serum levels
of calcium drop, resulting in hypocalcemia. Often the
patient with chronic hypoparathyroidism adapts to the
presence of hypocalcemia and is asymptomatic unless
situations that further reduce the calcium levels are
encountered. Such situations include metabolic alkalo-
sis, as seen during hyperventilation, when a state of
tetany may become evident.
Chvostek’s sign is an oral ﬁnding of signiﬁcance,
characterized by a twitching of the upper lip when the
facial nerve is tapped just below the zygomatic process.
A positive response suggests a latent degree of tetany.
If the hypoparathyroidism develops early in life during
odontogenesis, then a pitting enamel hypoplasia and
failure of tooth eruption may occur (Fig. 17-25).
The presence of persistent oral candidiasis in a young
patient may signal the onset of autoimmune poly-
endocrinopathy-candidiasis-ectodermal dystrophy syn-
drome (see page 219). Hypoparathyroidism may be
only one of several endocrine deﬁciencies associated
with this condition.
LABORATORY FINDINGS
PTH can be measured by means of a radioimmunoas-
say. If serum PTH levels are decreased in conjunction
with a decreased serum calcium concentration, ele-
vated serum phosphate level, and normal renal func-
tion, then a diagnosis of hypoparathyroidism can be
made.
TREATMENT AND PROGNOSIS
Patients with hypoparathyroidism are usually treated
with oral doses of a vitamin-D precursor (ergocalcif-
erol, vitamin D
2). Additional supplements of dietary
calcium may also be necessary to maintain the proper
serum calcium levels. With this regimen, patients can
often live a fairly normal life. Teriparatide, a recombinant
form of the active component of human parathormone,
has been developed recently. When given twice daily
as subcutaneous injections, this drug has also shown
promise as an alternative management strategy for hypo-
parathyroidism, although it is relatively expensive.
PSEUDOHYPOPARATHYROIDISM
(ALBRIGHT HEREDITARY
OSTEODYSTROPHY;
ACRODYSOSTOSIS)
The rare condition known as pseudohypoparathy-
roidism represents at least two broad disorders in
which normal parathyroid hormone (PTH) is present
in adequate amounts but the biochemical pathways
responsible for activating the target cells are not func-
tioning properly. The clinical result is a patient who
appears to have hypoparathyroidism.
In the case of pseudohypoparathyroidism type I,
three subcategories have been deﬁned. For type Ia,
a molecular defect of a speciﬁc intracellular binding
protein known as G
sa seems to prevent the formation
of cyclic adenosine monophosphate (cAMP), a critical
component in the activation of cell metabolism.
Fig. 17-25 Hypoparathyroidism. Enamel hypoplasia has
affected the dentition of this patient, who had
hypoparathyroidism while the teeth were forming. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

838 ORAL AND MAXILLOFACIAL PATHOLOGY
Because other hormones also require binding with G
sα
to carry out their functions, patients have multiple
problems with other endocrine organs and functions.
This condition is usually inherited as an autosomal
dominant trait.
With respect to pseudohypoparathyroidism type Ib,
the problem is thought to be caused by defective recep-
tors for the PTH on the surface of the target cells (the
proximal renal tubules). For this reason, no other endo-
crine tissues or functions are affected. An autosomal
dominant mode of inheritance has been suggested for
a few families affected by type Ib pseudohypoparathy-
roidism, but most cases are apparently sporadic. The
mechanism of action for pseudohypoparathyroidism
type Ic is less clear, but it may involve a defect in ade-
nylate cyclase or a subtle G
sα alteration.
Pseudohypoparathyroidism type II is characterized
by the induction of cAMP by PTH in the target cells;
however, a functional response by the cells is not
invoked. All of the reported cases of this form of the
disease appear to be sporadic.
CLINICAL FEATURES
Pseudohypoparathyroidism most commonly appears
as type Ia disease. Patients affected by pseudohypo-
parathyroidism, either type Ia or Ic, have a charac-
teristic array of features that includes mild mental
retardation, obesity, round face, short neck, and mark-
edly short stature. Midfacial hypoplasia is also com-
monly observed. The metacarpals and metatarsals are
usually shortened, and the ﬁngers appear short and
thick. Subcutaneous calciﬁcations (osteoma cutis)
may be identiﬁed in some patients. Other endocrine
abnormalities that are typically encountered include
hypogonadism and hypothyroidism.
Patients with type Ib and II disease clinically appear
normal, aside from their symptoms of hypocalcemia.
Dental manifestations of pseudohypoparathyroid-
ism include generalized enamel hypoplasia, widened
pulp chambers with intrapulpal calciﬁcations, oligo-
dontia, delayed eruption, and blunting of the apices of
the teeth. The pulpal calciﬁcations are often described
as “dagger” shaped.
The diagnosis of pseudohypoparathyroidism is made
based on elevated serum levels of PTH seen concur-
rently with hypocalcemia, hyperphosphatemia, and
otherwise normal renal function. More sophisticated
studies are necessary to delineate the various subtypes.
TREATMENT AND PROGNOSIS
Pseudohypoparathyroidism is managed by the admin-
istration of vitamin D and calcium. The serum calcium
levels and urinary calcium excretion are carefully
monitored. Because of individual patient differences,
the medication may need to be carefully adjusted;
however, the prognosis is considered to be good.
HYPERPARATHYROIDISM
Excess production of parathyroid hormone (PTH)
results in the condition known as hyperparathyroid-
ism. PTH normally is produced by the parathyroid
glands in response to a decrease in serum calcium
levels.
Primary hyperparathyroidism is the uncontrolled
production of PTH, usually as a result of a parathyroid
adenoma (80% to 90% of cases) or parathyroid hyper-
plasia (10% to 15% of cases). Rarely (approximately 1%
of cases), a parathyroid carcinoma may be the cause
of primary hyperparathyroidism. Infrequently this
endocrine disturbance is caused by any one of several
inherited syndromes, including multiple endocrine
neoplasia type 1 or type 2a, or hyperparathyroid-
ism–jaw tumor syndrome. In the latter condition,
affected patients develop multiple jaw lesions that
histopathologically are consistent with central cemento-
ossifying ﬁbroma. There also appears to be an in-
creased risk for these patients to develop parathyroid
carcinoma.
Secondary hyperparathyroidism develops when
PTH is continuously produced in response to chronic
low levels of serum calcium, a situation usually associ-
ated with chronic renal disease. The kidney processes
vitamin D, which is necessary for calcium absorption
from the gut. Therefore, in a patient with chronic renal
disease, active vitamin D is not produced and less
calcium is absorbed from the gut, resulting in lowered
serum calcium levels.
CLINICAL AND RADIOGRAPHIC
FEATURES
Most patients with primary hyperparathyroidism
are older than 60 years of age. Women have this condi-
tion two to four times more often than men do. Typi-
cally the condition is identiﬁed on routine serologic
testing, and the majority of patients are relatively
asymptomatic.
Patients with the classic triad of signs and symptoms
of hyperparathyroidism are described as having “stones,
bones, and abdominal groans.”
Stones refers to the fact that these patients, particu-
larly those with primary hyperparathyroidism, have a
marked tendency to develop renal calculi (kidney
stones, nephrolithiasis) because of the elevated serum
calcium levels. Metastatic calciﬁcations are also seen,
frequently involving other soft tissues, such as blood `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 839
vessel walls, subcutaneous soft tissues, the sclera, the
dura, and the regions around the joints.
Bones refers to a variety of osseous changes that
may occur in conjunction with hyperparathyroidism.
One of the ﬁrst clinical signs of this disease is seen
radiographically as subperiosteal resorption of the pha-
langes of the index and middle ﬁngers. Generalized
loss of the lamina dura surrounding the roots of the
teeth is also seen as an early manifestation of the condi-
tion (Fig. 17-26). Alterations in trabecular pattern
characteristically develop next. A decrease in trabecu-
lar density and blurring of the normal trabecular
pattern occur; often a “ground glass” appearance
results.
With persistent disease, other osseous lesions
develop, such as the so-called brown tumor of hyper-
parathyroidism. This lesion derives its name from the
color of the tissue specimen, which is usually a dark
red-brown because of the abundant hemorrhage and
hemosiderin deposition within the tumor. These lesions
appear radiographically as well-demarcated unilocular
or multilocular radiolucencies (Fig. 17-27). They com-
monly affect the mandible, clavicles, ribs, and pelvis.
They may be solitary but are often multiple, and long-
standing lesions may produce signiﬁcant cortical
expansion. Typically, the other osseous changes are
observable if brown tumors are present. The most
severe skeletal manifestation of chronic hyperparathy-
roidism has been called osteitis ﬁbrosa cystica, a con-
dition that develops from the central degeneration and
ﬁbrosis of long-standing brown tumors. In patients
with secondary hyperparathyroidism caused by end-
stage renal disease (renal osteodystrophy), striking
enlargement of the jaws has been known to occur (Fig.
17-28) and produce a “ground-glass” radiographic
pattern (see Fig. 17-26).
Abdominal groans refers to the tendency for the
development of duodenal ulcers. In addition, changes
in mental status are often seen, ranging from lethargy
and weakness to confusion or dementia.
HISTOPATHOLOGIC FEATURES
The brown tumor of hyperparathyroidism is histopath-
ologically identical to the central giant cell granu-
loma of the jaws, a benign tumorlike lesion that
usually affects teenagers and young adults (see page
626). Both lesions are characterized by a proliferation
of exceedingly vascular granulation tissue, which serves
as a background for numerous multinucleated osteo-
clast-type giant cells (Fig. 17-29). Some lesions may
also show a proliferative response characterized by a
parallel arrangement of spicules of woven bone set
in a cellular ﬁbroblastic background with variable
Fig. 17-26 Hyperparathyroidism. This periapical
radiograph reveals the “ground glass” appearance of the
trabeculae and loss of lamina dura in a patient with
secondary hyperparathyroidism. (Courtesy of Dr. Randy Anderson.)
Fig. 17-27 Hyperparathyroidism. This occlusal radiograph
of the edentulous maxillary anterior region shows a
multilocular radiolucency characteristic of a brown tumor of
primary hyperparathyroidism. (Courtesy of Dr. Brian Blocher.)
Fig. 17-28 Hyperparathyroidism. Palatal enlargement is
characteristic of the renal osteodystrophy associated with
secondary hyperparathyroidism. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

840 ORAL AND MAXILLOFACIAL PATHOLOGY
numbers of multinucleated giant cells (Fig. 17-30).
This pattern is often associated with secondary hyper-
parathyroidism related to chronic renal disease (renal
osteodystrophy).
TREATMENT AND PROGNOSIS
In primary hyperparathyroidism, the hyperplastic
parathyroid tissue or the functional tumor must be
removed surgically to reduce PTH levels to normal.
Secondary hyperparathyroidism may evolve to
produce signs and symptoms related to renal calculi or
renal osteodystrophy. Restriction of dietary phosphate,
use of phosphate-binding agents, and pharmacologic
treatment with an active vitamin D metabolite (e.g.,
calcitriol) may avert problems. Exposure to aluminum
salts, which inhibit bone mineralization, should be
eliminated also. Patients who do not respond to medical
therapy may require parathyroidectomy. Renal trans-
plantation may restore the normal physiologic process-
ing of vitamin D, as well as phosphorus and calcium
reabsorption and excretion; however, this does not
occur in every case. Cinacalcet is a recently approved
medical treatment for managing the overproduction of
parathormone associated with secondary hyperpara-
thyroidism. This medication is a calcimimetic agent
that sensitizes the calcium receptors of the parathyroid
cells to extracellular calcium, causing the cells to
reduce their output of parathormone.
HYPERCORTISOLISM (CUSHING’S
SYNDROME)
Hypercortisolism is a clinical condition that results
from a sustained increase in glucocorticoid levels. In
most cases this increase is due to corticosteroid therapy
that is prescribed for other medical purposes. If the
increase is caused by an endogenous source, such as
an adrenal or pituitary (adrenocorticotropic hormone
[ACTH]-secreting) tumor, then the condition is known
as Cushing’s disease. This latter condition is rather
rare and usually affects young adult women.
CLINICAL FEATURES
The signs of Cushing’s syndrome usually develop
slowly. The most consistent clinical observation is
weight gain, particularly in the central areas of the
body. The accumulation of fat in the dorsocervical
spine region results in a “buffalo hump” appearance;
fatty tissue deposition in the facial area results in the
characteristic rounded facial appearance known as
moon facies (Fig. 17-31). Other common ﬁndings
include the following:
●Red-purple abdominal striae
● Hirsutism
● Poor healing
● Osteoporosis
● Hypertension
●Mood changes (particularly depression)
●Hyperglycemia with thirst and polyuria
●Muscle wasting with weakness
DIAGNOSIS
If the patient has been receiving large amounts of cor-
ticosteroids (greater than the equivalent of 20 mg of
prednisone) on a daily basis for several months, then
the diagnosis is rather obvious, given the classic signs
Fig. 17-29 Hyperparathyroidism. This high-power
photomicrograph of a brown tumor of hyperparathyroidism
shows scattered multinucleated giant cells within a vascular
and proliferative ﬁbroblastic background.
Fig. 17-30 Hyperparathyroidism. This medium-power
photomicrograph shows trabeculae of cellular woven bone
and clusters of multinucleated giant cells within a
background of cellular ﬁbrous connective tissue. These
features are characteristic of tissue changes seen in renal
osteodystrophy. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 841
and symptoms described earlier. The diagnosis may be
more difﬁcult to establish in patients with a functioning
adrenal cortical tumor or an ACTH-secreting pituitary
adenoma. Evaluation of these patients should include
the measurement of free cortisol in the urine and an
assay of the effect of dexamethasone (a potent artiﬁcial
corticosteroid) on the serum ACTH and cortisol levels.
In an unaffected patient, the levels of free cortisol
should be within normal limits, and the administration
of an exogenous corticosteroid, such as dexametha-
sone, should suppress the normal level of ACTH, with
a concomitant decrease in the cortisol levels. Because
functioning tumors do not respond to normal feedback
mechanisms, the anticipated decreases in ACTH and
cortisol would not be seen in a patient with such a
tumor.
TREATMENT AND PROGNOSIS
The clinician should be aware of the signs and symp-
toms of hypercortisolism to refer affected patients for
appropriate endocrinologic evaluation and diagnosis.
Once the diagnosis is established and the cause is
determined to be an adrenal or pituitary tumor, surgi-
cal removal of the lesion is the treatment of choice.
Radiation therapy also may be effective, particularly in
younger patients. For patients with unresectable
tumors, drugs that inhibit cortisol synthesis, such as
ketoconazole, metyrapone, or aminoglutethimide, may
be used to help control the excess production of
cortisol.
Most cases of hypercortisolism, however, are caused
by systemic corticosteroid therapy that is given for a
variety of immunologic reasons, including treatment of
autoimmune diseases and allogeneic transplant recipi-
ents. Certain strategies, such as the use of corticoste-
roid-sparing agents or alternate-day therapy, may
minimize the corticosteroid dose needed. The goal
should be for patients to use the lowest dose possible
to manage immunologic disease.
In normal situations, cortisol is critical to the func-
tion of the body, particularly in dealing with stress. As
the hormone is metabolized and serum levels drop,
feedback to the pituitary gland signals it to produce
ACTH, which stimulates the adrenal gland to produce
additional cortisol. Unfortunately, therapeutic cortico-
steroids suppress the production of ACTH by the pitu-
itary gland to the extent that the pituitary gland may
not be able to produce ACTH in response to stress, and
an acute episode of hypoadrenocorticism (addisonian
crisis) may be precipitated. Therefore, the clinician
must be aware of the potential side effects of chronic
high-dose corticosteroid use and must be able to adapt
the treatment of the patient accordingly. For stressful
dental and surgical procedures especially, it is often
necessary to increase the corticosteroid dose because
of the greater need of the body for cortisol. Consulta-
tion with the physician who is managing the corticoste-
roid therapy is advised to determine to what extent the
dose should be adjusted.
ADDISON’S DISEASE
(HYPOADRENOCORTICISM)
Insufﬁcient production of adrenal corticosteroid hor-
mones caused by the destruction of the adrenal cortex
results in the condition known as Addison’s disease,
or primary hypoadrenocorticism. The incidence of
new cases diagnosed in the Western hemisphere is
110 to 140 per million population per year. The causes
are diverse and include the following:
● Autoimmune destruction
●Infections (e.g., tuberculosis and deep fungal
diseases, particularly in patients with acquired
immunodeﬁciency syndrome [AIDS])
●Rarely, metastatic tumors, sarcoidosis, hemochro-
matosis, or amyloidosis
If the pituitary gland is not functioning properly,
secondary hypoadrenocorticism may develop
Fig. 17-31 Cushing’s syndrome. The rounded facial
features (“moon facies”) of this patient are due to the
abnormal deposition of fat, which is induced by excess
corticosteroid hormone. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

842 ORAL AND MAXILLOFACIAL PATHOLOGY
because of decreased production of ACTH, the hor-
mone responsible for maintaining normal levels of
serum cortisol.
CLINICAL FEATURES
The clinical features of hypoadrenocorticism do not
actually begin to appear until at least 90% of the glan-
dular tissue has been destroyed. With gradual destruc-
tion of the adrenal cortex, an insidious onset of fatigue,
irritability, depression, weakness, and hypotension is
noted over a period of months. A generalized hyperpig-
mentation of the skin occurs, classically described as
bronzing. The hyperpigmentation is generally more
prominent on sun-exposed skin and over pressure
points, such as the elbows and knees; it is caused
by increased levels of beta-lipotropin or ACTH, each
of which can stimulate melanocytes. The patient
usually complains of gastrointestinal upset with
anorexia, nausea, vomiting, diarrhea, weight loss, and
a peculiar craving for salt. When hypoadrenocorticism
is accompanied by hypoparathyroidism and mucocu-
taneous candidiasis, the possibility of autoimmune
poly endocrinopathy-candidiasis-ectodermal dystrophy
syndrome should be considered (see page 219).
The oral manifestations include diffuse or patchy,
brown, macular pigmentation of the oral mucosa
caused by excess melanin production (Fig. 17-32).
Often the oral mucosal changes are the ﬁrst manifesta-
tion of the disease, with the skin hyperpigmentation
occurring afterward. Sometimes the oral hypermelano-
sis may be difﬁcult to distinguish from physiologic
racial pigmentation, but a history of a recent onset of
oral pigmentation should suggest the possibility of
Addison’s disease.
LABORATORY FINDINGS
The diagnosis of hypoadrenocorticism is conﬁrmed by
a rapid ACTH stimulation test and measurement of
serum cortisol levels and plasma ACTH levels. If serum
cortisol levels are below 20 μg/dL, then the patient
has adrenal insufﬁciency. In primary hypoadrenocorti-
cism, the plasma ACTH levels are high (>100 ng/L). In
secondary hypoadrenocorticism, the levels are normal
(9 to 52 ng/L) or low, as would be expected because
the condition results from decreased ACTH produc-
tion by the pituitary gland.
TREATMENT AND PROGNOSIS
Addison’s disease is managed with corticosteroid
replacement therapy. The physiologic dose of cortico-
steroid is considered to be approximately 5.0 to 7.5 mg
of prednisone or its equivalent per day, usually given
in divided doses. Because the body’s need for cortico-
steroid hormones increases during stressful events, the
patient must take this into account and increase the
dose accordingly. This adjustment is generally not
required for dental procedures performed using local
anesthesia and lasting less than 1 hour, but an increased
dose may be necessary for certain dental and oral sur-
gical procedures that are more lengthy or are done
under general anesthesia.
Before the availability of corticosteroids, the progno-
sis for patients with hypoadrenocorticism was poor,
with most patients surviving less than 2 years. Even
today, if the condition is not recognized promptly,
death may result in a relatively short period of time.
With proper diagnosis and management, most affected
patients can expect to have a normal life span.
DIABETES MELLITUS
Diabetes mellitus is a common disorder of carbohy-
drate metabolism that is thought to have several causes,
although the basic problem is one of either decreased
production of insulin or tissue resistance to the effects
of insulin. The net result of this abnormal state is an
increase in the blood glucose level (hyperglycemia).
Diabetes mellitus is usually divided into two pre-
sentations:
1.Type I—insulin-dependent diabetes mellitus
(IDDM) or juvenile-onset diabetes
2.Type II—non–insulin-dependent diabetes melli-
tus (NIDDM) or adult-onset diabetes
Type I diabetes mellitus is characterized by a lack
of insulin production. Patients usually exhibit severe
hyperglycemia and ketoacidosis. The disease is typi-
cally diagnosed during childhood, and patients require
exogenous insulin injections to survive.
Fig. 17-32 Addison’s disease. Diffuse pigmentation of the
ﬂoor of the mouth and ventral tongue in a patient with
Addison’s disease. (Courtesy of Dr. George Blozis.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 843
Type II diabetes mellitus is sometimes more dif-
ﬁcult to diagnose. It usually occurs in older, obese
adults. Although hyperglycemia is present, ketoacido-
sis rarely develops. Furthermore, patients can produce
some endogenous insulin. A few patients may take
insulin to help control their disease; the insulin injec-
tions, however, are usually not necessary for the
patient’s survival.
With respect to epidemiology, in the United States
diabetes mellitus affects approximately 7% of the popu-
lation, or 21 million people, although nearly 6 million
of these cases remain undiagnosed. More than 1 million
new cases are identiﬁed each year in the United States.
Of these affected patients, most have type II diabetes;
only 5% to 10% have type I.
Diabetes is an important disease when we consider
the many complications associated with it and the eco-
nomic effect it has on society. One of the main compli-
cations of diabetes is peripheral vascular disease, a
problem that results in kidney failure, as well as isch-
emia and gangrenous involvement of the limbs. By
some estimates, 25% of all new cases of kidney failure
occur in diabetic patients. Thus diabetes is the leading
cause of kidney failure in the United States. Each year
more than 50,000 amputations are performed for the
gangrenous complications of diabetes. This disease is
the leading cause of lower limb amputations in the
United States. Retinal involvement often results in
blindness; thus the leading cause of new cases of
blindness in working-age adults in the United States is
diabetes, with more than 12,000 people affected annu-
ally. Complications because of diabetes are estimated
to contribute to the deaths of more than 200,000
Americans each year.
The cause of diabetes mellitus is essentially un-
known, although most cases of type I diabetes appear
to be caused by autoimmune destruction of the pancre-
atic islet cells, and this immunologic attack may be
precipitated by a viral infection in a genetically suscep-
tible individual. Type II diabetes does not appear to
have an autoimmune cause, however, because no
destruction of the islet cells is seen microscopically.
Instead, genetic abnormalities have been detected in
patients with certain types of type II diabetes, which
may explain why the condition occurs so often in
families. If one parent is affected by type II diabetes,
then the chances of a child having the disorder is about
40%. Similarly, if one identical twin has type II diabe-
tes, then the chances are 90% that the disease will also
develop in the other twin.
CLINICAL FEATURES
Although a complete review of the pathophysiology of
diabetes mellitus is beyond the scope of this text, the
clinical signs and symptoms of a patient with this
disease are easier to understand with some basic
knowledge of the process. The hormone insulin, pro-
duced by the beta cells of the pancreatic islets of Lang-
erhans, is necessary for the uptake of glucose by the
cells of the body. When insulin binds to its speciﬁc cell
surface receptor, a resulting cascade of intracellular
molecular events causes the recruitment of intracellu-
lar glucose-binding proteins, which facilitate the uptake
of glucose by each cell.
TYPE I DIABETES MELLITUS
Because patients with type I diabetes have a deﬁciency
in the amount of insulin, the body’s cells cannot absorb
glucose and it remains in the blood. Normal blood
glucose levels are between 70 and 120 mg/dL; in dia-
betic patients, these levels are often between 200 and
400 mg/dL. Above 300 mg/dL, the kidneys can no
longer reabsorb the glucose; therefore, it spills over
into the urine. Because glucose is the main source of
energy for the body, and because none of this energy
can be used because glucose cannot be absorbed, the
patient feels tired and lethargic. The body begins to use
other energy sources, such as fat and protein, resulting
in the production of ketones as a by-product of those
energy consumption pathways. The patient often loses
weight, despite increased food intake (polyphagia).
With the hyperglycemia, the osmolarity of the blood
and urine increases. The increased osmolarity results
in frequent urination (polyuria) and thirst, which leads
to increased water intake (polydipsia). Clinically, most
patients with type I diabetes are younger (average age
at diagnosis being 14 years), and they have a thin body
habitus.
TYPE II DIABETES MELLITUS
By contrast, patients with type II diabetes are usually
older than 40 years of age at diagnosis, and 80% to 90%
of them are obese. In this situation, it is thought that a
decrease in the number of insulin receptors or abnor-
mal postbinding molecular events related to glucose
uptake results in glucose not being absorbed by the
body’s cells. Thus patients are said to show “insulin
resistance” because serum insulin levels are usually
within normal limits or even elevated. If the hypergly-
cemia is taken into account, however, the amount of
circulating insulin is typically not as much as would be
present in a normal person with a similar level of blood
glucose. Therefore, many of these patients are described
as having a relative lack of insulin.
The symptoms associated with type II diabetes are
much more subtle in comparison to those seen with
type I. The ﬁrst sign of type II diabetes is often detected
with routine hematologic examination rather than any
speciﬁc patient complaint. Ketoacidosis is almost never
seen in patients with type II diabetes. Nevertheless, `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

844 ORAL AND MAXILLOFACIAL PATHOLOGY
many of the other complications of diabetes are still
associated with this form of the disease.
COMPLICATIONS
Many complications of diabetes mellitus are directly
related to the microangiopathy caused by the disease.
The microangiopathy results in occlusion of the small
blood vessels, producing peripheral vascular disease.
The resultant decrease in tissue perfusion results in
ischemia. The ischemia predisposes the patient to infec-
tion, particularly severe infections such as gangrene.
Another contributing factor is the impairment of neu-
trophil function, particularly neutrophil chemotaxis.
Amputation of the lower extremity often is neces-
sary because of the lack of tissue perfusion and the
patient’s inability to cope with infection. Similar vascu-
lar occlusion may affect the coronary arteries (which
places the patient at risk for myocardial infarction) or
the carotid arteries and their branches (predisposing
the patient to cerebrovascular accident, or stroke).
When microvascular occlusion affects the retinal
vessels, blindness typically results. Kidney failure is the
outcome of renal blood vessel involvement. If the keto-
acidosis is not corrected in type I diabetes, the patient
may lapse into a diabetic coma.
The oral manifestations of diabetes mellitus are gen-
erally limited to patients with type I diabetes. Problems
include periodontal disease, which occurs more fre-
quently and progresses more rapidly than in normal
patients. Healing after surgery may be delayed, and the
likelihood of infection is probably increased. Diffuse,
nontender, bilateral enlargement of the parotid glands,
called diabetic sialadenosis (see page 470), may be
seen in patients with either form of diabetes. In uncon-
trolled or poorly controlled diabetic patients, a striking
enlargement and erythema of the attached gingiva has
been described (Fig. 17-33). In addition, these patients
appear to be more susceptible to oral candidiasis in
its various clinical forms (see page 213). Erythematous
candidiasis, which appears as central papillary atrophy
of the dorsal tongue papillae, is reported in up to 30%
of these patients. Zygomycosis (see page 232) may
occur in patients with poorly controlled type I diabetes.
Some investigators have identiﬁed an increased preva-
lence of benign migratory glossitis (see page 779) in
patients with type I diabetes; however, others have not
been able to conﬁrm this ﬁnding. Xerostomia, a sub-
jective feeling of dryness of the oral mucosa, has been
reported as a complaint in one third of diabetic patients.
Unfortunately, studies that attempt to conﬁrm an actual
decrease in salivary ﬂow rate in diabetic patients have
produced conﬂicting results. Some studies show a
decrease in salivary ﬂow; some, no difference from
normal; and some, an increased salivary ﬂow rate.
TREATMENT AND PROGNOSIS
For patients with type II diabetes, dietary modiﬁcation
coupled with exercise may be the only treatment nec-
essary, with the goal being weight loss. The dietary and
lifestyle changes may need to be coupled with one or
more oral hypoglycemic agents. These drugs are
designed to affect different pathophysiologic aspects of
the disease. For example, secretagogues increase the
insulin supply. These include the second-generation
sulfonylurea medications such as glipizide or glybu-
ride. Metformin is a biguanide that increases glucose
utilization and decreases insulin resistance and hepatic
glucose production. Thiazolidinediones, such as rosigli-
tazone and pioglitazone, also reduce insulin resistance.
Acarbose and miglitol are α-glucosidase inhibitors that
reduce the absorption of glucose from the gastrointes-
tinal tract by inhibiting enzymatic degradation of more
complex sugars. If these modalities do not control the
blood glucose levels, then treatment with insulin is
necessary.
A
B
Fig. 17-33 Diabetes mellitus. A, This diffuse,
erythematous enlargement of the gingival tissues developed
in a diabetic patient who discontinued taking her insulin.
B, The gingival tissues have greatly improved after
reinstitution of regular insulin injections. Several incisors
were extracted because of severe periodontal bone loss. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 845
For patients with type I diabetes, injections of insulin
are required to control blood glucose levels. Different
types of insulin are marketed, each type having differ-
ent degrees of duration and times of peak activity.
Insulin was previously extracted primarily from beef
and pork pancreata. In some patients, however, anti-
bodies developed to this foreign protein and rendered
the insulin useless. To overcome this problem, pharma-
ceutical companies have developed brands of insulin
that have the molecular structure of human insulin.
Laboratories produce this human insulin with geneti-
cally engineered bacteria using recombinant DNA
technology.
The patient’s schedule of insulin injections must be
carefully structured and monitored to provide optimal
control of blood glucose levels. This schedule is care-
fully formulated by the patient’s physician and takes
into account such factors as the patient’s activity level
and the severity of the insulin deﬁciency. It is impera-
tive that adequate dietary carbohydrates be ingested
after the administration of the insulin; otherwise, a
condition known as insulin shock may occur. If car-
bohydrates are not consumed after an insulin
injection, then the blood glucose levels may fall to dan-
gerously low levels. The brain is virtually dependent
on blood glucose as its energy source. If the blood
glucose level drops below 40 mg/dL, the patient may
go into shock. This condition can be treated by admin-
istration of sublingual dextrose paste, intravenous
(IV) infusion of a dextrose solution, or injection of
glucagon.
In summary, diabetes mellitus is a common, complex
medical problem with many complications. The prog-
nosis is guarded. Studies suggest that strict control of
blood glucose levels results in a slowing of the develop-
ment of the late complications of type I diabetes (e.g.,
blindness, kidney damage, neuropathy) and reduces
the frequency of these complications. Health care
practitioners should be aware of the problems these
patients may have and should be prepared to deal with
them. Consultation with the patient’s physician may
be necessary, particularly for patients with type I dia-
betes who show poor blood glucose control, have
active infections, or require extensive oral surgical
procedures.
HYPOPHOSPHATASIA
Hypophosphatasia is a rare metabolic bone disease
that is characterized by a deﬁciency of tissue-nonspe-
ciﬁc alkaline phosphatase. Approximately 150 distinct
mutations of the gene responsible for alkaline phos-
phatase production have been described. One of the
ﬁrst presenting signs of hypophosphatasia may be the
premature loss of the primary teeth, presumably caused
by a lack of cementum on the root surfaces. In the
homozygous autosomal recessive form, there are rather
severe manifestations, and many of these patients are
identiﬁed in infancy. The milder forms of the disease
are inherited in an autosomal dominant or recessive
fashion, appearing in childhood or even adulthood,
with variable degrees of expression. Generally, the
younger the age of onset, the more severe the expres-
sion of the disease. The common factors in all types
include the following:
● Reduced levels of the bone, liver, and kidney
isozyme of alkaline phosphatase
●Increased levels of blood and urinary phos-
phoethanolamine
●Bone abnormalities that resemble rickets
Most authorities believe that the decreased alkaline
phosphatase levels probably are responsible for the
clinically observed abnormalities. Alkaline phospha-
tase is thought to play a role in the production of bone,
but its precise mechanism of action is unknown.
CLINICAL AND RADIOGRAPHIC
FEATURES
Four types of hypophosphatasia are generally recog-
nized, depending on the severity and the age of onset
of the symptoms:
1.Perinatal
2.Infantile
3.Childhood
4.Adult
PERINATAL HYPOPHOSPHATASIA
The perinatal form has the most severe manifesta-
tions. It is usually diagnosed at birth, and the infant
rarely survives for more than a few hours. Death is due
to respiratory failure. Marked hypocalciﬁcation of the
skeletal structures is observed.
INFANTILE HYPOPHOSPHATASIA
Babies affected by infantile hypophosphatasia may
appear normal up to 6 months of age; after this time,
they begin to show a failure to grow. Vomiting and
hypotonia may develop as well. Skeletal malformations
that suggest rickets are typically observed; these mal-
formations include shortened, bowed limbs. Deformi-
ties of the ribs predispose these patients to pneumonia,
and skull deformities cause increased intracranial
pressure. Nephrocalcinosis and nephrolithiasis also
produce problems for these infants. Radiographs show
a markedly reduced degree of ossiﬁcation with a pre-
ponderance of hypomineralized osteoid. If these infants
survive, premature shedding of the deciduous teeth is
often seen. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

846 ORAL AND MAXILLOFACIAL PATHOLOGY
CHILDHOOD HYPOPHOSPHATASIA
The childhood form is usually detected at a later age
and has a wide range of clinical expression. One of the
more consistent features is the premature loss of the
primary teeth without evidence of a signiﬁcant inﬂam-
matory response (Figs. 17-34 and 17-35). The decidu-
ous incisor teeth are usually affected ﬁrst and may be
the only teeth involved. In some patients, this may be
the only expression of the disease. The teeth may show
enlarged pulp chambers in some instances, and a sig-
niﬁcant degree of alveolar bone loss may be seen. More
severely affected patients may have open fontanelles
with premature fusion of cranial sutures. This early
fusion occasionally leads to increased intracranial
pressure and subsequent brain damage. Affected
patients typically have a short stature, bowed legs, and
a waddling gait. The development of motor skills is
often delayed.
Radiographically, the skull has the appearance of
“beaten copper,” and it shows uniformly spaced, poorly
deﬁned, small radiolucencies. This pattern may be the
result of areas of thinning of the inner cortical plate
produced by the cerebral gyri.
ADULT HYPOPHOSPHATASIA
The adult form is typically mild. Patients often have a
history of premature loss of their primary or perma-
nent dentition, and many of these patients are edentu-
lous. Stress fractures that involve the metatarsal bones
of the feet may be a presenting sign of the condition,
or an increased number of fractures associated with
relatively minor trauma may alert the clinician to this
disorder.
DIAGNOSIS
The diagnosis of hypophosphatasia is based on the
clinical manifestations and the ﬁnding of decreased
levels of serum alkaline phosphatase and increased
amounts of phosphoethanolamine in both the urine
and the blood. Interestingly, as some patients grow
older, serum alkaline phosphatase levels may approach
normal.
HISTOPATHOLOGIC FEATURES
The histopathologic evaluation of bone sampled from
a patient affected with the infantile form of hypophos-
phatasia shows abundant production of poorly miner-
alized osteoid. In the childhood or adult form, the
bone may appear relatively normal or it may show
an increased amount of woven bone, which is a less
mature form of osseous tissue.
The histopathologic examination of either a primary
or permanent tooth that has been exfoliated from an
affected patient often shows an absence or a marked
reduction of cementum that covers the root’s surface
(Fig. 17-36). This reduced amount of cementum is
thought to predispose to tooth loss because of the
inability of periodontal ligament ﬁbers to attach to the
tooth and to maintain it in its normal position.
TREATMENT AND PROGNOSIS
The treatment of hypophosphatasia is essentially symp-
tomatic because the lack of alkaline phosphatase
cannot be corrected. Attempts to treat this condition by
infusing alkaline phosphatase have been unsuccessful,
presumably because the enzyme functions within the
cell rather than in the extracellular environment. Basi-
cally, fractures are treated with orthopedic surgery,
followed by rehabilitation. Prosthetic appliances are
indicated to replace missing teeth, but satisfactory
Fig. 17-34 Hypophosphatasia. Premature loss of the
mandibular anterior teeth. (Courtesy of Dr. Jackie Banahan.)
Fig. 17-35 Hypophosphatasia. This panoramic radiograph
shows the loss of the mandibular anterior teeth. (Courtesy of Dr.
Jackie Banahan.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 847
results are not always possible because the alveolar
bone is hypoplastic. Because mutational analysis of
DNA can identify carriers of the defective gene,
patients and their parents should be provided with
genetic counseling. As stated earlier, the prognosis
varies with the onset of symptoms; the perinatal and
infantile types are associated with a rather poor
outcome. The childhood and adult forms are usually
compatible with a normal life span.
VITAMIN D–RESISTANT RICKETS
(HEREDITARY HYPOPHOSPHATEMIA;
FAMILIAL HYPOPHOSPHATEMIC
RICKETS)
After the use of vitamin D to treat rickets became
widespread, it was recognized that some individuals
with clinical features characteristic of rickets did not
seem to respond to therapeutic doses of the vitamin.
For this reason, this condition in these patients was
called vitamin D–resistant rickets. Most cases of this
rare condition appear to be inherited as an X-linked
dominant trait; therefore, males are usually affected
more severely than females, who presumably have
attenuated features because of lyonization. In the
United States, this condition occurs at a frequency of 1
in 20,000 births. In addition to the rachitic changes,
these patients are also hypophosphatemic and show a
decreased capacity for reabsorption of phosphate from
the renal tubules. The disorder is caused by mutations
in a zinc metalloproteinase gene known as PHEX
(phosphate-regulating gene with endopeptidase activ-
ity on the X chromosome). Although the precise mech-
anisms of action of this gene are unclear, it appears to
play a role in vitamin D metabolism.
In contrast, patients affected by the rare autosomal
recessive condition known as vitamin D–dependent
rickets exhibit hypocalciﬁcation of the teeth, unlike
those with vitamin D–resistant rickets. Otherwise,
the two disorders have similar clinical features. Vitamin
D–dependent rickets is caused by a lack of 1α-
hydroxylase, the enzyme responsible for converting the
relatively inactive vitamin D precursor, 25-hydroxy-
cholecalciferol (calcifediol) to the active metabolite
1,25-dihydroxycholecalciferol (calcitriol) in the kidney.
Therefore, these patients respond to replacement
therapy with active vitamin D (calcitriol).
CLINICAL FEATURES
Patients with vitamin D–resistant rickets have a short
stature. The upper body segment appears more normal,
but the lower body segment is shortened. The lower
limbs are generally shortened and bowed.
Laboratory investigation reveals hypophosphatemia
with diminished renal reabsorption of phosphate and
decreased intestinal absorption of calcium. This typi-
cally results in rachitic changes that are unresponsive
to vitamin D (calciferol). With aging, ankylosis of the
spine frequently develops.
From a dental standpoint, the teeth have large pulp
chambers, with pulp horns extending almost to the
dentinoenamel junction (Figs. 17-37 and 17-38). In
some cases the cuspal enamel may be worn down by
attrition to the level of the pulp horn, causing pulpal
exposure and pulp death. The exposure may be so
small that the resulting periapical abscesses and gingi-
val sinus tracts seem to affect what appear to be other-
wise normal teeth (Fig. 17-39). Studies have also shown
that microclefts may develop in the enamel, giving the
Fig. 17-36 Hypophosphatasia. This medium-power
photomicrograph of an exfoliated tooth shows no cementum
associated with the root surface.
Fig. 17-37 Vitamin D–resistant rickets. This radiograph of
an extracted tooth shows a prominent pulp chamber with
pulp horns extending out toward the dentinoenamel
junction. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

848 ORAL AND MAXILLOFACIAL PATHOLOGY
oral microﬂora access to the dentinal tubules and sub-
sequently to the pulp. One study examined a series of
affected children and found that 25% of these
patients had multiple abscesses involving the primary
dentition.
HISTOPATHOLOGIC FEATURES
Microscopic examination of an erupted tooth from a
patient with vitamin D–resistant rickets usually shows
markedly enlarged pulp horns. The dentin appears
abnormal and is characterized by the deposition of
globular dentin, which often exhibits clefting. The clefts
may extend from the pulp chamber to the dentino-
enamel junction. Microclefts are also seen within the
enamel. The pulp frequently is nonvital, presumably
because of the bacterial contamination associated with
both the enamel and the dentinal clefts.
TREATMENT AND PROGNOSIS
For a normal stature to develop, patients with vitamin
D–resistant rickets usually need early treatment with
calcitriol and multiple daily doses of phosphate. End-
odontic therapy is necessary for the pulpally involved
teeth. Initiating therapy in early childhood with a
synthetic vitamin D compound (1α-hydroxycholecal-
ciferol) appears to reduce dental problems in affected
patients when compared with untreated historic con-
trols. Interestingly, the radiographic dental abnormali-
ties do not seem to be improved. Although serum
and urine calcium levels must be monitored care-
fully to prevent nephrocalcinosis with its potential for
kidney damage, patients generally have a normal life
span.
CROHN’S DISEASE (REGIONAL ILEITIS;
REGIONAL ENTERITIS)
Crohn’s disease is an inﬂammatory and probably
an immunologically mediated condition of unknown
cause that primarily affects the distal portion of the
small bowel and the proximal colon. It is now well
established that the manifestations of Crohn’s disease
may be seen anywhere in the gastrointestinal tract,
from the mouth to the anus. In addition, other extrain-
testinal sites of disease involvement, such as the skin,
eyes, and joints, have also been identiﬁed. The oral
lesions are signiﬁcant because they may precede the
gastrointestinal lesions in as many as 30% of the cases
that have both oral and gastrointestinal involvement.
It is interesting that the prevalence of Crohn’s disease
appears to be increasing, but the reasons for this
increase have not been determined.
CLINICAL FEATURES
Most patients with Crohn’s disease are teenagers when
the disease ﬁrst becomes evident, although another
diagnostic peak of disease activity occurs in patients
more than 60 years of age. Gastrointestinal signs and
symptoms usually include abdominal cramping and
pain, nausea, and diarrhea, occasionally accompanied
by fever. Weight loss and malnutrition may develop,
which can lead to anemia, decreased growth, and short
stature.
A wide range of oral lesions has been clinically
reported in Crohn’s disease; however, many of the
abnormalities described are relatively nonspeciﬁc and
may be associated with other conditions that cause
orofacial granulomatosis (see page 341). The more
prominent ﬁndings include diffuse or nodular swelling
of the oral and perioral tissues, a cobblestone appear-
ance of the mucosa, and deep, granulomatous-appear-
Fig. 17-38 Vitamin D–resistant rickets. Ground section of
the same tooth depicted in Fig. 17-37. A pulp horn extends
to the dentinoenamel junction. (Courtesy of Dr. Carl Witkop.)
Fig. 17-39 Vitamin D–resistant rickets. This patient
exhibits multiple nonvital teeth with associated parulides.
This arose in the absence of caries or trauma. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 849
ing ulcers. The ulcers are often linear and develop in
the buccal vestibule (Fig. 17-40). Patchy erythematous
macules and plaques involving the attached and un-
attached gingivae have been termed mucogingivitis
and may represent one of the more common lesions
related to Crohn’s disease. Soft tissue swellings that
resemble denture-related ﬁbrous hyperplasia may be
seen, as well as smaller mucosal tags. Another manifes-
tation that has been reported is aphthouslike oral
ulcerations, although the signiﬁcance of this ﬁnding is
uncertain because aphthous ulcerations are found
rather frequently in the general population, including
the same age group that is affected by Crohn’s disease.
One large study showed no difference in the preva-
lence of aphthous ulcers in patients with Crohn’s
disease compared with a control population. Fewer
than 1% of patients with Crohn’s disease may develop
diffuse stomatitis, with some cases apparently caused
by Staphylococcus aureus, and others being nonspeciﬁc.
In at least one instance, recurrent severe buccal space
infections resulted in cutaneous salivary ﬁstula forma-
tion. Infrequently, pyostomatitis vegetans (see next
topic) has been associated with Crohn’s disease.
HISTOPATHOLOGIC FEATURES
Microscopic examination of lesional tissue obtained
from the intestine or from the oral mucosa should
show nonnecrotizing granulomatous inﬂammation
within the submucosal connective tissue (Fig. 17-41).
The severity of the granulomatous inﬂammation may
vary tremendously from patient to patient and from
various sites in the same patient. Therefore, a negative
biopsy result at any one site and time may not neces-
sarily rule out a diagnosis of Crohn’s disease. As with
the clinical lesions, the histopathologic pattern is rela-
tively nonspeciﬁc, resembling orofacial granulomato-
sis. Special stains should be performed to rule out the
possibility of deep fungal infection, tertiary syphilis, or
mycobacterial infection.
TREATMENT AND PROGNOSIS
Most patients with Crohn’s disease are initially treated
medically with a sulfa type of drug (sulfasalazine), and
some patients respond well to this medication. Metro-
nidazole may be used if no response is seen with
sulfasalazine therapy. With moderate to severe
involvement, systemic prednisone may be used and is
often effective, particularly when combined with the
immunosuppressive drug, azathioprine. Inﬂiximab, a
monoclonal antibody directed against tumor necrosis
factor-α (TNF-α), has shown promise in refractory
cases of Crohn’s disease. Sometimes the disease
cannot be maintained in remission by medical therapy,
and complications develop that require surgical inter-
vention. Complications may include bowel obstruction
or ﬁstula or abscess formation. If a signiﬁcant segment
of the terminal ileum has been removed surgically or
is involved with the disease, then periodic injections of
vitamin B
12 may be necessary to prevent megaloblastic
anemia secondary to the lack of ability to absorb the
vitamin. Similar supplementation of magnesium, iron,
the fat-soluble vitamins, and folate may also be required
because of malabsorption.
Oral lesions have been reported to clear with treat-
ment of the gastrointestinal process in many cases.
Occasionally persistent oral ulcerations will develop,
and these may have to be treated with topical or intra-
lesional corticosteroids. Systemic thalidomide and
inﬂiximab have been used successfully to manage
refractory oral ulcers of Crohn’s disease.
Fig. 17-40 Crohn’s disease. This patient has a linear
ulceration of the mandibular vestibule. An adhesion between
the alveolar and labial mucosae was caused by repeated
ulceration and healing of the mucosa at this site.
Fig. 17-41 Crohn’s disease. This medium-power
photomicrograph of an oral lesion shows a nonnecrotizing
granuloma in the submucosal connective tissue. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

850 ORAL AND MAXILLOFACIAL PATHOLOGY
PYOSTOMATITIS VEGETANS
Pyostomatitis vegetans is a relatively rare condition
that has a controversial history. It has been associated
in the past with diseases such as pemphigus or pyoder-
matitis vegetans. Most investigators today, however,
believe that pyostomatitis vegetans is an unusual oral
expression of inﬂammatory bowel disease, particularly
ulcerative colitis or Crohn’s disease. The pathogen-
esis of the condition, like that of inﬂammatory bowel
disease, is poorly understood. A few patients with pyo-
stomatitis vegetans have also been noted to have one
of several concurrent liver abnormalities.
CLINICAL FEATURES
Patients with pyostomatitis vegetans exhibit character-
istic yellowish, slightly elevated, linear, serpentine pus-
tules set on an erythematous oral mucosa. The lesions
primarily affect the buccal and labial mucosa, soft
palate, and ventral tongue (Figs. 17-42 and 17-43).
These lesions have been called “snail track” ulcerations,
although in most instances the lesions are probably not
truly ulcerated. Oral discomfort is variable but can be
surprisingly minimal in some patients. This variation
in symptoms may be related to the number of pustules
that have ruptured to form ulcerations. The oral lesions
may appear concurrently with the bowel symptoms, or
they may precede the intestinal involvement.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of an oral lesion of pyostomatitis
vegetans usually shows marked edema, causing an
acantholytic appearance of the involved epithelium.
This may be the result of the accumulation of numer-
ous eosinophils within the spinous layer, often forming
intraepithelial abscesses (Fig. 17-44). Subepithelial
eosinophilic abscesses have been reported in some
instances. The underlying connective tissue usually
supports a dense mixed inﬁltrate of inﬂammatory cells
that consists of eosinophils, neutrophils, and lympho-
cytes. Perivascular inﬂammation may also be present.
TREATMENT AND PROGNOSIS
Usually, the intestinal signs and symptoms of inﬂam-
matory bowel disease are of most concern for patients
with pyostomatitis vegetans. Medical management of
the bowel disease with sulfasalazine or systemic corti-
costeroids also produces clearing of the oral lesions
(see Fig. 17-40). Often the oral lesions clear within
days after systemic corticosteroid therapy is begun,
and they may recur if the medication is withdrawn. If
the bowel symptoms are relatively mild, then the
oral lesions have been reported to respond to topical
therapy with some of the more potent corticosteroid
preparations.
Fig. 17-42 Pyostomatitis vegetans. The characteristic
lesions are seen on the buccal mucosa, appearing as yellow-
white pustules.
A
B
Fig. 17-43 Pyostomatitis vegetans. A, Characteristic “snail
track” lesions involve the soft palate. B, Same patient after 5
days of prednisone therapy. (From Neville BW, Laden SA, Smith SE
et al: Pyostomatitis vegetans, Am J Dermatopathol 7:69-77, 1985.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 851
UREMIC STOMATITIS
Patients who have either acute or chronic renal failure
typically show markedly elevated levels of urea and
other nitrogenous wastes in the bloodstream. Uremic
stomatitis represents a relatively uncommon compli-
cation of renal failure. In two series that included 562
patients with renal failure, only eight examples of this
oral mucosal condition were documented. Neverthe-
less, for the patients in whom uremic stomatitis devel-
ops, this can be a painful disorder. The cause of the oral
lesions is unclear, but some investigators suggest that
urease, an enzyme produced by the oral microﬂora,
may degrade urea secreted in the saliva. This degrada-
tion results in the liberation of free ammonia, which
presumably damages the oral mucosa.
CLINICAL FEATURES
Most cases of uremic stomatitis have been reported in
patients with acute renal failure. The onset may be
abrupt, with white plaques distributed predominantly
on the buccal mucosa, tongue, and ﬂoor of the mouth
(Fig. 17-45). Patients may complain of unpleasant taste,
oral pain, or a burning sensation with the lesions, and
the clinician may detect an odor of ammonia or urine
on the patient’s breath. The clinical appearance
occasionally has been known to mimic oral hairy
leukoplakia.
TREATMENT AND PROGNOSIS
In some instances, uremic stomatitis may clear within
a few days after renal dialysis, although such resolution
may take place over 2 to 3 weeks. In other instances,
treatment with a mildly acidic mouth rinse, such as
diluted hydrogen peroxide, seems to clear the oral
lesions. For control of pain while the lesions heal,
patients may be given palliative therapy with ice chips
or a topical anesthetic, such as viscous lidocaine or
dyclonine hydrochloride. Although renal failure itself
is life threatening, at least one example of a uremic
plaque that presumably caused a patient’s death has
been recorded. This event was thought to have been
caused by the dislodging of the plaque with subsequent
obstruction of the patient’s airway.
A
B
Fig. 17-44 Pyostomatitis vegetans. Medium-power
photomicrograph showing intraepithelial abscesses
composed of eosinophils.
Fig. 17-45 Uremic stomatitis. A, Ragged white plaques
affect the ventral tongue and ﬂoor of the mouth. B, Same
patient after renal dialysis. (From Ross WF, Salisbury PL: Uremic
stomatitis associated with undiagnosed renal failure, Gen Dent 42:410-
412, 1994.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

852 ORAL AND MAXILLOFACIAL PATHOLOGY
BIBLIOGRAPHY
Mucopolysaccharidosis
Alpöz AR, Çoker M, Çelen E et al: The oral manifestations of
Maroteaux-Lamy syndrome (mucopolysaccharidosis VI): a
case report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
101:632-637, 2006.
Brady RO: Enzyme replacement for lysosomal diseases, Annu Rev
Med 57:283-296, 2006.
Danos O, Heard J-M: Mucopolysaccharidosis, Mol Cell Biol Hum
Dis Ser 5:350-367, 1995.
Downs AT, Crisp T, Ferretti G: Hunter’s syndrome and oral
manifestations: a review, Pediatr Dent 17:98-100, 1995.
Fahnehjelm KT, Törnquist A-L, Malm G et al: Ocular ﬁndings in
four children with mucopolysaccharidosis I-Hurler (MPS
I-H) treated early with haematopoietic stem cell transplanta-
tion, Acta Ophthalmol Scand 84:781-785, 2006.
Harmatz P, Giugliani R, Schwartz I et al: Enzyme replacement
therapy for mucopolysaccharidosis VI: a phase 3, random-
ized, double-blind, placebo-controlled, multinational study
of recombinant human N-acetylgalactosamine 4-sulfatase
(recombinant human arylsulfatase B or RHASB) and follow-
on, open-label extension study, J Pediatr 148:533-539, 2006.
Kinirons MJ, Nelson J: Dental ﬁndings in mucopolysaccharidosis
type IV A (Morquio’s disease type A), Oral Surg Oral Med Oral
Pathol 70:176-179, 1990.
Meikle PJ, Hopwood JJ, Clague AE et al: Prevalence of lysosomal
storage disorders, JAMA 281:249-254, 1999.
Mikles M, Stanton RP: A review of Morquio syndrome, Am J
Orthop 26:533-540, 1997.
Muenzer J: The mucopolysaccharidoses: a heterogeneous group
of disorders with variable pediatric presentations, J Pediatr
144:S27-S34, 2004.
Nakamura T, Miwa K, Kanda S et al: Rosette formation of
impacted molar teeth in mucopolysaccharidoses and related
disorders, Dentomaxillofac Radiol 21:45-49, 1992.
Nelson J, Crowhurst J, Carey B et al: Incidence of the mucopoly-
saccharidoses in Western Australia, Am J Med Genet 123A:310-
313, 2003.
Northover H, Cowie RA, Wraith JE: Mucopolysaccharidosis type
IVA (Morquio syndrome): a clinical review, J Inherit Metab Dis
19:357-365, 1996.
Nussbaum BL: Dentistry for the at-risk patient—mucopolysac-
charidosis III (Sanﬁlippo syndrome): a nine-year case study,
ASDC J Dent Child 57:466-469, 1990.
Pastores GM, Arn P, Beck M et al: The MPS I registry: design,
methodology, and early ﬁndings of a global disease registry
for monitoring patients with mucopolysaccharidosis type I,
Mol Genet Metab 91:37-47, 2007.
Peters C, Shapiro EG, Anderson J et al: Hurler syndrome: II.
Outcome of HLA-genotypically identical sibling and HLSA-
haploidentical related donor bone marrow transplantation in
ﬁfty-four children, Blood 91:2601-2608, 1998.
Scott HS, Bunge S, Gal A et al: Molecular genetics of mucopoly-
saccharidosis type I: diagnostic, clinical, and biological impli-
cations, Hum Mutat 6:288-302, 1995.
Sifuentes M, Doroshow R, Hoft R et al: A follow-up study of MPS
I patients treated with laronidase enzyme replacement
therapy for 6 years, Mol Genet Metab 90:171-180, 2007.
Simmons MA, Bruce IA, Penney S et al: Otorhinolarygological
manifestations of the mucopolysaccharidoses, Int J Pediatr
Otorhinolaryngol 69:589-595, 2005.
Smith KS, Hallett KB, Hall RK et al: Mucopolysaccharidosis:
MPS VI and associated delayed tooth eruption, Int J Oral
Maxillofac Surg 24:176-180, 1995.
Staba SL, Escolar ML, Poe M et al: Cord-blood transplants from
unrelated donors in patients with Hurler’s syndrome, N Engl
J Med 350:1960-1969, 2004.
Vellodi A, Young EP, Cooper A et al: Bone marrow transplanta-
tion for mucopolysaccharidosis type I: experience of two
British centres, Arch Dis Child 76:92-99, 1997.
Vijay S, Wraith JE: Clinical presentation and follow-up of patients
with the attenuated phenotype of mucopolysaccharidosis
type I, Acta Paediatrica 94:872-877, 2005.
Wraith JE: The mucopolysaccharidoses: a clinical review and
guide to management, Arch Dis Child 72:263-267, 1995.
Wraith JE, Hopwood JJ, Fuller M et al: Laronidase treatment of
mucopolysaccharidosis I, BioDrugs 19:1-7, 2005.
Lipid Reticuloendothelioses
Barranger JA, Rice E, Sakallah SA et al: Enzymatic and molecular
diagnosis of Gaucher disease, Clin Lab Med 15:899-913,
1995.
Beutler E: Lysosomal storage diseases: natural history and ethical
and economic aspects, Mol Genet Metab 88:208-215, 2006.
Beutler E, Nguyen NJ, Henneberger MW et al: Gaucher disease:
gene frequencies in the Ashkenazi Jewish population, Am J
Hum Genet 52:85-88, 1993.
Blitzer MG, McDowell CA: Tay-Sachs disease as a model for
screening inborn errors, Clin Lab Med 12:463-479, 1992.
Dayan B, Elstein D, Zimran A et al: Decreased salivary output in
patients with Gaucher disease, Q J Med 96:53-56, 2003.
Fernandes-Filho JA, Shapiro BE: Tay-Sachs disease, Arch Neurol
61:1466-1468, 2004.
Gieselmann V: Lysosomal storage diseases, Biochim Biophys Acta
1270:103-136, 1995.
Grabowski GA: Recent clinical progress in Gaucher disease, Curr
Opin Pediatr 17:519-524, 2005.
Gravel RA, Triggs-Raine BL, Mahuran DJ: Biochemistry and
genetics of Tay-Sachs disease, Can J Neurol Sci 18:419-423,
1991.
Imrie J, Dasgupta S, Besley GTN et al: The natural history of
Niemann-Pick disease type C in the UK, J Inherit Metab Dis
30:51-59, 2007.
Kolodny EH: Niemann-Pick disease, Curr Opin Hematol 7:48-52,
2000.
Levran O, Desnick RJ, Schuchman EH: Niemann-Pick disease: a
frequent missense mutation in the acid sphingomyelinase
gene of Ashkenazi Jewish type A and B patients, Proc Natl
Acad Sci U S A 88:3748-3752, 1991.
Lustmann J, Ben-Yehuda D, Somer M et al: Gaucher’s disease
affecting the mandible and maxilla: report of a case, Int J Oral
Maxillofac Surg 20:7-8, 1991.
McGovern MM, Aron A, Brodie SE et al: Natural history of type
A Niemann-Pick disease. Possible endpoints for therapeutic
trials, Neurology 66:228-232, 2006.
Morales LE: Gaucher’s disease: a review, Ann Pharmacother
30:381-388, 1996.
Morris JA, Carstea ED: Niemann-Pick disease: cholesterol han-
dling gone awry, Mol Med Today 4:525-531, 1998.
Rosenthal DI, Doppelt SH, Mankin HJ et al: Enzyme replace-
ment therapy for Gaucher disease: skeletal responses to mac-
rophage-targeted glucocerebrosidase, Pediatrics 96:629-637,
1995.
Sévin M, Lesca G, Baumann N et al: The adult form of Niemann-
Pick disease type C, Brain 130:120-133, 2007.
Shiran A, Brenner B, Laor A et al: Increased risk of cancer in
patients with Gaucher disease, Cancer 72:219-224, 1993.
Sidransky E, Tayebi N, Ginns EI: Diagnosing Gaucher disease.
Early recognition, implications for treatment, and genetic
counseling, Clin Pediatr (Phila) 34:365-371, 1995. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 853
Starzyk K, Richards S, Yee J et al: The long-term international
safety experience of imiglucerase therapy for Gaucher
disease, Mol Genet Metab 90:157-163, 2007.
Tamura H, Takahashi T, Ban N et al: Niemann-Pick type C
disease: Novel NPC1 mutations and characterization of the
concomitant acid sphingomyelinase deﬁciency, Mol Genet
Metab 87:113-121, 2006.
Vanier MT: Prenatal diagnosis of Niemann-Pick diseases types
A, B and C, Prenat Diagn 22:630-632, 2002.
Weinstein LB: Selected genetic disorders affecting Ashkenazi
Jewish families, Fam Community Health 30:50-62, 2007.
Lipoid Proteinosis
Aroni K, Lazaris AC, Papadimitriou K et al: Lipoid proteinosis of
the oral mucosa: case report and review of the literature,
Pathol Res Pract 194:855-859, 1998.
Bahadir S, Çobanogˇlu Ü, Kapiciogˇlu Z et al: Lipoid proteinosis: a
case with ophthalmological and psychiatric ﬁndings, J Derma-
tol 3:215-218, 2006.
Bazopoulou-Kyrkanidou E, Tosios KI, Zabelis G et al: Hyalinosis
cutis et mucosae: gingival involvement, J Oral Pathol Med
27:233-237, 1998.
Botha P: Oral lipoid proteinosis, SADJ 54:371-373, 1999.
Chaudhary SJ, Dayal PK: Hyalinosis cutis et mucosae. Review
with a case report, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 80:168-171, 1995.
Hamada T: Lipoid proteinosis, Clin Exp Dermatol 27:624-629,
2002.
Hamada T, Wessagowit V, South AP et al: Extracellular matrix
protein 1 gene (ECM1) mutations in lipoid proteinosis and
genotype-phenotype correlation, J Invest Dermatol 120:345-
350, 2003.
Horev L, Potikha T, Ayalon S et al: A novel splice-site mutation
in ECM-1 gene in a consanguineous family with lipoid pro-
teinosis, Exp Dermatol 14:891-897, 2005.
Lupo I, Cefalu AB, Bongiorno MR et al: A novel mutation of the
extracellular matrix protein 1 gene (ECM1) in a patient with
lipoid proteinosis (Urbach-Wiethe disease) from Sicily, Br J
Dermatol 153:1019-1022, 2005.
Muda AO, Paradisi M, Angelo C et al: Lipoid proteinosis: clinical,
histologic, and ultrastructural investigations, Cutis 56, 220-
224, 1995.
Staut CCV, Naidich TP: Urbach-Wiethe disease (lipoid proteino-
sis), Pediatr Neurosurg 28:212-214, 1998.
Jaundice
Bansal V, Schuchert VD: Jaundice in the intensive care unit, Surg
Clin North Am 86:1495-1502, 2006.
Cohen SM: Jaundice in the full-term newborn, Pediatr Nurs
32:202-208, 2006.
Gordon SC: Jaundice and cholestasis, Postgrad Med 90:65-71,
1991.
Hass PL: Differentiation and diagnosis of jaundice, AACN Clin
Issues 10:433-441, 1999.
Pratt DS, Kaplan MM: Jaundice. In Kasper DL, Braunwald E,
Fauci AS et al: Harrison’s principles of internal medicine, pp 238-
243, ed 16, New York, 2005, McGraw-Hill.
Murtagh J: Jaundice, Aust Fam Physician 20:457-466, 1991.
Roche SP, Kobos R: Jaundice in the adult patient, Am Fam Physi-
cian 69:299-304, 2004.
Amyloidosis
Fahrner KS, Black CC, Gosselin BJ: Localized amyloidosis of the
tongue: a review, Am J Otolaryngol 25:186-189, 2004.
Falk RH, Comenzo RL, Skinner M: The systemic amyloidoses, N
Engl J Med 337:898-909, 1997.
Gertz MA, Lacy MQ, Dispenzieri A: Amyloidosis: recognition,
conﬁrmation, prognosis, and therapy, Mayo Clin Proc 74:490-
494, 1999.
Hachulla E, Grateau G: Diagnostic tools for amyloidosis, Joint
Bone Spine 69:538-545, 2002.
Hachulla E, Janin A, Flipo RM et al: Labial salivary gland biopsy
as a reliable test for the diagnosis of primary and secondary
amyloidosis: a prospective clinical and immunohistologic
study in 59 patients, Arthritis Rheum 36:691-697, 1993.
Hirschﬁeld GM: Amyloidosis: a clinico-pathophysiological syn-
opsis, Semin Cell Dev Biol 15:39-44, 2004.
Johansson I, Ryberg M, Steen L et al: Salivary hypofunction in
patients with familial amyloidotic polyneuropathy, Oral Surg
Oral Med Oral Pathol 74:742-748, 1992.
Kaplan B, Martin BM, Livneh A et al: Biochemical subtyping of
amyloid in formalin-ﬁxed tissue samples conﬁrms and sup-
plements immunohistologic data, Am J Clin Pathol 121:794-
800, 2004.
Lachmann HJ, Hawkins PN: Systemic amyloidosis, Curr Opin
Pharmacol 6:214-220, 2006.
Mardinger O, Rotenberg L, Chaushu G et al: Surgical manage-
ment of macroglossia due to primary amyloidosis, Int J Oral
Maxillofac Surg 28:129-131, 1999.
Merlini G, Westermark P: The systemic amyloidoses: clearer
understanding of the molecular mechanisms offers hope for
more effective therapies, J Intern Med 255:159-178, 2004.
Nandapalan V, Jones TM, Morar P et al: Localized amyloidosis
of the parotid gland: a case report and review of the localized
amyloidosis of the head and neck, Head Neck 20:73-78,
1998.
Penner CR, Müller S: Head and neck amyloidosis: a
clinicopathologic study of 15 cases, Oral Oncol 42:421-429,
2006.
Raymond AK, Sneige N, Batsakis JG: Amyloidosis in the upper
aerodigestive tract, Ann Otol Rhinol Laryngol 101:794-796,
1992.
Skinner M, Anderson JJ, Simms R et al: Treatment of 100 patients
with primary amyloidosis: a randomized trial of melphalan,
prednisone, and colchicine versus colchicine only, Am J Med
100:290-298, 1996.
Stoopler ET, Alawi F, Laudenbach JM et al: Bullous amyloidosis
of the oral cavity: a rare clinical presentation and review, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 101:734-740,
2006.
Stoopler ET, Sollecito TP, Chen S-Y: Amyloid deposition in the
oral cavity: a retrospective study and review of the literature,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:674-680,
2003.
Westermark P, Benson MD, Buxbaum JN et al: Amyloid: toward
terminology clariﬁcation. Report from the Nomenclature
Committee of the International Society of Amyloidosis,
Amyloid 12:1-4, 2005.
Xavier SD, Filho IB, Müller H: Macroglossia secondary to sys-
temic amyloidosis: case report and literature review, Ear Nose
Throat J 84:358-361, 2005.
Vitamin Deﬁciency
Blanck HM, Bowman BA, Serdula MK et al: Angular stomatitis
and riboﬂavin status among adolescent Bhutanese refugees
living in southeastern Nepal, Am J Clin Nutr 76:430-435,
2002.
Fairﬁeld KM, Fletcher RH: Vitamins for chronic disease preven-
tion in adults, JAMA 287:3116-3126, 2002.
Halligan TJ, Russell NG, Dunn WJ et al: Identiﬁcation and treat-
ment of scurvy: a case report, Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 100:688-692, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

854 ORAL AND MAXILLOFACIAL PATHOLOGY
Harper C: Thiamine (vitamin B1) deﬁciency and associated brain
damage is still common throughout the world and prevention
is simple and safe! Eur J Neurol 13:1078-1082, 2006.
Heath ML, Sidbury R: Cutaneous manifestations of nutritional
deﬁciency, Curr Opin Pediatr 18:417-422, 2006.
Hirschmann JV, Raugi GJ: Adult scurvy, J Am Acad Dermatol
41:895-906, 1999.
Mason ME, Jalagani H, Vinik AI: Metabolic complications of
bariatric surgery: diagnosis and management issues, Gastro-
enterol Clin North Am 34:25-33, 2005.
Nield LS, Mahajan P, Joshi A et al: Rickets: not a disease of the
past, Am Fam Physician 74:619-626, 629-630, 2006.
Olmedo JM, Yiannias JA, Windgassen EB et al: Scurvy: a disease
almost forgotten, Int J Dermatol 45:909-913, 2006.
Powers HJ: Riboﬂavin (vitamin B2) and health, Am J Clin Nutr
77:1352-1360, 2003.
Sethuraman U: Vitamins, Pediatr Rev 27:44-55, 2006.
Thacher TD, Fischer PR, Pettifor JM et al: A comparison of
calcium, vitamin D, or both for nutritional rickets in Nigerian
children, N Engl J Med 341:563-568, 1999.
Touyz LZG: Oral scurvy and periodontal disease, J Can Dent Assoc
63:837-845, 1997.
Russell RM: Vitamin and trace mineral deﬁciency and excess. In
Kasper DL, Braunwald E, Fauci AS et al: Harrison’s principles
of internal medicine, pp 403-411, ed 16, New York, 2005,
McGraw-Hill.
Wolpowitz D, Gilchrest BA: The vitamin D questions: how much
do you need and how should you get it? J Am Acad Dermatol
54:301-317, 2006.
Iron-Deﬁciency Anemia
Brigden ML: Iron deﬁciency anemia: every case is instructive,
Postgrad Med 93:181-192, 1993.
Brown RG: Normocytic and macrocytic anemias, Postgrad Med
89:125-136, 1991.
Cook JD: Diagnosis and management of iron-deﬁciency anaemia,
Best Pract Res Clin Haematol 18:319-332, 2005.
Killip S, Bennett JM, Chambers MD: Iron deﬁciency anemia, Am
Fam Physician 75:671-678, 2007.
Massey AC: Microcytic anemia: differential diagnosis and man-
agement of iron deﬁciency anemia, Med Clin North Am
76:549-566, 1992.
Osaki T, Ueta E, Arisawa K et al: The pathophysiology of glossal
pain in patients with iron deﬁciency anemia, Am J Med Sci
318:324-329, 1999.
Provan D: Mechanisms and management of iron deﬁciency
anaemia, Br J Haematol 105(suppl 1):19-26, 1999.
Umbreit J: Iron deﬁciency: a concise review, Am J Hematol
78:225-231, 2005.
Plummer-Vinson Syndrome
Atmatzidis K, Papaziogas B, Pavlidis T et al: Plummer-Vinson
syndrome, Dis Esophagus 16:154-157, 2003.
Bredenkamp JK, Castro D J, Mickel RA: Importance of iron
repletion in the management of Plummer-Vinson syndrome,
Ann Otol Rhinol Laryngol 99:51-54, 1990.
Chen TSN, Chen PSY: Rise and fall of the Plummer-Vinson syn-
drome, J Gastroenterol Hepatol 9:654-658, 1994.
Dantas RO, Villanova MG: Esophageal motility impairment in
Plummer-Vinson syndrome: correction by iron treatment,
Dig Dis Sci 38:968-971, 1993.
Geerlings SE, Statius van Eps LW: Pathogenesis and conse-
quences of Plummer-Vinson syndrome, Clin Invest 70:629-
630, 1992.
Hoffman RM, Jaffe PE: Plummer-Vinson syndrome: a case report
and literature review, Arch Intern Med 155:2008-2011,
1995.
Nagai T, Susami E, Ebiham T: Plummer-Vinson syndrome com-
plicated by gastric cancer: a case report, Keio J Med 39:106-
111, 1990.
Seitz ML, Sabatino D: Plummer-Vinson syndrome in an adoles-
cent, J Adolesc Health 12:279-281, 1991.
Wahlberg PCG, Andersson KEH, Biörklund AT et al: Carcinoma
of the hypopharynx: analysis of incidence and survival in
Sweden in over a 30-year period, Head Neck 20:714-719,
1998.
Yukselen V, Karaoglu AO, Yasa MH: Plummer-Vinson syndrome:
a report of three cases, Int J Clin Pract 57:646-648, 2003.
Pernicious Anemia
Colon-Otero G, Menke D, Hook CC: A practical approach to the
differential diagnosis and evaluation of the adult patient with
macrocytic anemia, Med Clin North Am 76:581-596, 1992.
Dharmarajan TS, Adiga GU, Norkus EP: Vitamin B
12 deﬁciency:
recognizing subtle symptoms in older adults, Geriatrics 58:30-
38, 2003.
Drummond JF, White DK, Damm DD: Megaloblastic anemia
with oral lesions: a consequence of gastric bypass surgery,
Oral Surg Oral Med Oral Pathol 59:149-153, 1985.
Field EA, Speechley JA, Rugman FR et al: Oral signs and symp-
toms in patients with undiagnosed vitamin B12 deﬁciency, J
Oral Pathol Med 24:468-470, 1995.
Greenberg M: Clinical and histologic changes of the oral mucosa
in pernicious anemia, Oral Surg Oral Med Oral Pathol 52:38-
42, 1981.
Hsing AW, Hansson L-E, McLaughlin JK et al: Pernicious anemia
and subsequent cancer: a population-based cohort study,
Cancer 71:745-750, 1993.
Kleinegger CL, Krolls SO: Severe pernicious anemia presenting
with burning mouth symptoms, Miss Dent Assoc J 52:12-14,
1996.
Lehman JS, Bruce AJ, Rogers RS: Atrophic glossitis from vitamin
B12 deﬁciency: a case misdiagnosed as burning mouth disor-
der, J Periodontol 77:2090-2092, 2006.
Loffeld BCAJ, van Spreeuwel JP: The gastrointestinal tract in
pernicious anemia, Dig Dis 9:70-77, 1991.
Oh RC, Brown DL: Vitamin B12 deﬁciency, Am Fam Physician
67:979-986, 993-994, 2003.
Toh B-H, Alderuccio F: Pernicious anemia, Autoimmunity 37:357-
361, 2004.
Toh B-H, van Driel IR, Gleeson PA: Pernicious anemia, N Engl J
Med 337:1441-1448, 1997.
Pituitary Dwarﬁsm
Ayuk J, Sheppard MC: Growth hormone and its disorders, Post-
grad Med J 82:24-30, 2006.
Buduneli N, Alpoz AR, Candan U et al: Dental management of
isolated growth hormone deﬁciency: a case report, J Clin
Pediatr Dent 29:263-266, 2005.
Carvalho LR, Justamante de Faria ME, Farah-Osorio MG et al:
Acromegalic features in growth hormone (GH)-deﬁcient
patients after long-term GH therapy, Clin Endocrinol 59:788-
792, 2003.
Funatsu M, Sato K, Mitani H: Effects of growth hormone on cra-
niofacial growth, Angle Orthod 76:970-977, 2006.
Grumbach MM, Bin-Abbas BS, Kaplan SL: The growth hormone
cascade: progress and long-term results of growth hormone
treatment in growth hormone deﬁciency, Horm Res 49(suppl
2):41-57, 1998.
Kosowicz J, Rzymski K: Abnormalities of tooth development in
pituitary dwarﬁsm, Oral Surg Oral Med Oral Pathol 44:853-
863, 1977.
Lamberts SWJ, de Herder WW, van der Lely AJ: Pituitary insuf-
ﬁciency, Lancet 352:127-134, 1998. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 855
Laron Z: Short stature due to genetic defects affecting growth
hormone activity, N Engl J Med 334:463-465, 1996.
Gigantism
Daughaday WH: Pituitary gigantism, Endocrinol Metab Clin North
Am 21:633-647, 1992.
Eugster EA, Pescovitz OH: Gigantism, J Clin Endocrinol Metab
84:4379-4384, 1999.
Kant SG, Wit JM, Breuning MH: Genetic analysis of tall stature,
Horm Res 64:149-156, 2005.
Van Haelst MM, Hoogeboom JJM, Baujat G et al: Familial gigan-
tism caused by an NSD1 mutation, Am J Med Genet 139A:40-
44, 2005.
Acromegaly
Ayuk J, Sheppard MC: Growth hormone and its disorders, Post-
grad Med J 82:24-30, 2006.
Ben-Shlomo A, Melmed S: Skin manifestations in acromegaly,
Clin Dermatol 24:256-259, 2006.
Burt MG, Ho KKY: Newer options in the management of acro-
megaly, Intern Med J 36:437-444, 2006.
Cohen RB, Wilcox CW: A case of acromegaly identiﬁed after
patient complaint of apertognathia, Oral Surg Oral Med Oral
Pathol 75:583-586, 1993.
Farinazzo-Vitral RW, Motohiro-Tanaka O, Reis-Fraga M et al:
Acromegaly in an orthodontic patient, Am J Orthod Dentofacial
Orthop 130:388-390, 2006.
Gayle C, Sonksen P: The presentation of acromegaly in general
practice, Practitioner 243:110-117, 1999.
Guistina A, Barkan A, Casanueva FF et al: Criteria for cure of
acromegaly: a consensus statement, J Clin Endocrinol Metab
85:526-529, 2000.
Laws ER, Vance ML, Thapar K: Pituitary surgery for the manage-
ment of acromegaly, Horm Res 53(suppl 3):71-75, 2000.
Melmed S: Acromegaly, N Engl J Med 355:2558-2573, 2006.
Newman CB: Medical therapy for acromegaly, Endocrinol Metab
Clin North Am 28:171-190, 1999.
Ron E, Gridley G, Hrubec Z et al: Acromegaly and gastrointesti-
nal cancer, Cancer 68:1673-1677, 1991.
Hypothyroidism
Burman KD, McKinley-Grant L: Dermatologic aspects of thyroid
disease, Clin Dermatol 24:247-255, 2006.
LaFranchi S: Congenital hypothyroidism: etiologies, diagnosis,
and management, Thyroid 9:735-740, 1999.
Lazarus JH, Obuobie K: Thyroid disorders—an update, Postgrad
Med J 76:529-536, 2000.
Martinez M, Derksen D, Kapsner P: Making sense of hypothy-
roidism, Postgrad Med 93:135-145, 1993.
Mg’ang’a PM, Chindia ML: Dental and skeletal changes in juve-
nile hypothyroidism following treatment: case report, Odon-
tostomatol Trop 13:25-27, 1990.
Roberts CGP, Ladenson PW: Hypothyroidism, Lancet 363:793-
803, 2004.
Topliss DJ, Eastman CJ: Diagnosis and management of hyper-
thyroidism and hypothyroidism, Med J Aust 180:186-193,
2004.
Woeber KA: Update on the management of hyperthyroidism
and hypothyroidism, Arch Fam Med 9:743-747, 2000.
Hyperthyroidism
Caruso DR, Mazzaferri EL: Intervention in Graves’ disease, Post-
grad Med 92:117-134, 1992.
Cooper DS: Hyperthyroidism, Lancet 362:459-468, 2003.
McKeown NJ, Tews MC, Gossain VV et al: Hyperthyroidism,
Emerg Med Clin North Am 23:669-685, 2005.
Pearce EN: Diagnosis and management of thyrotoxicosis, Br Med
J 332:1369-1373, 2006.
Pérusse R, Goulet J-P, Turcotte J-Y: Contraindications to vaso-
constrictors in dentistry. Part II: hyperthyroidism, diabetes,
sulﬁte sensitivity, cortico-dependent asthma, and pheochro-
mocytoma, Oral Surg Oral Med Oral Pathol 74:687-691,
1992.
Reid JR, Wheeler SF: Hyperthyroidism: diagnosis and treatment,
Am Fam Physician 72:623-30, 635-636, 2005.
Singer PA, Cooper DS, Levy EG et al: Treatment guidelines for
patients with hyperthyroidism and hypothyroidism, JAMA
273:808-812, 1995.
Tietgens ST, Leinung MC: Thyroid storm, Med Clin North Am
79:169-184, 1995.
Topliss DJ, Eastman CJ: Diagnosis and management of hyper-
thyroidism and hypothyroidism, Med J Aust 180:186-193,
2004.
Yeatts RP: Graves’ ophthalmopathy, Med Clin North Am 79:195-
209, 1995.
Hypoparathyroidism
Ahonen P, Myllärniemi S, Sipilä I et al: Clinical variation
of autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy (APECED) in a series of 68 patients, N Engl J Med
322:1829-1836, 1990.
Angelopoulos NG, Goula A, Tolis G: Sporadic hypoparathy-
roidism treated with teriparatide: a case report and
literature review, Exp Clin Endocrinol Diabetes 115:50-54,
2007.
Greenberg MS, Brightman VJ, Lynch MA et al: Idiopathic hypo-
parathyroidism, chronic candidiasis, and dental hypoplasia,
Oral Surg Oral Med Oral Pathol 28:42-53, 1969.
Perheentupa J: Autoimmune polyendocrinopathy-candidiasis-
ectodermal dystrophy, J Clin Endocrinol Metab 91:2843-2850,
2006.
Walls AWG, Soames JV: Dental manifestations of autoimmune
hypoparathyroidism, Oral Surg Oral Med Oral Pathol 75:452-
454, 1993.
Winer KK, Ko CW, Reynolds JC et al: Long-term treatment of
hypoparathyroidism: a randomized controlled study compar-
ing parathyroid hormone-(1-34) versus calcitriol and calcium,
J Clin Endocrinol Metab 88:4214-4220, 2003.
Yasuda T, Niimi H: Hypoparathyroidism and pseudohypopara-
thyroidism, Acta Paediatr Jpn 39:485-490, 1997.
Pseudohypoparathyroidism
Brown MD, Aaron G: Pseudohypoparathyroidism: case report,
Pediatr Dent 13:106-109, 1991.
Faull CM, Welbury RR, Paul B et al: Pseudohypoparathyroidism:
its phenotypic variability and associated disorders in a large
family, Q J Med 78:251-264, 1991.
Gelfand IM, Eugster EA, DiMeglio LA: Presentation and clin-
ical progression of pseudohypoparathyroidism with multi-
hormone resistance and Albright hereditary osteodystrophy:
a case series, J Pediatr 149:877-880, 2006.
Goeteyn V, De Potter CR, Naeyaert JM: Osteoma cutis in pseu-
dohypoparathyroidism, Dermatology 198:209-211, 1999.
Jüppner H, Linglart A, Fröhlich LF et al: Autosomal-dominant
pseudohypoparathyroidism type Ib is caused by different
microdeletions within or upstream of the GNAS locus, Ann N
Y Acad Sci 1068:250-255, 2006.
Levine MA: Pseudohypoparathyroidism: from bedside to bench
and back, J Bone Miner Res 14:1255-1260, 1999.
Mallette LE: Pseudohypoparathyroidism, Curr Ther Endocrinol
Metab 6:577-581, 1997.
Potts JT: Diseases of the parathyroid gland and other hyper- and
hypocalcemic disorders. In Kasper DL, Braunwald E, Fauci
AS et al: Harrison’s principles of internal medicine, pp 2249-
2268, ed 16, New York, 2005, McGraw-Hill. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

856 ORAL AND MAXILLOFACIAL PATHOLOGY
Simon A, Koppeschaar HP, Roijers JF et al: Pseudohypoparathy-
roidism type Ia, Albright hereditary osteodystrophy: a model
for research on G protein-coupled receptors and genomic
imprinting, Neth J Med 56:100-109, 2000.
Hyperparathyroidism
Aggunlu L, Akpek S, Coskun B: Leontiasis ossea in a patient with
hyperparathyroidism secondary to chronic renal failure,
Pediatr Radiol 34:630-632, 2004.
Antonelli JR, Hottel TL: Oral manifestations of renal osteodystro-
phy: case report and review of the literature, Spec Care Dentist
23:28-34, 2003.
Daniels JSM: Primary hyperparathyroidism presenting as a
palatal brown tumor, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 98:409-413, 2004.
Farford B, Presutti J, Moraghan TJ: Nonsurgical management of
primary hyperparathyroidism, Mayo Clin Proc 82:351-355,
2007.
Gavaldá C, Bagán JV, Scully C et al: Renal hemodialysis patients:
oral, salivary, dental and periodontal ﬁndings in 105 adult
cases, Oral Dis 5:299-302, 1999.
Hata T, Irei I, Tanaka K et al: Macrognathia secondary to dialysis-
related renal osteodystrophy treated successfully by parathy-
roidectomy, Int J Oral Maxillofac Surg 35:378-382, 2006.
Kalyvas D, Tosios KI, Leventis MD et al: Localized jaw enlarge-
ment in renal osteodystrophy: report of a case and review of
the literature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
97:68-74, 2004.
Khan A, Bilezikian J: Primary hyperparathyroidism: pathophysi-
ology and impact on bone, CMAJ 163:173-175, 2000.
Ogata H, Koiwa F, Ito H et al: Therapeutic strategies for second-
ary hyperparathyroidism in dialysis patients, Ther Apher Dial
10:355-363, 2006.
Prado FO, Rosales AC, Rodrigues CI et al: Brown tumor of the
mandible associated with secondary hyperparathyroidism: a
case report and review of the literature, Gen Dent 54:341-
343, 2006.
Sakhaee K, Gonzalez GB: Update on renal osteodystrophy:
pathogenesis and clinical management, Am J Med Sci 317:251-
260, 1999.
Silverman S Jr, Gordon G, Grant T et al: The dental structures in
primary hyperparathyroidism. Studies in forty-two consecu-
tive patients, Oral Surg Oral Med Oral Pathol 15:426-436,
1962.
Silverman S Jr, Ware WH, Gillooly C: Dental aspects of hyper-
parathyroidism, Oral Surg Oral Med Oral Pathol 26:184-189,
1968.
Slatopolsky E, Brown A, Dusso A: Pathogenesis of secondary
hyperparathyroidism, Kidney Int Suppl 73:S14-19, 1999.
Solt DB: The pathogenesis, oral manifestations, and implications
for dentistry of metabolic bone disease, Curr Opin Dent 1:783-
791, 1991.
Tejwani NC, Schachter AK, Immerman I et al: Renal osteodys-
trophy, J Am Acad Orthop Surg 14:303-311, 2006.
Triantaﬁllidou K, Zouloumis L, Karakinaris G et al: Brown tumors
of the jaws associated with primary or secondary hyperpara-
thyroidism. A clinical study and review of the literature, Am
J Otolaryngol 27:281-286, 2006.
Cushing’s Disease
Findling JW, Raff H: Cushing’s syndrome: important issues in
diagnosis and management, J Clin Endocrinol Metab 91:3746-
3753, 2006.
Gabrilove JL: Cushing’s syndrome, Compr Ther 18:13-16, 1992.
Katz J, Bouloux P-MG: Cushing’s: how to make the diagnosis,
Practitioner 243:118-124, 1999.
Newell-Price J, Bertagna X, Grossman AB et al: Cushing’s syn-
drome, Lancet 367:1605-1617, 2006.
Shibli-Rahhal A, Van Beek M, Schlechte JA: Cushing’s syndrome,
Clin Dermatol 24:260-265, 2006.
Tsigos C: Differential diagnosis and management of Cushing’s
syndrome, Annu Rev Med 47:443-461, 1996.
Addison’s Disease
Coursin DB, Wood KE: Corticosteroid supplementation for
adrenal insufﬁciency, JAMA 287:236-240, 2002.
Jabbour SA: Cutaneous manifestations of endocrine disorders: a
guide for dermatologists, Am J Clin Dermatol 4:315-331,
2003.
Marzotti S, Falorni A: Addison’s disease, Autoimmunity 37:333-
336, 2004.
Neiman LK, Chanco-Turner ML: Addison’s disease, Clin Dermatol
24:276-280, 2006.
Porter SR, Haria S, Scully C et al: Chronic candidiasis, enamel
hypoplasia, and pigmentary anomalies, Oral Surg Oral Med
Oral Pathol 74:312-314, 1992.
Shah SS, Oh CH, Cofﬁn SE et al: Addisonian pigmentation of the
oral mucosa, Cutis 76:97-99, 2005.
Werbel SS, Ober KP: Acute adrenal insufﬁciency, Endocrinol
Metab Clin North Am 22:303-328, 1993.
Ziccardi VB, Abubaker AO, Sotereanos GC et al: Precipitation of
an addisonian crisis during dental surgery: recognition and
management, Compend Contin Educ Dent 13:518-523, 1992.
Diabetes Mellitus
Belazi M, Velegraki A, Fleva A et al: Candidal overgrowth in
diabetic patients: potential predisposing factors, Mycoses
48:192-196, 2005.
Bergman SA: Perioperative management of the diabetic patient,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:731-
737, 2007.
Cianciola LJ, Park BH, Bruck E et al: Prevalence of periodontal
disease in insulin-dependent diabetes mellitus (juvenile dia-
betes), J Am Dent Assoc 104:653-660, 1982.
Emancipator K: Laboratory diagnosis and monitoring of diabetes
mellitus, Am J Clin Pathol 112:665-674, 1999.
Franco OH, Steyerberg EW, Hu FB et al: Associations of diabetes
mellitus with total life expectancy and life expectancy with
and without cardiovascular disease, Arch Intern Med 167:
1145-1151, 2007.
Guggenheimer J, Moore PA, Rossie K et al: Insulin-dependent
diabetes mellitus and oral soft tissue pathologies: II. Preva-
lence and characteristics of non-candidal lesions, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 89:563-569, 2000.
Guggenheimer J, Moore PA, Rossie K et al: Insulin-dependent
diabetes mellitus and oral soft tissue pathologies: II. Preva-
lence and characteristics of Candida and candidal lesions,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89:570-576,
2000.
Manfredi M, Al-Karaawi Z, McCullough MJ et al: The isolation,
identiﬁcation and molecular analysis of Candida spp. isolated
from the oral cavities of patients with diabetes mellitus, Oral
Microbiol Immunol 17:181-185, 2002.
Manfredi M, McCollough MJ, Vescovi P et al: Update on diabetes
mellitus and related oral diseases, Oral Dis 10:187-200,
2004.
McKenna SJ: Dental management of patients with diabetes, Dent
Clin North Am 50:591-606, 2006.
Mealey BL, Oates TW: Diabetes mellitus and periodontal dis-
eases, J Periodontol 77:1289-1303, 2006.
Miley DD, Terezhalmy GT: The patient with diabetes mellitus:
etiology, epidemiology, principles of medical management, `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
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Chapter 17 ORAL MANIFESTATIONS OF SYSTEMIC DISEASES 857
oral disease burden, and principles of dental management,
Quintessence Int 36:779-795, 2005.
Moore PA, Weyant RJ, Mongelluzzo MB et al: Type 1 diabetes
mellitus and oral health: assessment of tooth loss and eden-
tulism, J Public Health Dent 58:135-142, 1998.
Murrah VA: Diabetes mellitus and associated oral manifesta-
tions: a review, J Oral Pathol 14:271-281, 1985.
Newton CA, Raskin P: Diabetic ketoacidosis in type 1 and type
2 diabetes mellitus: clinical and biochemical differences,
Arch Intern Med 164:1925-1931, 2004.
Seppälä B, Seppälä M, Ainamo J: A longitudinal study on insulin-
dependent diabetes mellitus and periodontal disease, J Clin
Periodontol 20:161-165, 1993.
Tsai C, Hayes C, Taylor GW: Glycemic control of type 2 diabetes
and severe periodontal disease in the US adult population,
Community Dent Oral Epidemiol 30:182-192, 2002.
Wang PH, Lau J, Chalmers TC: Meta-analysis of effects of inten-
sive blood-glucose control on late complications of type I
diabetes, Lancet 341:1306-1309, 1993.
Winer N, Sowers JR: Epidemiology of diabetes, J Clin Pharmacol
44:397-405, 2004.
Wysocki GP, Daley T: Benign migratory glossitis in patients with
juvenile diabetes, Oral Surg Oral Med Oral Pathol 63:68-70,
1987.
Zachariasen RD: Diabetes mellitus and xerostomia, Compend
Contin Educ Dent 13:314-322, 1992.
Hypophosphatasia
Brun-Heath I, Taillandier A, Serre J-L et al: Characterization of
11 novel mutations in the tissue non-speciﬁc alkaline phos-
phatase gene responsible for hypophosphatasia and geno-
type-phenotype correlations, Mol Genet Metab 84:273-277,
2005.
Caswell AM, Whyte MP, Russell RGG: Hypophosphatasia and
the extracellular metabolism of inorganic pyrophosphate:
clinical and laboratory aspects, Crit Rev Clin Lab Sci 28:175-
232, 1991.
Fallon MD, Teitelbaum SL, Weinstein RS et al: Hypophosphata-
sia: clinicopathologic comparison of the infantile, childhood,
and adult forms, Medicine 63:12-24, 1984.
Hu C-C, King DL, Thomas HF et al: A clinical and research pro-
tocol for characterizing patients with hypophosphatasia,
Pediatr Dent 18:17-23, 1996.
Mornet E: Hypophosphatasia: the mutations in the tissue-non-
speciﬁc alkaline phosphatase gene, Hum Mutat 15:309-315,
2000.
Olsson A, Matsson L, Blomquist HK et al: Hypophosphatasia
affecting the permanent dentition, J Oral Pathol Med 25:343-
347, 1996.
Plagmann H-H, Kocher T, Kuhrau N et al: Periodontal manifes-
tation of hypophosphatasia. A family case report, J Clin Peri-
odontol 21:710-716, 1994.
Spentchian M, Merrien Y, Herasse M et al: Severe hypophospha-
tasia: characterization of ﬁfteen novel mutations in the ALPL
gene, Hum Mutat 22:105-106, 2003.
Van den Bos T, Handoko G, Niehof A et al: Cementum and
dentin in hypophosphatasia, J Dent Res 84:1021-1025,
2005.
Vitamin D–Resistant Rickets
Archard HO, Witkop CJ: Hereditary hypophosphatemia (vitamin
D-resistant rickets) presenting primary dental manifestations,
Oral Surg Oral Med Oral Pathol 22:184-193, 1966.
Batra P, Tejani Z, Mars M: X-linked hypophosphatemia:
dental and histologic ﬁndings, J Can Dent Assoc 72:69-72,
2006.
Berndt M, Ehrich JHH, Lazovic D et al: Clinical course of hypo-
phosphatemic rickets in 23 adults, Clin Nephrol 45:33-41,
1996.
Carpenter TO: New perspectives on the biology and treatment
of X-linked hypophosphatemic rickets, Pediatr Clin North Am
44:443-466, 1997.
Chaussin-Miller C, Sinding C, Wolikow M et al: Dental abnor-
malities in patients with familial hypophosphatemic vitamin
D-resistant rickets: prevention by early treatment with 1-
hydroxyvitamin D, J Pediatr 142:324-331, 2003.
Fadavi S, Rowold E: Familial hypophosphatemic vitamin D-resis-
tant rickets: review of the literature and report of case, ASDC
J Dent Child 57:212-215, 1990.
Hanna JD, Niimi K, Chart JCM: X-linked hypophosphatemia:
genetic and clinical correlates, Am J Dis Child 145:865-870,
1991.
Hillman G, Geurtsen W: Pathohistology of undecalciﬁed primary
teeth in vitamin D-resistant rickets. Review and report of two
cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:218-
224, 1996.
McWhorter AG, Seale NS: Prevalence of dental abscess in a
population of children with vitamin D-resistant rickets,
Pediatr Dent 13:91-96, 1991.
Miller WL, Portale AA: Genetic causes of rickets, Curr Opin
Pediatr 11:333-339, 1999.
Murayama T, Iwatsubo R, Akiyama S et al: Familial hypophos-
phatemic vitamin D-resistant rickets: dental ﬁndings and
histologic study of teeth, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 90:310-316, 2000.
Pereira CM, de Andrade CR, Vargas PA et al: Dental alterations
associated with X-linked hypophosphatemic rickets, J Endod
30:241-245, 2004.
Scriver CR, Tenenhouse HS, Glorieux HI: X-linked hypophos-
phatemia: an appreciation of a classic paper and a survey of
progress since 1958, Medicine (Baltimore) 70:218-228, 1991.
Seow WK, Needleman HL, Holm IA: Effect of familial hypophos-
phatemic rickets on dental development: a controlled, longi-
tudinal study, Pediatr Dent 17:346-350, 1995.
Shroff DV, McWhorter AG, Seale NS: Evaluation of aggressive
pulp therapy in a population of vitamin D-resistant rickets
patients: a follow-up of 4 cases, Pediatr Dent 24:347-349,
2002.
Wang JT, Lin C-J, Burridge SM et al: Genetics of vitamin D 1α-
hydroxylase deﬁciency in 17 families, Am J Hum Genet
63:1694-1702, 1998.
Zambrano M, Nikitakis NG, Sanchez-Quevedo MC et al: Oral
and dental manifestations of vitamin D-dependent rickets
type I: report of a pediatric case, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 95:705-709, 2003.
Crohn’s Disease
Brunner B, Hirschi C, Weimann R et al: Treatment-resistant
lingual Crohn’s disease disappears after inﬂiximab, Scand J
Gastroenterol 40:1255-1259, 2005.
Challacombe SJ: Oro-facial granulomatosis and oral Crohn’s
disease: are they speciﬁc diseases and do they predict sys-
temic Crohn’s disease? Oral Dis 3:127-129, 1997.
Dunlap CL, Friesen CA, Shultz R: Chronic stomatitis: an early
sign of Crohn’s disease, J Am Dent Assoc 128:347-348,
1997.
Dupuy A, Cosnes J, Revuz J et al: Oral Crohn disease: clinical
characteristics and long-term follow-up of 9 cases, Arch Der-
matol 135:439-442, 1999.
Galbraith SS, Drolet BA, Kugathasan S et al: Asymptomatic
inﬂammatory bowel disease presenting with mucocutaneous
ﬁndings, Pediatrics 116:e439-e444, 2005. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

858 ORAL AND MAXILLOFACIAL PATHOLOGY
Girlich C, Bogenrieder T, Palitzsch K-D et al: Orofacial granulo-
matosis as initial manifestation of Crohn’s disease: a report of
two cases, Eur J Gastroenterol Hepatol 14:873-876, 2002.
Friedman S, Blumberg RS: Inﬂammatory bowel disease. In
Kasper DL, Braunwald E, Fauci AS et al: Harrison’s principles
of internal medicine, pp 1776-1789, ed 16, New York, 2005,
McGraw-Hill.
Harty S, Fleming P, Rowland M et al: A prospective study of the
oral manifestations of Crohn’s disease, Clin Gastroenterol
Hepatol 3:886-891, 2005.
Hegarty A, Hodgson T, Porter S: Thalidomide for the treatment
of recalcitrant oral Crohn’s disease and orofacial granuloma-
tosis, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:576-
585, 2003.
Hoffmann JC, Zeitz M: Treatment of Crohn’s disease, Hepatogas-
troenterology 47:90-100, 2000.
Kalmar JR: Crohn’s disease: orofacial considerations and disease
pathogenesis, Periodontol 2000 6:101-115, 1994.
Lisciandrano D, Ranzi T, Carrassi A et al: Prevalence of oral
lesions in inﬂammatory bowel disease, Am J Gastroenterol
91:7-10, 1996.
Mills CC, Amin M, Manisali M: Salivary duct ﬁstula and recur-
rent buccal space infection: a complication of Crohn’s disease,
J Oral Maxillofac Surg 61:1485-1487, 2003.
Ottaviani F, Schindler A, Capaccio P et al: New therapy for oro-
laryngeal manifestations of Crohn’s disease, Ann Otol Rhinol
Laryngol 112:37-39, 2003.
Plauth M, Jenss H, Meyle J: Oral manifestations of Crohn’s
disease: an analysis of 79 cases, J Clin Gastroenterol 13:29-37,
1991.
Podolsky DK: Inﬂammatory bowel disease, N Engl J Med 347:417-
429, 2002.
Rehberger A, Püspök A, Stallmeister T et al: Crohn’s disease
masquerading as aphthous ulcers, Eur J Dermatol 8:274-276,
1998.
Sánchez AR, Rogers RS, Sheridan PJ: Oral ulcerations are associ-
ated with the loss of response to inﬂiximab in Crohn’s disease,
J Oral Pathol Med 34:53-55, 2005.
Scheper HJ, Brand HS: Oral aspects of Crohn’s disease, Int Dent
J 52:163-172, 2002.
Scully C, Cochran KM, Russell RI et al: Crohn’s disease of the
mouth: an indicator of intestinal involvement, Gut 23:198-
201, 1982.
Van de Scheur MR, van der Waal RIF, Völker-Dieben HJ et al:
Orofacial granulomatosis in a patient with Crohn’s disease, J
Am Acad Dermatol 49:952-954, 2003.
Weinstein TA, Sciubba JJ, Levine J: Thalidomide for the treat-
ment of oral aphthous ulcers in Crohn’s disease, J Pediatr
Gastroenterol Nutr 28:214-216, 1999.
Pyostomatitis Vegetans
Ayangco L, Rogers RS, Sheridan PJ: Pyostomatitis vegetans as an
early sign of reactivation of Crohn’s disease: a case report, J
Periodontol 73:1512-1516, 2002.
Ballo FS, Camisa C, Allen CM: Pyostomatitis vegetans: report of
a case and review of the literature, J Am Acad Dermatol
21:381-387, 1989.
Calobrisi SD, Mutasim DF, McDonald JS: Pyostomatitis vegetans
associated with ulcerative colitis. Temporary clearance with
ﬂuocinonide gel and complete remission after colectomy,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:452-454,
1995.
Chan SWY, Scully C, Prime SS et al: Pyostomatitis vegetans: oral
manifestation of ulcerative colitis, Oral Surg Oral Med Oral
Pathol 72:689-692, 1991.
Chaudhry SI, Philpot NS, Odell EW et al: Pyostomatitis vegetans
associated with asymptomatic ulcerative colitis: a case report,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:327-330,
1999.
Ficarra G, Cicchi P, Amorosi A et al: Oral Crohn’s disease and
pyostomatitis vegetans: an unusual association, Oral Surg Oral
Med Oral Pathol 75:220-224, 1993.
Healy CM, Farthing PM, Williams DM et al: Pyostomatitis
vegetans and associated systemic disease. A review and two
case reports, Oral Surg Oral Med Oral Pathol 78:323-328,
1994.
Hegarty AM, Barrett AW, Scully C: Pyostomatitis vegetans, Clin
Exp Dermatol 29:1-7, 2004.
Markiewicz M, Suresh L, Margarone J et al: Pyostomatitis vege-
tans: a clinical marker of silent ulcerative colitis, J Oral Maxil-
lofac Surg 65:346-348, 2007.
Neville BW, Laden SA, Smith SE et al: Pyostomatitis vegetans,
Am J Dermatopathol 7:69-77, 1985.
Philpot HC, Elewski BE, Banwell JG et al: Pyostomatitis vegetans
and primary sclerosing cholangitis: markers of inﬂammatory
bowel disease, Gastroenterology 103:668-674, 1992.
Thornhill MH, Zakrzewska JM, Gilkes JJH: Pyostomatitis vege-
tans: report of three cases and review of the literature, J Oral
Pathol Med 21:128-133, 1992.
Uremic Stomatitis
Halazonetis J, Harley A: Uremic stomatitis: report of a case, Oral
Surg Oral Med Oral Pathol 23:573-577, 1967.
Hovinga J, Roodvoets AP, Gailliard J: Some ﬁndings in patients
with uraemic stomatitis, J Maxillofac Surg 3:124-127, 1975.
Larato DC: Uremic stomatitis: report of a case, J Periodontol
46:731-733, 1975.
Leão JC, Gueiros LAM, Segundo AVL et al: Uremic stomatitis in
chronic renal failure, Clinics 60:259-262, 2005.
McCreary CE, Flint SR, McCartan BE et al: Uremic stomatitis
mimicking oral hairy leukoplakia. Report of a case, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 83:350-353, 1997.
Proctor R, Kumar N, Stein A et al: Oral and dental aspects of
chronic renal failure, J Dent Res 84:199-208, 2005.
Ross WF, Salisbury PL: Uremic stomatitis associated with undi-
agnosed renal failure, Gen Dent 42:410-412, 1994. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

859
18
Facial Pain and
Neuromuscular Diseases
Revised by THERESA S. GONZALES
CHAPTER OUTLINE
Bell’s Palsy
Trigeminal Neuralgia
Glossopharyngeal Neuralgia
Postherpetic Neuralgia
Atypical Facial Pain
Neuralgia-Inducing Cavitational Osteonecrosis
Cluster Headache
Paroxysmal Hemicrania
Migraine
Temporal Arteritis
Bell’s palsy is diagnosed in 24 of every 100,000
persons each year, with increased frequency in the fall
and winter seasons. In demyelinating diseases, such as
multiple sclerosis (MS), it occurs much more frequently
(one in ﬁve cases), usually appearing late in the disease
but occasionally being the ﬁrst symptom. Rarely, other
anatomic sites also will become paralyzed, usually in
persons with Melkersson-Rosenthal syndrome (see
page 342), Lyme disease (Borrelia burgdorferi infection,
Lyme peripheral facial palsy, transient facial nerve
palsy), or sarcoidosis.
CLINICAL FEATURES
People of all ages are susceptible to Bell’s palsy, but
middle-aged people are affected most frequently.
Women are affected more often (71%) than men.
Childhood involvement is usually associated with a
viral infection, Lyme disease, or earache.
BELL’S PALSY (IDIOPATHIC SEVENTH
NERVE PARALYSIS; IDIOPATHIC
FACIAL PARALYSIS)
Bell’s palsy is a dramatic but self-limiting, unilateral
facial paralysis. It represents the most common form of
facial paralysis. A variety of potential triggering events
are known (Box 18-1), although a trigger cannot be
identiﬁed in at least one fourth of all cases. The precise
cause remains unclear; however, familial occurrences
have been reported, and suspected causes include
reactivation of herpes simplex or zoster in the genicu-
late ganglion, nerve demyelination, nerve edema or
ischemia, autoimmune damage to nerves, and vaso-
spasm of vessels associated with nerves.
A similar presentation can be seen with obvious
damage to the facial nerve (e.g., from facial and salivary
gland tumors or from severance of the nerve caused by
trauma or surgery). When the cause is known, the term
Bell’s palsy is not usually used.
Myasthenia Gravis
Motor Neuron Disease
Burning Mouth Syndrome
Dysgeusia and Hypogeusia
Frey Syndrome
Osteoarthritis
Rheumatoid Arthritis
Temporomandibular Joint Dysfunction
Temporomandibular Joint Ankylosis `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

860 ORAL AND MAXILLOFACIAL PATHOLOGY
Considerable variation exists in the severity of signs
and symptoms. The palsy is characterized by an abrupt
loss of muscular control on one side of the face, impart-
ing a rigid masklike appearance and resulting in the
inability to smile, to close the eye, to wink, or to raise
the eyebrow (Fig. 18-1). A few patients, especially those
with MS, experience prodromal pain on the affected
side before the onset of paralysis. Infrequently, bilat-
eral involvement is seen. The paralysis may take several
hours to become complete, but patients frequently
awaken in the morning with a full-ﬂedged case. Rapid
onset of bilateral facial weakness should alert the clini-
cian to the possibility of such diseases as Guillain-
Barre syndrome, a form of sarcoidosis known as
uveoparotid fever (see Heerfordt’s syndrome, page 339),
or other types of vasculitis causing multiple cranial
neuropathies. If multiple cranial nerve deﬁcits accom-
pany the observed facial weakness, then central
nervous system (CNS) infectious diseases and basilar
skull tumors must be considered in the differential
diagnosis. When vertigo or tinnitus is a major symptom,
an occult herpes zoster ear infection should be sus-
pected, and the diagnosis may be changed to Ramsay
Hunt syndrome (see page 252).
The corner of the mouth usually droops, causing
saliva to drool onto the skin. Speech becomes slurred
and taste may be abnormal. Because the eyelid cannot
close, conjunctival dryness or ulceration may occur.
TREATMENT AND PROGNOSIS
No universally preferred treatment exists for Bell’s
palsy. Histamine and other vasodilators may shorten
Box 18-1
Triggering Events or Phenomena
Related to Bell’s Palsy
●Acute otitis media
●Atmospheric pressure change (diving, ﬂying)
●Exposure to cold
●Ischemia of the nerve near the stylomastoid foramen
●Local and systemic infections (viral, bacterial, fungal)
● Melkersson-Rosenthal syndrome
●Multiple sclerosis (MS)
●Pregnancy (third trimester, early eclampsia)
A B
Fig. 18-1 Bell’s palsy. Paralysis of the facial muscles on the patient’s left side. A, Patient is
trying to raise the eyebrows. B, Patient is attempting to close the eyes and smile. (Courtesy of Dr.
Bruce B. Brehm.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 861
the duration, as will systemic corticosteroids and hyper-
baric oxygen therapy. Surgical decompression of the
intratemporal facial nerve is used in select cases.
Topical ocular antibiotics and artiﬁcial tears may be
required to prevent corneal ulceration, and the eyelid
may have to be taped shut.
Symptoms usually begin to regress slowly and spon-
taneously within 1 to 2 months of onset; more severe
cases take longer, as do those in older patients. Overall,
more than 82% of patients recover completely within
6 months. Residual symptoms that remain after 1 year
will probably remain indeﬁnitely. Recurrence is rare,
except in Melkersson-Rosenthal syndrome.
TRIGEMINAL NEURALGIA
(TIC DOULOUREUX; TIC)
The head and neck region is a common site for neural-
gias (pain extending along the course of a nerve) (Box
18-2). Because facial neuralgias produce pain that
often mimics pain of dental origin, the dental profes-
sion is frequently called on to rule out odontogenic or
inﬂammatory causes. Trigeminal neuralgia, the most
serious and the most common of the facial neuralgias,
is characterized by an extremely severe electric shock-
like or lancinating (i.e., sharp, jabbing) pain limited to
one or more branches of the trigeminal nerve. In the
majority of cases the pain is located in the maxillary
(V2) or the mandibular (V3) distribution of the nerve.
It is often idiopathic but is usually associated with
pathosis somewhere along the course of the nerve.
Occasionally, trigeminal neuralgia results from a brain-
stem tumor or infarction and is referred to as secondary
trigeminal neuralgia.
Trigeminal neuralgia is diagnosed in 6 of every
100,000 persons each year, but it develops in 4% of per-
sons with multiple sclerosis (MS). Moreover, patients
with neuralgia-inducing cavitational osteonecrosis
(NICO) of the jaws (see page 866), Gradenigo syn-
drome (suppurative otitis media, trigeminal nerve pain,
abducens nerve palsy), and chronic paroxysmal hemi-
crania-tic syndrome may have pain so similar as to be
virtually indistinguishable from trigeminal neuralgia.
Because so many of its features are consistent with
a CNS disease, trigeminal neuralgia has been called “a
pain syndrome with a peripheral cause but a central
pathogenesis.” The seriousness of the disorder is under-
scored by the fact that it has one of the highest suicide
rates of any disease and is regarded as one of the most
painful afﬂictions known.
CLINICAL FEATURES
Trigeminal neuralgia characteristically affects individ-
uals older than 40 years of age (the average age at onset
is 50 years), although it may affect persons as early as
puberty. Women are affected slightly more often than
men, and the right side is involved more often than the
left. Any branch of the trigeminal nerve may be
involved, but the ophthalmic division is affected in only
5% of cases. More than one branch may be involved,
and the pain is occasionally bilateral.
Speciﬁc and strict criteria must be met for an accu-
rate diagnosis (Box 18-3). If the pain pattern does not
meet these criteria, then a different diagnosis should
be considered. When these criteria are partially ful-
ﬁlled, alternative terms such as atypical trigeminal neu-
ralgia, atypical facial pain, and atypical facial neuralgia are
applied.
Box 18-2
Types of Facial and Cervical Neuralgias
● Atypical pain/neuralgia
● Geniculate neuralgia
● Glossopharyngeal neuralgia
● Migrainous neuralgia
● Occipital neuralgia
●Raeder’s paratrigeminal neuralgia
●Postherpetic facial neuralgia
●Sphenopalatine ganglion neuralgia
●Superior laryngeal neuralgia
● Trigeminal neuralgia
●Tympanic plexus neuralgia
Box 18-3
Necessary Criteria for a Diagnosis of
Trigeminal Neuralgia
●The onset of a pain “attack” is abrupt, often initiated
by a light touch to a speciﬁc and constant trigger
point.
●The pain is extreme, paroxysmal, and lancinating.
●The duration of a single pain “spasm” is less than 2
minutes, although the overall attack may consist of
numerous repeating spasms of short duration.
●For several minutes after an attack (the “refractory
period”), touching the trigger point usually cannot
induce additional attacks.
●The pain must be limited to the known distribution
of one or more branches of the trigeminal nerve with
no motor deﬁcit in the affected area.
●The pain is dramatically diminished, at least initially,
with the use of carbamazepine.
●Spontaneous remissions occur, often lasting more
than 6 months, especially during the early phase of
the disease. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

862 ORAL AND MAXILLOFACIAL PATHOLOGY
In the early stages, the pain of trigeminal neuralgia
may be rather mild and is often described by the
patient as a twinge, dull ache, or burning sensation.
This clinical presentation may be erroneously attrib-
uted to disorders of the teeth, jaws, and paranasal
sinuses and lead to escalation of treatment and a
variety of therapeutic misadventures. Many docu-
mented cases of idiopathic trigeminal neuralgia are
preceded by this dull, continuous, aching type of jaw
pain that may persist for days to years without obvious
dental pathology before the onset of the characteristic
paroxysmal pain in the same region of the face. This
has come to be regarded in the literature as pretrigemi-
nal neuralgia. Pretrigeminal neuralgia has been reported
in approximately 18% of documented trigeminal neu-
ralgia cases. Moreover, pretrigeminal neuralgia has
shown a dramatic response to carbamazepine in con-
trolled clinical drug trials.
There are long, asymptomatic refractory periods
between painful attacks. With time, the attacks occur
at more frequent intervals and the pain becomes
increasingly intense. At this point, patients often state
that the pain is like “a lightning bolt” or a “hot ice pick
jabbed into the face.” A distinguishing feature of tri-
geminal neuralgia is that objective signs of sensory loss
cannot be demonstrated on physical examination. The
presence of objective facial sensory loss, facial weak-
ness, or ataxia should raise the distinct possibility of a
CNS tumor.
Although individual pains or pain spasms last only
a few seconds, several attacks may follow each other
for up to 30 minutes of rapidly repeating volleys.
Patients often clutch at the face and experience spas-
modic contractions of the facial muscles during attacks,
a feature that long ago led to the use of the term tic
douloureux (i.e., painful jerking) for this disease. Similar
to other neuralgic disorders, a refractory period follows
a paroxysm of pain during which time the pain cannot
be elicited. This refractory period can be useful, clini-
cally, in distinguishing neuralgic pain from a stimulus-
provoked odontogenic pain source. The paroxysmal
facial pain is occasionally accompanied by excess lac-
rimation, conjunctival injection, and intense headache.
This presentation may represent the SUNCT (short-
lasting, unilateral, neuralgiform headache with con-
junctival injection and tearing) syndrome rather than
trigeminal neuralgia. Other differential considerations
include but are not limited to glossopharyngeal neural-
gia, Raeder’s syndrome, atypical facial pain, and cluster
headache. Raeder’s syndrome is applied to pain of tri-
geminal distribution usually in the ophthalmic distri-
bution in association with an ocular sympathetic deﬁcit
comprising ptosis, miosis, and an impairment of
sweating limited to the medial aspect of the forehead.
Because this constellation of clinical ﬁndings may have
a variety of causes, the recognition of Raeder’s syn-
drome serves only to draw attention to the region of
the disturbance and does not imply causation.
When an obvious trigger point is present in trigem-
inal neuralgia, a pain attack may be brought on by a
stimulus to the area as mild as a breeze, a gentle move-
ment, or a feather-light touch. Trigger points are found
most frequently on the nasolabial fold, the vermilion
border of the lip, or the midfacial and periorbital skin.
Intraoral trigger points are uncommon but do occur,
especially on the alveolus.
HISTOPATHOLOGIC FEATURES
No unique histopathologic characteristic to the nerves
in trigeminal neuralgia exists, although the trigger
points may show ﬁbrosis and inﬁltration by small
numbers of chronic inﬂammatory cells. Focal areas of
myelin degeneration have been reported within the
gasserian ganglion and along the course of the cranial
nerve itself, but these also have been occasionally seen
in persons without trigeminal neuralgia. MS patients
with trigeminal neuralgia show unique amorphous
plaques in the ganglion.
TREATMENT AND PROGNOSIS
There have been rare reports of spontaneous per-
manent remissions of trigeminal neuralgia. However,
more often than not, this disease is characterized by a
protean and protracted clinical course with regard to
the frequency and severity of exacerbations. The initial
treatment for trigeminal neuralgia is medical. Topical
capsaicin cream (a nociceptive substance-P suppres-
sor) over the affected skin may be effective. Almost all
patients with trigeminal neuralgia respond favorably to
the anticonvulsant, carbamazepine, and an unequivo-
cal response to this medication can be used as a diag-
nostic test for this disease. Anticonvulsant medica-
tions (phenytoin, carbamazepine, gabapentin) often
are effective in pain control, probably because they
decrease conductance in Na+ channels and inhibit
ectopic (i.e., arising from abnormal sites) discharges.
These drugs, unfortunately, often have severe side
effects and may not be tolerated for long by the patient.
Moreover, the pain usually returns on discontinuance
of the medication. If drug treatment fails, then surgical
therapy may be considered.
Various neurosurgical procedures such as microvas-
cular decompression and radiofrequency rhizotomy
also are effective in severe or refractory cases, espe-
cially in younger patients (Box 18-4). Recent reports
have shown some success with gamma knife radio-
surgery of the gasserian ganglion and its associated
nerves. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 863
Neurosurgical methods provide relief for years in
the majority of trigeminal neuralgia patients. Repeated
surgical procedures often are necessary, however, and
techniques that deliberately damage neural tissues
leave the patient with a sensory deﬁcit. After surgery,
up to 8% of patients develop distorted sensations of the
facial skin (facial dysesthesia) or a combination of
anesthesia and spontaneous pain (anesthesia dolo-
rosa). Anesthesia dolorosa is a dreaded form of central
pain that can occur after any neurosurgical procedure
that causes a variable amount of sensory loss, but this
complication occurs more commonly with proce-
dures that totally denervate a region. Overall, long-
term success from surgical procedures is 70% to 85%.
GLOSSOPHARYNGEAL NEURALGIA
(VAGOGLOSSOPHARYNGEAL
NEURALGIA)
Neuralgia of the ninth cranial nerve, glossopharyn-
geal neuralgia, is similar in every way to trigeminal
neuralgia (see previous topic) except in the anatomic
location of the pain. In glossopharyngeal neuralgia, the
pain is centered on the tonsil and the ear. The pain
often radiates from the throat to the ear because of
the involvement of the tympanic branch of the glosso-
pharyngeal nerve. Some unfortunate individuals have
a combination of glossopharyngeal neuralgia and
trigeminal neuralgia.
Glossopharyngeal neuralgia is rare, occurring only
once for every 100 cases of trigeminal neuralgia. The
pain also may affect sensory areas supplied by the pha-
ryngeal and auricular branches of the vagus nerve. As
with trigeminal neuralgia, the cause is unknown.
CLINICAL FEATURES
The age of onset for glossopharyngeal neuralgia varies
from 15 to 85 years, but the average age is 50 years.
There is no sex predilection, and only rarely is there
bilateral involvement. The paroxysmal pain may be felt
in the ear (tympanic plexus neuralgia), infra-auricu-
lar area, tonsil, base of the tongue, posterior man-
dible, or lateral wall of the pharynx; however, the
patient often has difﬁculty localizing the pain in the
oropharynx.
The episodic pain in this unilateral neuralgia is
sharp, lancinating (jabbing), and extremely intense.
Attacks have an abrupt onset and a short duration
(30- to 60-second bursts that may repeat for 5 to 30
minutes). The pain typically radiates upward from the
oropharynx to the ipsilateral ear. Talking, chewing,
swallowing, yawning, or touching a blunt instrument to
the tonsil on the affected side may precipitate the pain,
but a deﬁnite trigger zone is not easily identiﬁed.
Because the pain is related to jaw movement, it may be
difﬁcult to differentiate it from the severe pain of tem-
poromandibular joint dysfunction (TMD).
Patients frequently point to the neck immediately
below the angle of the mandible as the site of greatest
pain, but trigger points are not found on the external
skin, except within the ear canal. Rarely, syncope,
hypotension, seizures, arrhythmia, or cardiac arrest
may accompany the paroxysmal pain, as may coughing
or excessive salivation. As with trigeminal neuralgia,
idiopathic and secondary forms of glossopharyngeal
neuralgia exist. The clinician should be careful to rule
out Eagle syndrome (see page 23) and other conditions
before applying the glossopharyngeal neuralgia diag-
nosis. The literature suggests that approximately 25%
of cases of glossopharyngeal neuralgia are the result
of secondary causes such as neoplasms involving
the skull base or aneurysms in the posterior cranial
fossa.
TREATMENT AND PROGNOSIS
As in trigeminal neuralgia, glossopharyngeal neuralgia
is subject to unpredictable remissions and recurrences.
It is not unusual during the early stages for remissions
to last 6 months or more. Painful episodes are of
varying severity but generally become more severe and
more frequent with time.
Approximately 80% of patients experience immedi-
ate pain relief when a topical anesthetic agent is applied
to the tonsil and pharynx on the side of the pain.
Because this relief lasts only 60 to 90 minutes, it is used
more as a diagnostic tool and emergency measure than
a long-term treatment. Repeated applications to a
trigger point for 2 or 3 days may extend the pain-free
episode enough to allow the patient to obtain much
needed rest and nutrition. Carbamazepine, oxcarbaze-
pine, baclofen, phenytoin, and lamotrigine may relieve
the neuralgic pain for a long period, but no therapy is
considered to be uniformly effective or even adequate.
Box 18-4
Intracranial Neurosurgical Therapies for
Trigeminal Neuralgia
●Injection of caustic material near nerves leaving or
entering the gasserian ganglion (glycerol rhizotomy)
●Removal of skull base bony irregularities impinging
on trigeminal nerve (decompression)
●Repositioning of blood vessels impinging on trigemi-
nal nerve (microvascular decompression)
●Selective destruction of the sensory ﬁbers of the
nerve by crushing or by the application of heat (per-
cutaneous radiofrequency rhizotomy)
●Severing the trigeminal sensory roots (neurectomy) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

864 ORAL AND MAXILLOFACIAL PATHOLOGY
Moreover, glossopharyngeal neuralgia is considerably
less responsive than trigeminal neuralgia to treatment
with anticonvulsant medications. If the patient fails
drug therapy, then surgical options should be consid-
ered. The preferred neurosurgical treatments are
microvascular decompression or surgical sectioning of
the glossopharyngeal nerve and the upper two rootlets
of the vagus nerve.
POSTHERPETIC NEURALGIA
An acute painful disorder (herpes zoster) (see page
250) and a chronic pain syndrome (postherpetic
neuralgia [PHN]) are associated with the varicella-
zoster virus (VZV). Herpes zoster, commonly referred
to as shingles, is characterized by a unilateral vesicular
eruption within a dermatome. More often than not, this
eruption is accompanied by severe pain. Herpes zoster
usually involves the thoracic dermatomes; in 23% of
cases, the rash and its associated pain follow a trigemi-
nal distribution. The ophthalmic division of the tri-
geminal nerve (V1) is affected most frequently. Herpes
zoster is caused by the reactivation of the latent VZV
that is thought to lie dormant in the gasserian, genicu-
late, and dorsal root ganglia after chickenpox infection
in early life. The onset of acute herpes zoster is fre-
quently preceded by exquisite pain in the affected
dermatome. Approximately 48 to 72 hours later, an
erythematous maculopapular rash evolves rapidly
into vesicular lesions (see discussion of herpes zoster,
page 250).
When the trigeminal nerve is involved, the lesions
may appear on the face, the eye, and the tongue.
Herpes zoster ophthalmicus is a debilitating condi-
tion that can result in blindness if aggressive antiviral
therapy is not promptly instituted. The combination of
a herpetic rash in the external auditory canal and a
facial palsy secondary to viral invasion of the geniculate
ganglion of the sensory branch of the facial nerve is
known as Ramsay Hunt syndrome (see page 252).
Often these patients lose their taste discrimination in
the anterior two thirds of the tongue before the devel-
opment of the ipsilateral facial palsy.
CLINICAL FEATURES
The most signiﬁcant complication of herpes zoster is
the pain that is associated with acute neuritis and PHN.
PHN is deﬁned as pain persisting for anywhere from 1
to 6 months or more after the onset of the rash. Posther-
petic pain is described as a burning sensation with
episodic “stabbing” pains. Light touch over the previ-
ously involved area may elicit a painful response (tac-
tile allodynia) from the patient. Changes in sensation
within the affected area may result in hypoesthesia or
hyperesthesia.
The pain of PHN should not be confused with
“shocklike” pain of trigeminal neuralgia that can be
triggered by similar stimuli. The pain is constant and
described as “burning and aching.” The burning char-
acter of the pain is thought to be the result of spontane-
ous activity in nociceptor C ﬁbers. The VZV damages
the peripheral nerve by a combination of demyelin-
ation, wallerian degeneration, ﬁbrosis, and sclerosis.
The pain associated with PHN is thought to arise from
a disturbed pattern of afferent impulses combined with
the loss of some central inhibitory inﬂuence in the pain
modulatory systems. The mechanism of the pain in
PHN is characteristic of deafferentation pain. Patho-
logically, degenerative lesions are observed in the
axons, the dorsal root ganglion, and the dorsal horn of
the spinal cord.
Age appears to be the major risk factor associated
with the development of PHN. Approximately 50% of
patients over the age of 50 with herpes zoster report
some pain in the affected dermatome after the resolu-
tion of the cutaneous presentation, and 75% of patients
older than 70 years of age are afﬂicted. Severe pain in
the acute phase of the disease (acute neuritis) com-
bined with advanced age appears to make the patient
more prone to the development of PHN. Another sus-
ceptible group consists of those patients with diseases
that compromise immunity.
Clinically, scarring and pigmentary changes are
observed within the affected dermatome. The pain is
usually accompanied by a sensory deﬁcit. Researchers
have found lowered sensory thresholds for cold,
warmth, vibration, and two-point discrimination in
patients whose rash was followed by neuralgia pain. In
one recent study, allodynia (i.e., pain in response to a
nonnoxious stimulus) was present in 85% of patients
with PHN.
TREATMENT AND PROGNOSIS
As with most diseases, the best treatment option is
prevention. Many argue that the administration of
antiviral medication (most notably famciclovir) or
corticosteroids, either alone or in combination, early in
the course of herpes zoster possibly could prevent the
development of PHN. Patients with acute herpes zoster
beneﬁt from the administration of oral antivirals.
Accelerated healing of the lesions and an attenuation
of zoster-associated pain have both been reported
in placebo-controlled clinical drug trials. Further
research is necessary to determine the most predict-
able way of preventing PHN. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 865
Once PHN has established itself, a variety of treat-
ment options are available for pain management. In
addition to the judicious use of analgesics, including
both nonnarcotic and narcotic preparations, a wide
variety of drugs ranging from gabapentin, pregabalin,
and amitriptyline hydrochloride to topical agents, such
as lidocaine patches, EMLA (eutectic mixture of lido-
caine and prilocaine), and capsaicin (0.025%), have
been reported to be beneﬁcial in pain relief. The topical
application of capsaicin, an extract of hot chili peppers,
has been reported to deplete the neurotransmitter sub-
stance P from nerve terminals, thereby desensitizing
them.
Tricyclic antidepressants such as amitriptyline, nor-
triptyline, and desiprimine have proven to be quite
useful in the management of the persistent pain that
characterizes PHN; however, the anticholinergic and
cardiovascular side effects may limit their utility, espe-
cially in older patients. Amitriptyline has consis-
tently proven to be the single most effective drug, with
approximately 60% of patients reporting relief with this
agent. Patients are started at a low dose (10 mg) and
titrated to effect, with the majority of patients obtaining
signiﬁcant relief with a median dose of 75 mg daily.
These medications are usually given at bedtime to
prevent daytime somnolence and to improve tolerance.
Patients who report a stabbing pain in addition to the
burning sensation may derive additional beneﬁt from
the use of anticonvulsant medications such as carbam-
azepine or phenytoin. In recent studies, gabapentin and
pregabalin have been shown to reduce pain associated
with PHN by more than 30%, and these drugs are typi-
cally well tolerated in all patient cohorts.
Patients who fail medical therapy have a limited
range of surgical treatments available to them. How-
ever, the outcome of procedures (e.g., blockade of
peripheral nerves, roots, or sympathetic nervous
system; surgery at the level of the affected nerve [neu-
rectomy] or dorsal root) is far from certain with regard
to pain management.
ATYPICAL FACIAL PAIN
(ATYPICAL FACIAL NEURALGIA;
IDIOPATHIC FACIAL PAIN;
ATYPICAL TRIGEMINAL NEURALGIA;
TRIGEMINAL NEUROPATHIC PAIN)
The International Headache Society (IHS) deﬁnes
atypical facial pain as “persistent facial pain that does
not have the characteristics of the cranial neuralgias
classiﬁed above and is not associated with physical
signs or a demonstrable organic cause.” In short, atypi-
cal facial pain is deﬁned less in terms of what it is but
rather in terms of what it is not. In other words, it is
a diagnosis of exclusion, and its use by the clinician
implies that all potential causes of pain have been ruled
out (Box 18-5). Although not the most common facial
pain, this condition is the facial disease that most often
brings a patient to a pain clinic. No acceptable popula-
tion studies are available.
Atypical facial pain is such a difﬁcult diagnostic
and therapeutic condition that patients travel from
one health professional to another and receive many
different diagnoses and treatments in a frustrated
attempt to ﬁnd relief. Patients are often described
as being neurotic (“hysterical”) and suffering from
hypochondriasis, obsessive-compulsive disorder,
anxiety disorder, depression, somatization disorder, or
a “lack of insight.” Whether this is true or not, the
strong emotional overtones of this condition make it
difﬁcult to distinguish functional (psychogenic) from
organic (physiologic) pain.
CLINICAL FEATURES
Atypical facial pain affects women far more frequently
than men. It usually develops during the fourth
through sixth decades of life, but can occur as early as
the teenage years. The pain may be localized to a small
area of the face or alveolus (e.g., atypical odontalgia,
“phantom” toothache) but more frequently affects
most of a quadrant and may extend to the temple,
neck, or occipital area. Patients have great difﬁculty
describing the pain, but most often portray it as a con-
tinuous, deep, diffuse, gnawing ache; an intense
burning sensation; a pressure; or a sharp pain. The
patient may nominally describe the pain using such
terms as “drawing, aching, or pulling.” It is important
Box 18-5
Diseases That Must Be Ruled Out
Before Making a Diagnosis of Atypical
Facial Pain
●Allergy of sinuses
●Cracked tooth syndrome
●Headache with referred pain to face
●Impingement of bone or blood vessel on nerve
●Infection: dental, periodontal, sinuses, ear
●Ischemic and inﬂammatory marrow disease
● Myofascial pain
● Neuralgias, other
●Temporomandibular joint disorder (TMD)
●Trauma to nerve (including traumatic neuroma)
● Tumors `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

866 ORAL AND MAXILLOFACIAL PATHOLOGY
to differentiate the pain from that of trigeminal neu-
ralgia (see page 861).
Bilateral involvement occasionally occurs, and
patients frequently attribute the onset of the pain to
trauma or a dental procedure. The mucosa of the
affected quadrant appears normal but typically con-
tains a zone of increased temperature, tenderness, or
bone marrow activity (“hot spot” on technetium-99m
methylene diphosphonate [MDP] bone scan). Radio-
graphic changes are not present. In some cases initially
diagnosed as atypical facial pain, signiﬁcant underlying
disease has ultimately been identiﬁed (e.g., nasopha-
ryngeal carcinoma, occult lung tumors).
TREATMENT AND PROGNOSIS
Occasional cases of spontaneous remission are noted,
but the great majority of atypical facial pain patients
will obtain little relief without therapy. Symptoms
tend to become more intense gradually, and patients
become irritable, fatigued, and depressed. Most
patients are not beneﬁted substantially from the drugs
used for trigeminal neuralgia, although the new anti-
convulsant, gabapentin, dramatically reduces the pain
in one third of affected patients. Opioid analgesics
(codeine, fentanyl, hydrocodone, morphine, and oxy-
codone) may be of considerable beneﬁt, but their
effectiveness characteristically diminishes over time
and, of course, they are associated with the risk of
abuse and addiction.
The tricyclic antidepressants (amitriptyline, nortrip-
tyline) are popular therapies for neuropathic pain.
They appear to block reuptake of norepinephrine and
serotonin, transmitters released by pain-modulating
systems in the spinal cord and brain stem, thereby
allowing long periods of diminished neural activity.
Other antidepressants (e.g., the selective serotonin
reuptake inhibitors, paroxetine and citalopram) are
generally not as effective as the tricyclic antidepres-
sants for managing atypical facial pain, although some
patients may respond to this therapy. It is important to
remember, however, that antidepressant medications
may be quite hazardous to frail older adults or to
patients with coronary disease. When a localized area
(usually alveolar) of tenderness can be found in the
quadrant of pain, the application of topical capsaicin
or injection with local anesthetics may be temporarily
beneﬁcial. Psychotherapy, behavior modiﬁcation,
transcutaneous electric nerve stimulation, and sympa-
thetic nerve blocks are helpful in a subset of patients
with atypical facial pain.
The frequent failure of medical treatment for atypi-
cal facial pain may lead to surgical intervention, usually
the removal of a portion of the affected trigeminal
nerve branch or the injection of a caustic solution
(phenol, glycerol, alcohol) into the nerve, designed to
destroy a portion of the nerve. These therapies often
provide relief for several weeks or months, but there is
seldom a permanent cure.
NEURALGIA-INDUCING
CAVITATIONAL OSTEONECROSIS
(NICO; ALVEOLAR CAVITATIONAL
OSTEOPATHOSIS; ISCHEMIC
OSTEONECROSIS; BONE
MARROW EDEMA)
One of the most controversial topics in the diagnosis
and management of orofacial pain is the entity referred
to as neuralgia-inducing cavitational osteonecrosis
(NICO). Since this concept ﬁrst appeared in the scien-
tiﬁc literature in the late 1970s, there have been
numerous attempts by science-based investigators to
deﬁne the clinical and radiographic features, as well
as the histopathology and neuropathology of these
lesions. However, to date, there is no consensus
among pain practitioners regarding this entity. The
following information is presented in the context of
completeness with regard to orofacial pain and to
facial neuralgias in particular.
Ischemic osteonecrosis is a bone disease character-
ized by degeneration and death of marrow and bone
from a slow or abrupt decrease in marrow blood ﬂow.
Along with its lesser variants, bone marrow edema and
regional ischemic osteoporosis, it is one of the most
common bone diseases in humans, but only recently
has it been appreciated as a disorder of the head and
neck region. Numerous local and systemic factors are
associated with ischemic damage to marrow (Box
18-6), the most common being a hereditary (autosomal
dominant) tendency toward blood clot formation
within blood vessels. Bone is particularly susceptible to
this problem, which in the jaws may be accentuated by
dental infections and the vasoconstrictors in local
anesthetics.
The ischemia and infarctions of osteonecrosis are
typically associated with pain, often with an ill-deﬁned
neuralgic or neuropathic character. Because of this,
presumed examples of this process in the jaws have
been referred to as NICO. NICO is included in this
chapter because of its strong association with pain, but
it should be remembered that osteonecrosis is not nec-
essarily a painful condition and our understanding of
this disease is still incomplete.
Ischemic osteonecrosis most often affects the hips,
maxillofacial bones, and knees. NICO has been found
in 1 of every 11,000 adults, a prevalence rate similar
to that of hip cases. The NICO prevalence rate for
women (1 per 2000) is much higher than the rate for
men (1 per 20,000). `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 867
CLINICAL AND RADIOGRAPHIC
FEATURES
NICO characteristically affects women 35 to 60 years
of age but has been diagnosed in men and in teenagers.
Third molar regions are affected in half of all cases, but
any alveolar site may become involved, as may the
walls of the sinuses and the mandibular condyle. At
least one third of patients have more than one maxil-
lofacial site of involvement, and 10% have lesions in all
four alveolar quadrants.
Patients often have trouble describing and localiz-
ing their pain, which can be intermittent or constant,
deep or superﬁcial, aching or sharp, mild or extremely
intense. Most often the pain is described as a deep
ache or sharp bone pain. It typically begins as quite
mild and vague, increasing slowly in frequency and
intensity over months and years, but may also have a
sudden onset, especially after a dental procedure using
vasoconstrictors in the anesthetic. The pain may roam
in the general anatomic area or be referred some dis-
tance from the affected bone (neck, shoulder). Many
describe pressure and deep burning sensations, and
local anesthesia typically relieves the pain.
Osteonecrosis is not visualized readily on radio-
graphs, but when visible it usually appears as an area
of regional osteoporosis or ill-deﬁned radiolucency,
often with irregular vertical remnants of lamina dura
representing old extraction sites (Fig. 18-2). Occasional
lesions show an admixture of irregular sclerotic and
radiolucent areas (ischemic osteosclerosis), or there
may be a faint central sclerotic oval surrounded by a
thick radiolucent circle that is, in turn, surrounded
by a thick but faint sclerotic ring (bull’s-eye lesion).
More than 60% of the lesions will exhibit a hot spot of
increased isotope uptake with the technetium-99m
MDP bone scan (Fig. 18-3).
HISTOPATHOLOGIC FEATURES
The microscopic appearance of ischemic osteonecro-
sis depends on the duration and intensity of the
diminished marrow blood ﬂow. The features of bone
Box 18-6
Diseases and Phenomena Associated
with Ischemic Osteonecrosis
COMMONLY ASSOCIATED
●Coagulation disorders (thrombophilia,
hypoﬁbrinolysis)
● Alcohol abuse
● Trauma
● Prednisone, prednisolone
● Estrogen, pregnancy
●Sickle cell disease
● Lupus erythematosus
●Cancer chemotherapy (including prednisone)
LESS COMMONLY ASSOCIATED
● Tobacco use
● Arteriosclerosis
●Deep-sea diving (“bends”)
●Shwartzman reaction (serum sickness)
RARELY ASSOCIATED
● Osteomyelitis
●Starvation (anorexia nervosa)
Fig. 18-2 Neuralgia-inducing cavitational osteonecrosis
(NICO). Periapical radiograph demonstrates an oval
radiolucency in the third molar region and thin lamina dura
remnants (residual socket) more anteriorly.
Fig. 18-3 Neuralgia-inducing cavitational osteonecrosis
(NICO). Technetium-99m bone scan reveals multifocal and
extensive NICO involvement (hot spots) years after extraction
of the entire dentition for “atypical facial pain.” None of the
sites were visualized by radiographs, magnetic resonance
imaging (MRI), computed tomography (CT) scans, or other
forms of radioisotope bone scans. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

868 ORAL AND MAXILLOFACIAL PATHOLOGY
marrow edema include dilated marrow capillaries and
sinusoids, serous ooze (plasmostasis) around blood
vessels and adipocytes, wispy ﬁbrous streaming (isch-
emic myeloﬁbrosis) between fat cells, areas of dense
ﬁbrosis (intramedullary ﬁbrous scar), and a light
sprinkling of chronic inﬂammatory cells in regions of
myeloﬁbrosis (Fig. 18-4). Bony trabeculae usually
remain viable at this stage but are inactive, thin, and
often widely spaced.
Degenerative extracellular cystic spaces (cavita-
tions) are commonly seen and may dominate the
picture, eventually coalescing to form spaces large
enough to extend from cortex to cortex (Fig. 18-5).
Focal areas of marrow hemorrhage (microinfarction)
are frequently present and considered by some to be
pathognomonic for osteonecrosis.
Bubbles of coalesced, liqueﬁed fat (oil cysts) may be
seen. However, because high-speed rotary instruments
can produce similar bubbles as an artifact, it is impor-
tant that only hand-curetted marrow samples be sub-
mitted for histopathologic evaluation.
Bone death, when present, is represented by focal
loss of osteocytes. However, this feature can be evalu-
ated properly only if formic acid or another very weak
acid is used for slow, gentle laboratory decalciﬁcation.
In addition, smudged, globular, often dark masses of
calciﬁc necrotic detritus may be seen. These repre-
sent destroyed trabeculae that have literally dissolved
over time and contributed their calcium to other salts
precipitated within necrotic fat. The heat of high-speed
rotary instrumentation can create similar calciﬁc
debris, but this debris remains at the edges of tissue
fragments.
TREATMENT AND PROGNOSIS
Antibiotics may temporarily diminish the associated
pain of NICO in those cases with a superimposed low-
grade infection (chronic nonsuppurative osteomyeli-
tis), but the pain typically returns when antibiotics
are stopped. Usually the diseased marrow must be
removed surgically by decortication and curettage.
Once removed, the defect frequently heals and the
intense facial pain subsides dramatically or disappears
completely, although pain abatement may take several
months to occur. Unfortunately, one third of patients
thus treated experience no pain relief. In addition, the
disease has a strong tendency to recur or to develop in
additional jawbone sites. A repetition of the surgical
procedure is, therefore, often necessary. Overall, the
cure rate (free of pain for at least 5 years) for curettage
is better than 70%.
CLUSTER HEADACHE (MIGRAINOUS
NEURALGIA; SPHENOPALATINE
NEURALGIA; HISTAMINIC CEPHALGIA;
HORTON’S SYNDROME)
Cluster headache is an exquisitely painful afﬂiction
of the midface and upper face, particularly in and
around the eye. The name is derived from the fact that
the headache attacks occur in temporal groups or
clusters, with extended periods of remission between
attacks. Cluster headache is an uncommon disease of
unknown origin and has been called “the most severe
pain syndrome known to humans.” A vascular (vasodi-
lation) cause has been suggested, possibly related to
abnormal hypothalamic function, head trauma, or
abnormal release of histamine from mast cells. The
majority of patients suffer from sleep apnea and dimin-
ished oxygen saturation, but it is not known whether
Fig. 18-4 Neuralgia-inducing cavitational osteonecrosis
(NICO). Photomicrograph showing ischemic myeloﬁbrosis
with a sprinkling of chronic inﬂammatory cells and serous
ooze.
Fig. 18-5 Neuralgia-inducing cavitational osteonecrosis
(NICO). Gross photo of section of posterior mandible
showing extensive cavitation that has hollowed out most of
the bone. (From Bouquot JE, McMahon RE: Neuropathic pain in
maxillofacial osteonecrosis, J Oral Maxillofacial Surg 58:1003-1020, 2000.) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 869
this is a cause or effect of the disease. Headache can be
initiated by alcohol, cocaine, and nitroglycerin; 80% of
affected persons are cigarette smokers.
This disorder is diagnosed in 10 of every 100,000
persons each year, and there is a predilection for blacks.
There is also a strong familial inﬂuence: when a ﬁrst-
degree relative has the headache, there is a ﬁftyfold
increase in the chance that another family member
also will be affected.
CLINICAL FEATURES
Cluster headache may occur at any age, although it
usually affects persons in the third and fourth decades
of life and is rare before puberty. There is a strong male
predilection (a 6:1 male-to-female ratio). The pain is
almost always unilateral and follows the distribution of
the ophthalmic division of the trigeminal nerve.
It is usually felt deep within or behind the orbit,
radiating to the temporal and upper cheek regions.
However, it may simulate a toothache or neuralgic jaw
pain in the anterior maxillary region. Because of this,
patients may be treated inappropriately for dental pain
with endodontic therapy or tooth extraction, which is
thought to be successful when the pain subsequently
resolves. When each successive cluster returns, the
next tooth is treated, sometimes resulting in multiple,
repeated episodes of unnecessary dental therapy.
The pain is described as paroxysmal (i.e., abrupt
onset) and intense, with a burning or lancinating quality
and without a trigger zone. The attacks may last from
15 minutes to 3 hours and occur up to eight times daily
(or on alternate days). The cluster periods typically last
for weeks, with the intervening periods of remission
usually lasting for months (sometimes years). The pain
often begins at the same time in a given 24-hour period
(alarm clock headache), with most attacks occurring
in the middle of the night.
A chronic form occurs occasionally, with no re-
missions for years at a time, and episodic forms may
convert to the constant, chronic form. In addition,
cluster headache is rarely accompanied by the aura so
common to migraine headache. An important behav-
ioral difference between migraine and cluster head-
ache is that the patient is usually hyperactive during
the latter and retreats to a dark, quiet room during the
former.
In addition to the pain, the patient may experience
autonomic alterations such as nasal stufﬁness, tearing,
facial ﬂush, or congestion of conjunctival blood ves-
sels. The latter sign, especially when associated with
increased intraocular pressure, may indicate chronic
paroxysmal hemicrania (Sjaastad syndrome), a rare
syndrome with short-duration, highly recurring, non-
clustered pain (see following topic).
TREATMENT AND PROGNOSIS
The proper diagnosis is important to avoid sequential,
unnecessary endodontic or extraction procedures.
Systemic prednisone, ergotamine, lithium carbonate,
indomethacin, methysergide maleate, and verapamil
all provide relief in some cases. Sumatriptan (agonistic
to 5-HTID receptors) and other drugs of this class
shorten the symptoms in 74% of cases. However, no
single drug is universally effective. Inhaling oxygen
may abort impending attacks, and various neurosurgi-
cal interventions to the affected nerve have provided
relief in some patients, as has the recently reported use
of gamma knife radiosurgery. Overall, only 50% of
patients with cluster headache beneﬁt signiﬁcantly
and permanently from the available therapeutic
modalities.
It is important to distinguish cluster headache from
chronic paroxysmal hemicrania because the latter
disease responds almost universally to indomethacin.
PAROXYSMAL HEMICRANIA
Paroxysmal hemicrania has a clinical presentation
similar to cluster headache. The headaches are strictly
unilateral, brief, and excruciating and have associated
autonomic features. Paroxysmal hemicrania can be dif-
ferentiated from cluster headache primarily by the
high frequency but shorter duration of the attacks.
Although the differentiation can be subtle, it is worth
pursuing because paroxysmal hemicrania responds
dramatically and predictably to indomethacin. There-
fore, an “indomethacin challenge” can be used to rule
out other trigeminal autonomic cephalgias. A predict-
able response to indomethacin is also observed in
hemicrania continua, a type of chronic daily head-
ache that is unilateral, moderately severe, and associ-
ated with autonomic signs similar to those of cluster
headache.
CLINICAL FEATURES
In contradistinction to cluster headache, paroxysmal
hemicrania is more common in women by a ratio of
2:1. The headache is for the most part strictly unilat-
eral, and the pain is centered on the ocular, maxillary,
temporal, and frontal regions. The symptoms typically
last from 2 to 30 minutes, and the pain is described as
a “boring” sensation that can be excruciating in terms
of severity. The headache has an abrupt onset and an
equally abrupt cessation. Ipsilateral cranial autonomic
features such as lacrimation, conjunctival injection,
and rhinorrhea also invariably occur. The patient may
experience anywhere from 2 to 40 attacks daily,
and the mean attack frequency is 14 per day. The `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

870 ORAL AND MAXILLOFACIAL PATHOLOGY
headaches occur regularly throughout the 24-hour day
and do not demonstrate a preponderance of nocturnal
attacks as is commonly observed in cluster headache.
About half of these patients desire reductions in stimuli
similar to the preference demonstrated by those with
migraines; the remaining 50% prefer hyperactivity
during the attack similar to the response preference of
individuals with cluster headache.
TREATMENT AND PROGNOSIS
Indomethacin is the treatment of choice for paroxys-
mal hemicrania. Effective resolution of the headache is
prompt, typically occurring within 1 to 2 days of initiat-
ing the effective dose. The therapeutic trial of oral indo-
methacin should be initiated at 25 mg three times daily
for 10 days. If the response is suboptimal, then the
dosage should be increased to 50 mg three times daily
for an additional 10 days. If there is a suspicion that
the optimal dose has not been achieved, the dosage can
be increased further to 75 mg three times daily for an
additional 14 days. The typical maintenance dose is
between 25 mg and 100 mg daily, but higher doses can
be tolerated relatively well. A “drug holiday” should be
attempted at least once every 6 months because long-
lasting remissions have been reported in some patients
after cessation of indomethacin. Long-term treatment
with indomethacin may result in the gastrointestinal
side effects common to this class of drugs. These side
effects can be effectively managed with antacids, hista-
mine H
2-receptor antagonists, or proton pump inhibi-
tors. In patients who fail to demonstrate a predictable
response to indomethacin, the diagnosis of paroxysmal
hemicrania should be reconsidered.
MIGRAINE (MIGRAINE SYNDROME;
MIGRAINE HEADACHE)
Migraine is a common, disabling, paroxysmal, unilat-
eral headache that is experienced at least once by more
than 14% of teenagers and young adults (lifetime risk:
21%). More than 400 new cases are diagnosed each
year for every 100,000 persons. At least 14 different
types of migraine exist; they are broadly classiﬁed into
two groups: (1) migraine with aura and (2) migraine
without aura.
The cause of migraine is still unclear, but it appears
to be related to vasoconstriction or vasospasm of por-
tions of the cerebral arteries, possibly in response to a
chronically reduced activity of serotonin (5-hydroxy-
tryptamine, 5-HT
1). The vasoconstriction apparently
leads to cerebral ischemia, which is followed by a com-
pensating vasodilation (mediated by nitric oxide), with
subsequent pain and cerebral edema. Many affected
persons (migraineurs) have a family history of migraine,
sometimes with a clear autosomal dominant inheri-
tance pattern. Migraine headaches are often associated
with endogenous or environmental triggers. Common
triggering events are listed in Table 18-1.
CLINICAL FEATURES
Migraine affects women three times more frequently
than men, and women tend to experience more severe
attacks than men. The disease is most prevalent in the
third through ﬁfth decades of life, but the ﬁrst symp-
toms often begin at puberty or shortly thereafter.
The unilateral headache lasts for 4 to 72 hours and
is usually felt in the temporal, frontal, and orbital
regions, as well as occasionally in the parietal, postau-
ricular, or occipital areas. It begins as a poorly localized
Table 18-1 Common Triggers for Migraine
Headache
Type of Trigger Subtypes
Hormonal Menstruation
Ovulation
Oral contraceptives
Hormonal replacement therapy
Dietary Alcohol
Nitrite-laden meat
Monosodium glutamate
Aspartame
Chocolate
Aged cheese
Missing a meal
Psychologic Stress/poststress
Anxiety/worry
Depression
Physical/environmentalGlare
Flashing lights
Fluorescent lights
Odors
Weather changes
High altitude
Sleep related Lack of sleep
Excessive sleep
Drugs Nitroglycerine
Histamine
Reserpine
Hydralazine
Ranitidine
Estrogen
Miscellaneous Head trauma
Physical exertion
Fatigue
From Campbell JK, Sakai F: Diagnosis and differential diagnosis. In
Olesen J, Tfelt-Hansen P, Welch KMA: The headaches, ed 2, Philadelphia,
2000, Lippincott, Williams & Wilkins. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 871
discomfort in the head that soon becomes a mild ache
and then increases in severity over the next 30 minutes
to 2 hours. At its peak, the pain has a throbbing quality,
is quite severe, and is typically associated with nausea,
vomiting, diarrhea, photophobia, and phonophobia.
Usually, the pain is so severe as to be incapacitating,
and the patient must lie down in a dark, quiet room.
The headache recurs frequently, although the time
between attacks varies widely. Rarely, bilateral exam-
ples occur.
It is important for the dentist to remember that
referred migraine pain may initially mimic a tooth-
ache, especially of the anterior maxilla. Symptoms may
also mimic sinusitis or allergic rhinitis.
Many migraineurs experience an “aura” before the
actual headache pain. The aura may appear as visual
hallucination, “seeing sparks” (scintillation), tempo-
rary and partial blindness, partial or complete loss of
light perception (scotoma), nausea, vertigo, lethargy,
mental confusion, loss of the ability to express thou-
ghts (aphasia), or unilateral facial paresthesia or
weakness.
TREATMENT AND PROGNOSIS
Nonpharmacologic approaches to the management
of migraine involve the recognition and avoidance of
known environmental triggers, as well as volitional
modulation of the stress response (cognitive behav-
ioral therapy). The pharmacologic treatment of
migraine includes a wide variety of medications, and
the two basic forms, with and without aura, respond
in a similar fashion. The drugs that have shown the
greatest efﬁcacy in the treatment of migraine are
members of the following three pharmacologic
classes: (1) antiinﬂammatory agents, (2) 5-HT
1 ago-
nists, and (3) dopamine antagonists. The optimal treat-
ment regimen for a migraine attack depends primarily
on the severity of the attack and must be individual-
ized for each patient. Severe attacks frequently are
diminished by ergotamine tartrate, perhaps combined
with caffeine, aspirin, acetaminophen, phenobarbital,
or belladonna. The drugs known as triptans are selec-
tive 5-HT
1 receptor agonists, and a variety of these
medications are now available for the treatment of
acute migraine attacks. Less severe but more frequent
attacks are best treated prophylactically using other
ergot compounds (e.g., methergine), β-adrenergic
agents (e.g., propranolol, metoprolol), calcium channel
blockers (e.g., nifedipine, diltiazem), or serotonin
receptor agonists (e.g., methysergide, cyproheptadine).
Some patients are aided by simple pressure on the
ipsilateral carotid artery. The headaches tend to
become less severe and less frequent over time, with
or without effective therapy.
TEMPORAL ARTERITIS (GIANT CELL
ARTERITIS; CRANIAL ARTERITIS)
Temporal arteritis is a multifocal vasculitis of cranial
arteries, especially the superﬁcial temporal artery. Its
cause remains unknown, but autoimmunity to the
elastic lamina of the artery has been proposed. The
disease most often affects head and neck vessels, but it
is considered to be a systemic problem. There may be
a genetic predisposition.
The annual incidence rate of temporal arteritis in
the United States is approximately 6 per 100,000 pop-
ulation. Incidence rises with age and has been increas-
ing over time, perhaps because the population is aging.
There is a strong predilection for whites.
CLINICAL FEATURES
Women are affected by temporal arteritis somewhat
more often than men, and patients are usually older
than 50 years of age at the time of diagnosis (average
age, 70 years). The disease is most frequently a unilat-
eral, throbbing headache that is gradually replaced by
an intense, aching, burning temporal and facial pain.
The throbbing frequently coincides with the patient’s
heartbeat (systole), and the pain may be lancinating.
The superﬁcial temporal artery is exquisitely sensitive
to palpation and eventually appears erythematous,
swollen, tortuous, or rarely ulcerated.
Most patients complain of pain during mastication
(jaw claudication) or with the wearing of hats (pressure
over the artery). The pain occasionally mimics tooth-
ache or a neuralgic jaw or tongue pain. Signiﬁcantly,
ocular symptoms, such as loss of vision or retro-orbital
pain, may be the ﬁrst complaint. Prompt recognition of
signs and symptoms of temporal arteritis is important
because it is a preventable cause of blindness. The
blindness is caused by involvement of the posterior
ciliary artery supplying the optic disc, which results in
ischemic papillopathy. The visual loss may be transient
or permanent, unilateral or bilateral.
Fever, malaise, fatigue, nausea, anorexia, vomiting,
sore throat, and earache often occur, perhaps as pro-
dromal symptoms, and the erythrocyte sedimentation
rate is usually elevated. A generalized muscle aching
and stiffness (polymyalgia rheumatica) frequently
follow an acute attack. Because muscle and joint aches
are quite common in older adults, the potential exists
for missed opportunities in the diagnosis and manage-
ment of temporal arteritis.
HISTOPATHOLOGIC FEATURES
Biopsy conﬁrms the diagnosis of temporal arteritis.
Microscopic changes tend to be segmental and can be
missed if the specimen is too small. At least 1 cm of the `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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872 ORAL AND MAXILLOFACIAL PATHOLOGY
affected vessel must, therefore, be examined for proper
evaluation.
The disease is characterized by chronic inﬂamma-
tion of the tunica intima and tunica media of the
involved artery, with narrowing of the lumen from
edema and proliferation of the tunica intima. Necrosis
of the smooth muscle and elastic lamina is frequent. A
variable number of foreign body–type multinucleated
giant cells are mixed with macrophages, plasma cells,
and lymphocytes. Thrombosis or complete occlusion of
the lumen is not unusual.
TREATMENT AND PROGNOSIS
Temporal arteritis responds well to systemic and local
corticosteroids; the symptoms subside within a few
days. However, many cases are chronic and need treat-
ment for years. In addition, permanent loss of vision
occurs in more than 50% of untreated patients (and
even in the occasional patient refractory to treatment).
With some individuals, vascular involvement is so
widespread throughout the body that the disease is
fatal, even with aggressive corticosteroid therapy.
MYASTHENIA GRAVIS
Myasthenia gravis is an autoimmune disease that
affects the acetylcholine receptors (AChR) of muscle
ﬁbers and results in an abnormal and progressive fati-
gability of skeletal muscle. Defective neuromuscular
transmission occurs, probably secondary to the coating
of the AChRs by circulating antibodies to those recep-
tors. Such antibodies are not normally found in humans;
hence, the measurement of serum AChR antibody
levels is an important diagnostic tool for this disease.
The motor end plate itself is normal, and smooth and
cardiac muscles are not affected.
Many patients demonstrate either thymus hyperpla-
sia or an actual neoplasm (thymoma) of the thymus
gland. Conversely, 75% of patients with thymoma have
myasthenia gravis, and 90% have circulating AChR
antibodies. The infant of an affected mother may be
affected for several weeks or months by maternal anti-
bodies that traverse the placenta. Almost half of the
patients with myasthenia gravis have at least one addi-
tional autoimmune disorder, especially of the thyroid
gland. Each year 1 person in every 100,000 is diag-
nosed with myasthenia gravis.
CLINICAL FEATURES
Myasthenia gravis is more common in females (1:2
male-to-female ratio). It can begin at any age, and con-
genital cases have been reported. The disease appears
as a subtle but progressive muscle weakness that is
most frequently noticed ﬁrst in the small muscles of
the head and neck (Box 18-7).
Repeated muscle contractions, in particular, lead to
progressively less power in the contracting muscle;
hence, affected patients usually become weaker as
the day progresses. The muscles of mastication may
become so weak from eating a single meal that the
jaws literally “hang open.” Bite force is especially
weak when circulating AChR antibody titers are high.
Lateral tongue forces exerted during swallowing,
speech, and mastication, are reduced signiﬁcantly in a
number of patients.
DIAGNOSIS
The diagnosis of myasthenia gravis is based on the
clinical symptoms, an elevated serum AChR antibody
level, and improved strength after intravenous (IV)
injection of edrophonium, a cholinesterase inhibitor.
Degenerated muscle ﬁbers are the only characteristic
histopathologic feature, with ﬁbers appearing much
smaller than normal (hypotrophy, atrophy), having
fewer nuclei, and showing a loss of the normal rounded
cross-sectional appearance.
TREATMENT AND PROGNOSIS
The prognosis for myasthenia gravis is usually good.
Spontaneous remission sometimes occurs, and approx-
imately 10% of patients never have more than weak eye
muscles. Unfortunately, more severe cases often pro-
gress, after months or years, to permanent muscular
weakness and wasting of the neck, limbs, and
trunk. Respiratory paralysis is sometimes a fatal
complication.
The defective neuromuscular transmission can be
reversed partially by cholinesterase inhibitors (e.g.,
edrophonium, neostigmine), often in combination with
intermittent corticosteroid therapy. For patients with
Box 18-7
Head and Neck Manifestations of
Myasthenia Gravis
●Inability to focus the eyes (extraocular muscular
paresis)
●Drooping eyelids (ptosis)
●Double vision (diplopia)
● Difﬁculty in chewing
● Difﬁculty in swallowing (dysphagia)
●Slurring of words (dysarthria) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 873
evidence of thymoma or with elevated AChR antibody
titers, thymectomy is recommended. Complete, per-
manent recovery often results from thymectomy and,
to a lesser extent, from medical therapy.
MOTOR NEURON DISEASE
(PROGRESSIVE MUSCULAR ATROPHY;
PROGRESSIVE BULBAR PALSY;
AMYOTROPHIC LATERAL SCLEROSIS)
First described by Charcot in the 1870s, motor neuron
disease is a fatal neurodegenerative disorder that is
characterized by progressive weakness and wasting of
muscles. The basic defect is progressive degeneration
and death of the motor neurons of the cranial nerves,
the anterior horn of the spinal cord, and the pyramidal
tract.
There are three distinct clinical syndromes with
considerable overlapping of signs and symptoms:
1.Progressive muscular atrophy
2.Progressive bulbar palsy
3.Amyotrophic lateral sclerosis (ALS)
Confusion exists over the appropriate terminology,
because some authors have used ALS to include all
three disease syndromes. Including all subtypes, new
cases of motor neuron disease are diagnosed in 15 of
every 100,000 persons each year.
Many cases appear to be genetic defects associated
with mRNA processing. Progressive muscular atrophy
is, for example, the most common autosomal recessive
disorder (mutated SMN gene on chromosome 5q)
lethal to infants; it now can be identiﬁed with a prena-
tal test for the involved gene. Likewise, up to 10% of
cases of ALS are inherited as an autosomal dominant
trait (mutated superoxide dismutase-1 gene on chro-
mosome 21). Proposed causes for the nonhereditary
cases include toxic accumulation of the neurotransmit-
ter glutamate, trauma, and slow viruses, especially the
poliovirus.
CLINICAL FEATURES
Progressive muscular atrophy occurs in childhood.
Most cases occur at birth or within the ﬁrst few months
of life, although adult onset is rarely seen. Males and
females are affected equally. There is progressive limb
weakness and sensory disturbances, which result in
difﬁculty in walking, leg pain, paresthesia, and atrophy
of the feet and hands. Facial muscles are spared.
Progressive bulbar palsy typically affects children
and young adults and has no gender predilection. It
usually begins with a subtle but progressive difﬁculty
in speaking or swallowing (dysphagia). Attempts to
swallow food produce bouts of choking and regurgita-
tion, with liquids frequently thrown into the naso-
pharynx and nasal sinuses because of palatal paralysis.
Chronic hoarseness may develop. Atrophy of the facial
muscles, tongue, and soft palate eventually occurs, as
do weakness and spasticity of the limbs. There are no
altered sensory perceptions.
ALS (commonly called Lou Gehrig disease, named
after the professional baseball player who died of the
disease) affects males more frequently than females
and begins to manifest itself in middle age (the average
age of onset is 59 years). The disease begins with difﬁ-
culty in walking because of bilateral, generalized leg
stiffness. Occasionally, one leg is affected more than the
other, forcing the patient to drag it behind the other.
Swallowing difﬁculty develops early in 29% of cases.
The physical examination in ALS reveals spastic
quadriparesis, often with a remarkable increase in the
tendon reﬂexes of all four limbs and with extensor
plantar responses. Small, synchronous, subcutaneous
muscle contractions (fasciculation) of the shoulders
and thighs are an early symptom, with muscle atrophy
eventually developing at affected sites. Central reﬂexes,
such as those of the abdomen, are not altered until late
in the disease, and there are no changes in sense per-
ception. Dysfunction of the muscles controlled by the
medulla oblongata (bulbar paralysis) appears late in
the disease, predominantly as spasticity and weakness.
Patients become completely disabled, often requiring
respiratory support and gastrostomy.
TREATMENT AND PROGNOSIS
Although each of these conditions may have temporary
remissions, the course of motor neuron disease is
invariably fatal. Progressive muscular atrophy and pro-
gressive bulbar palsy almost always result in death
within 2 years, usually from respiratory distress caused
by weak intercostal muscles.
ALS usually results in death within 5 years of diag-
nosis, most often from respiratory failure or cachexia,
although 20% of patients survive more than 10 years
without ventilator use. The antiglutamate agent, rilu-
zole, has shown some promise in slowing the progres-
sion of ALS and improving the morbidity in patients
with disease of bulbar onset, but in general there is no
cure at this time. Palliative and rehabilitative strategies
are used to ease suffering.
BURNING MOUTH SYNDROME
(STOMATOPYROSIS; STOMATODYNIA;
GLOSSOPYROSIS; GLOSSODYNIA;
BURNING TONGUE SYNDROME)
Burning mouth syndrome is a common dysesthesia
(i.e., distortion of a sense) typically described by the
patient as a burning sensation of the oral mucosa in the `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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874 ORAL AND MAXILLOFACIAL PATHOLOGY
absence of clinically apparent mucosal alterations.
Although the tongue is most commonly affected (glos-
sopyrosis), other mucosal surfaces may be symptom-
atic (stomatopyrosis). In addition to the burning
sensation, some patients also experience mucosal pain
that is often described as “rawness” (stomatodynia,
glossodynia). Idiopathic burning and painful sensa-
tions (the “dynias”) also can affect the urogenital (vul-
vodynia) and intestinal mucosa. The so-called scalded
mouth syndrome is an apparently unrelated immune
response to certain medications, especially angioten-
sin-converting enzyme (ACE) inhibitors.
Various local and systemic factors have been postu-
lated to cause this condition (Box 18-8), but none have
been proven. The fact that most patients are postmeno-
pausal women has led to the common belief that estro-
gen or progesterone deﬁcit is responsible, but a strong
correlation between such deﬁcits and burning tongue
syndrome has not been established. Some evidence
exists for an autoimmune origin. Abnormal levels of
antinuclear antibodies (ANAs) and rheumatoid factor
(RF), for example, are found in the serum of more than
50% of patients, although these may also be found in
older persons without burning mouth syndrome. The
disorder has been reported to be strongly associated
with depression and anxiety states, leading some
authorities to consider it a psychosomatic disease.
Well-controlled comparison studies, however, are
lacking.
Burning tongue syndrome affects 2% to 3% of adults
to some degree (14% of postmenopausal women).
Asians and Native Americans have a considerably
higher risk than whites or blacks, and there is increas-
ing prevalence with advancing age, especially after 55
years of age. This disorder is one of the most common
problems encountered in the clinical practice of oral
and maxillofacial pathology.
CLINICAL FEATURES
Women are four to seven times more likely to have
burning tongue syndrome than men. The syndrome is
rare before the age of 30 years (40 years for men), and
the onset in women usually occurs within 3 to 12 years
after menopause.
This disorder also has a typically abrupt onset,
although it may be quite gradual. The dorsum of the
tongue develops a burning sensation, usually strongest
in the anterior third. Occasionally, patients will describe
an irritated or raw feeling. Mucosal changes are seldom
visible, although some patients will show diminished
numbers and size of ﬁliform papillae, and individuals
who rub the tongue against the teeth often have ery-
thematous and edematous papillae on the tip of the
tongue. If the dorsum is signiﬁcantly erythematous and
smooth, an underlying systemic or local infectious
process, such as anemia or erythematous candidiasis,
should be suspected.
Close questioning often determines that additional
oral sites are affected similarly, especially the anterior
hard palate and the lips. There is seldom a signiﬁcant
decrease in stimulated salivary output in tests, despite
the frequent patient complaint of xerostomia. Salivary
levels of various proteins, immunoglobulins, and phos-
phates may be elevated, and there may be a decreased
salivary pH or buffering capacity.
One frequently described pattern is that of mild
discomfort on awakening, with increasing intensity
throughout the day. Other affected patients describe a
waxing and waning pattern that occurs over several
days or weeks. Usually the condition does not interfere
with sleep. A persistently altered (salty, bitter) or dimin-
ished taste may accompany the burning sensation.
Contact with hot food or liquid often intensiﬁes the
symptoms. A minority describe a constant degree of
discomfort.
As with other chronic discomforts, affected pa-
tients frequently demonstrate psychologic dysfunction,
usually depression, anxiety, or irritability. The dysfunc-
tion often disappears, however, with resolution of the
burning or painful tongue condition, and there is no
correlation between duration and intensity of the
Box 18-8
Local and Systemic Factors Reportedly
Associated with Burning Tongue
Syndrome (Glossopyrosis)
Local Factors Systemic Factors
Xerostomia Vitamin B deﬁciency
Chronic mouth breathing Vitamin B
1 or B
2
Chronic tongue thrust habit deﬁciency
Chronic mechanical trauma Pernicious anemia (B12)
Referred pain from teeth or Pellagra (niacin
tonsils deﬁciency)
Trigeminal neuralgia Folic acid deﬁciency
Atypical facial pain or Diabetes mellitus
neuralgia Chronic gastritis or
Angioedema (angioneuroti regurgitation
edema) Chronic gastric hypoacidity
Oral candidiasis Hypothyroidism
Temporomandibular Mercurialism
dysfunction Estrogen deﬁciency
Oral submucous ﬁbrosis Anxiety, stress, depression
Fusospirochetal infection Parkinson’s disease
Contact stomatitis (allergy) Acquired immunodeﬁciency
Trauma to lingual nerve syndrome (AIDS) `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 875
burning sensation and the amount of psychologic
dysfunction.
TREATMENT AND PROGNOSIS
If an underlying systemic or local cause can be identi-
ﬁed and corrected, the lingual symptoms should disap-
pear. Almost two thirds of patients with idiopathic
disease show at least some improvement of their symp-
toms when they take one of the mood-altering drugs
(e.g., chlordiazepoxide). Additional therapies that have
been used include clonazepam, α-lipoic acid (thioctic
acid, a neuroprotective drug), amitriptyline, transcuta-
neous electrical nerve stimulation, analgesics, antibiot-
ics, antifungals, vitamin B complex, and psychologic
counseling. However, none of these treatments has
been proven to be effective in a double-blind, placebo-
controlled trial.
The long-term prognosis for idiopathic burning
tongue or mouth syndrome is variable. It is reported
that one third to one half of patients experience a spon-
taneous or gradual remission months or years after the
onset of symptoms. However, other patients may con-
tinue to experience symptoms throughout the rest of
their lives. Even though the condition is chronic and
may not always respond to therapy, patients should be
reassured that it is benign and not a symptom of oral
cancer.
DYSGEUSIA AND HYPOGEUSIA
(PHANTOM TASTE;
DISTORTED TASTE)
Dysgeusia is deﬁned as a persistent abnormal taste. It
is much less common than simple deﬁciencies in smell
(hyposmia, anosmia) and taste (hypogeusia, ageusia)
perception, which are found in approximately 2 million
adult Americans. Dysgeusia is less tolerated than
hypogeusia or hyposmia, explaining why it accounts
for more than a third of patients in chemosensory
centers.
Most cases of dysgeusia are produced by or associ-
ated with an underlying systemic disorder or by radia-
tion therapy to the head and neck region (Box 18-9).
Trauma, tumors, or inﬂammation of the peripheral
nerves of the gustatory system usually produce tran-
sient hypogeusia rather than dysgeusia. In con-
trast, relatively common upper respiratory tract
infections produce a temporary and mild dysgeusia in
almost one third of cases, although they seldom produce
hypogeusia. CNS neoplasms predominantly produce
dysgeusia, not hypogeusia or ageusia, and taste halluci-
nations are fairly common during migraine headaches,
Bell’s palsy, or herpes zoster of the geniculate ganglion.
Ischemia and infarction of the brainstem can lead to
ageusia of only half of the tongue (hemiageusia) on the
same side as the brainstem lesion.
The perception of a particular taste depends on its
concentration in a liquid environment; hence, persons
with severe dry mouth may suffer from both hypogeu-
sia and dysgeusia. In addition, more than 200 drugs
are known to produce taste disturbances (Table 18-2).
Even without medication-induced alterations, 40% of
persons with clinical depression complain of dysgeu-
sia. The clinician should be especially diligent in assess-
ing local, intraoral causes of dysgeusia, such as
periodontal or dental abscess, oral candidiasis, and
routine gingivitis or periodontitis. The latter may
Box 18-9
Local and Systemic Factors Associated
with Altered Taste Sensations
(Dysgeusia) or Diminished Taste
Sensations (Hypogeusia)
Local Factors Systemic Factors
Oral candidiasis Vitamin A deﬁciency
Oral trichomoniasis Vitamin B
12 deﬁciency
Desquamative gingivitis Zinc deﬁciency
Oral galvanism Iron deﬁciency
Periodontitis or Nutritional overdose (zinc,
gingivitis vitamin A, pyridoxine)
Chlorhexidine rinse Food sensitivity or allergy
Oral lichen planus Sjögren syndrome
Xerostomia Chorda tympani nerve damage
Anorexia, cachexia, bulimia
Severe vomiting during
pregnancy
Liver dysfunction
Crohn’s disease
Cystic ﬁbrosis
Familial dysautonomia
Addison’s disease
Turner syndrome
Alcoholism
Medications (200 types)
Psychosis or depression
Pesticide ingestion
Lead, copper, or mercury
poisoning
Temporal arteritis
Brainstem ischemia or infarction
Migraine headaches
Temporal lobe central nervous
system (CNS) tumor
Nerve trauma, gustatory nerves
Herpes zoster, geniculate
ganglion
Upper respiratory tract infection
Chronic gastritis or regurgitation
Bell’s palsy
Radiation therapy to head and
neck `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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876 ORAL AND MAXILLOFACIAL PATHOLOGY
produce a salty taste because of the high sodium chlo-
ride content of oozing crevicular ﬂuids.
CLINICAL FEATURES
In contrast to hypogeusia, dysgeusia is discerned
promptly and distressingly by affected individuals. The
clinician must be certain that the patient’s alteration is,
in fact, a taste disorder rather than an olfactory one,
because 75% of “ﬂavor” information (e.g., taste, aroma,
texture, temperature, irritating properties) is derived
from smell. Abnormal taste function should be veriﬁed
through formal taste testing by using standard tastants
that are representative of each of the four primary taste
qualities (i.e., sweet, sour, salty, bitter) in a nonodorous
solution. Additional electrical and chemical analysis of
taste bud function is frequently required. Because this
is outside the scope of most general practices, patients
are typically referred to a taste and smell center.
Affected patients may describe their altered taste as
one of the primary ones, but many describe the new
taste as metallic, foul, or rancid. The latter two are
more likely to be associated with aberrant odor percep-
tion (parosmia) than with dysgeusia. The altered taste
may require a stimulus, such as certain foods or liquids,
in which case the taste is said to be distorted. If no
stimulus is required, then the dysgeusia is classiﬁed as
a phantom taste.
TREATMENT AND PROGNOSIS
If an underlying disease or process is identiﬁed and
treated successfully, the taste function should return to
normal. For idiopathic cases there is no effective phar-
macologic or surgical therapy. Dysgeusia in particular
tends to affect lifestyles and interpersonal relationships
signiﬁcantly, perhaps leading to depression, anxiety, or
nutritional deﬁciencies from altered eating habits. For-
tunately, two thirds of dysgeusia patients experience
spontaneous resolution (average duration, 10 months).
Idiopathic hypogeusia is less of a problem for the
patient, but tends to slowly become worse over time.
Occasionally, even this will undergo spontaneous
resolution.
FREY SYNDROME
(AURICULOTEMPORAL SYNDROME;
GUSTATORY SWEATING
AND FLUSHING)
First described by Baillarger in 1853, Frey syndrome
is characterized by facial ﬂushing and sweating along
the distribution of the auriculotemporal nerve. These
signs occur in response to gustatory stimuli, and the
syndrome results from injury to the nerve.
This nerve, in addition to supplying sensory ﬁbers to
the preauricular and temporal regions, carries para-
sympathetic ﬁbers to the parotid gland and sympa-
thetic vasomotor and sudomotor (sweat stimulating)
ﬁbers to the preauricular skin. After parotid abscess,
trauma, mandibular surgery, or parotidectomy, the
parasympathetic nerve ﬁbers may be severed. In their
attempt to reestablish innervation, these ﬁbers occa-
sionally become misdirected and regenerate along the
sympathetic nerve pathways, establishing communica-
tion with the sympathetic nerve ﬁbers of sweat glands
and blood vessels of the facial skin. The most widely
accepted mechanism of Frey’s syndrome is aberrant
neuronal regeneration. Subsequent to these aberrant
neural connections, when salivation is stimulated, local
Table 18-2 Examples of Pharmaceutical Agents That May Be Associated with Altered Taste
Pharmaceutical Action Examples
Anticoagulant Phenindione
Antihistamine Chlorpheniramine maleate
Antihypertensive or diuretic Captopril, diazoxide, ethacrynic acid
Antimicrobial Amphotericin B, ampicillin, griseofulvin, idoxuridine, lincomycin, metronidazole,
streptomycin, tetracycline, tyrothricin
Antineoplastic or immunosuppressant Doxorubicin, methotrexate, vincristine, azathioprine, carmustine
Antiparkinsonian agent Baclofen, chlormezanone, levodopa
Antipsychotic or anticonvulsant Carbamazepine, lithium, phenytoin
Antirheumatic Allopurinol, colchicine, gold, levamisole, penicillamine, phenylbutazone
Antiseptic Hexetidine, chlorhexidine
Antithyroid agent Carbimazole, methimazole, thiouracil
Hypoglycemic Glipizide, phenformin
Opiate Codeine, morphine
Sympathomimetic Amphetamines, phenmetrazine
Vasodilator Oxyfedrine, bamifylline `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 877
sweat glands are activated inadvertently and the
patient’s cheek becomes ﬂushed and moist.
More than 40% of patients with parotidectomies
develop Frey syndrome as a complication of surgery.
The condition is rare in infancy but has been seen after
forceps delivery. Neonatal cases do not typically occur
until the child begins to eat solid foods, at which time
it is usually interpreted as an allergy. Additionally,
more than one third of diabetics with neuropathy will
experience gustatory sweating, especially those who
also have severe kidney damage. The nerve damage in
this case is presumably from chronic ischemia and
immune attacks.
Related phenomena may accompany an operation
or injury to the submandibular gland (chorda tympani
syndrome) or the facial nerve proximal to the genicu-
late ganglion (gustatory lacrimation syndrome,
“crocodile tears”). The chin and submental skin dem-
onstrate sweating and ﬂushing in the former. Chewing
food in the latter syndrome produces abundant tear
formation.
CLINICAL FEATURES
The presenting signs and symptoms of Frey syndrome
include sweating, ﬂushing, warmth, and occasionally
pain in the preauricular and temporal regions
during chewing. Within 2 months to 2 years (average,
9 months) after the nerve injury, the sweating and
ﬂushing reactions commence and become steadily
more severe for several months, remaining constant
thereafter. When ﬂushing occurs, the local skin tem-
perature may be raised as much as 2° C. This may
occur without sweating, especially in females. Pain,
when present, is usually mild, and hypesthesia (hypo-
esthesia) or hyperesthesia are common features.
To detect sweating, Minor’s starch-iodine test may
be used. A 1% iodine solution is painted on the affected
area of the skin. This solution is allowed to dry, and the
area is then coated with a layer of starch. When the
patient is given something to eat, the moisture of the
sweat that is produced will mix with the iodine on the
skin. This allows the iodine to react with the starch and
produce a blue color (Fig. 18-6). Iodine-sublimated
paper, which changes color when wet, also can be
used, and thermography or surface thermometers will
document the temperature changes of the skin.
TREATMENT AND PROGNOSIS
Most cases are mild enough that treatment is not
required. Moreover, approximately 5% of adult patients
and almost all affected infants experience spontaneous
resolution of the syndrome. About 5% of Frey syndrome
patients with diabetically damaged kidneys will show
considerable improvement or complete resolution of
the facial problem after renal transplant.
Severing the auriculotemporal or glossopharyngeal
nerve on the affected side inhibits or abolishes the
sweating and ﬂushing reaction of auriculotemporal
syndrome, as may atropine injections, botulinum toxin
injections, scopolamine creams, and the systemic use
of oxybutynin chloride, an antimuscarinic agent. The
risk of this syndrome is greatly diminished by position-
ing a temporoparietal fascia ﬂap between the gland
and the overlying skin of the cheek at the time of
parotidectomy.
OSTEOARTHRITIS
(DEGENERATIVE ARTHRITIS;
DEGENERATIVE JOINT DISEASE)
Osteoarthritis is a common degenerative and destruc-
tive alteration of the joints that until recently was con-
sidered to be the inevitable result of simple wear and
tear on aging anatomic structures. It is now known to
have a strong inﬂammatory component as well, espe-
cially in small joints, such as the temporomandibular
joint (TMJ), where there appears to be little association
with the aging process. The disease represents approxi-
mately 10% of patients evaluated for TMJ pain.
Osteoarthritis is thought by some to be unavoidable;
almost everyone older than 50 years of age is affected
to some extent. The TMJ is less affected than the heavy
weight–bearing joints, but even that joint is involved at
the microscopic level in 40% of older adults and at the
radiographic level in 14%. Although osteoarthritis is
deﬁnitely an aging phenomenon, recent research also
has identiﬁed osteoarthritis in a majority of young
persons referred to a TMJ clinic for joint pain and
dysfunction.
Fig. 18-6 Frey syndrome. This patient received an injury
to her auriculotemporal nerve during orthognathic surgery 3
years earlier. Notice the region of sweating detected during
mastication by a color change of the starch in the Minor’s
starch-iodine test. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

878 ORAL AND MAXILLOFACIAL PATHOLOGY
Presumably, with advancing age, there is slower and
less complete replacement of chondroblasts and chon-
drocytes in joint cartilage. The cartilage matrix (ﬁbro-
cartilage in the case of the TMJ) turns over less rapidly,
forcing available ﬁbers to work longer and become sus-
ceptible to fatigue. The matrix also holds less water,
becoming desiccated and brittle, in part because under-
lying marrow blood ﬂow diminishes, providing poor
nutrition. With continued joint use, the surface ﬁbers
break down and portions of the hyaline or ﬁbrocartilage
are destroyed, often breaking away to expose underly-
ing bone. The exposed bone then undergoes a dual
process of degenerative destruction and proliferation.
CLINICAL AND RADIOGRAPHIC
FEATURES
Osteoarthritis usually involves multiple joints, typically
the large weight-bearing joints. The disease is charac-
terized by a gradually intensifying deep ache and pain,
usually worse in the evening than in the morning.
Some degree of morning joint stiffness and stiffness
after inactivity is present in 80% of cases. The affected
joint may become swollen and warm to the touch,
rarely with erythema of the overlying skin. Degenera-
tive changes occur in areas of greatest impact, and the
joint may become so deformed that it limits motion.
Crepitation (i.e., crackling noise during motion) is a
late sign of the disease and is, therefore, associated with
more pronounced damage.
These changes are seen also when the TMJ is
affected, except that patients seldom experience stiff-
ness of the TMJ. In addition, the muscles of mastication
frequently exhibit tenderness because of the constant
strain of “muscle guarding” (i.e., attempting to keep the
painful joint immobile).
On radiography, joints affected by osteoarthritis
demonstrate a narrowing or obliteration of the joint
space, surface irregularities and protuberances (exos-
toses, osteophytes), ﬂattening of the articular surface,
osteosclerosis and osteolysis of bone beneath the carti-
lage, radiolucent subchondral cysts, and ossiﬁcation
within the synovial membrane (ossicles). More sensi-
tive diagnostic techniques, such as computed tomogra-
phy (CT) scanning arthrography, magnetic resonance
imaging (MRI), and arthroscopy, reveal the same fea-
tures but in much more detail; hence, they are able to
identify earlier changes. With arthroscopy, 90% of the
joints will show evidence of synovitis, usually before
cartilage surface changes are visible.
HISTOPATHOLOGIC FEATURES
The articulating surface of a joint affected by osteoar-
thritis has a diminished number of chondrocytes, is
roughened, and contains variable numbers of vertical
clefts; in older cases the clefts extend to the underlying
bone. The surface is proliferative in some areas and
degenerative in others. The bone beneath the cartilage
shows a loss of osteocytes, minimal osteoblastic or
osteoclastic activity, fatty degeneration or necrosis of
the marrow, marrow ﬁbrosis, inﬁltration by chronic
inﬂammatory cells, and perhaps the formation of a
large degenerative space beneath the articular carti-
lage (subchondral cyst). Inﬂammation and thickening
of the synovial membrane is seen, sometimes with the
formation of metaplastic bone (ossicles) or hyaline car-
tilage granules (chondral bodies), which may number
in the hundreds within a single joint. The synovial joint
ﬂuid typically contains inﬂammatory and degra-
dation molecules, the levels of which have prognostic
signiﬁcance.
The TMJ is unique because of its ﬁbrocartilage cov-
ering and its meniscus. The disk may be centrally
destroyed, and there is little vertical clefting of the
articular surface. All other features of TMJ osteoarthri-
tis, however, are similar to those noted in other joints.
TREATMENT AND PROGNOSIS
The treatment of osteoarthritis is usually palliative and
consists of analgesics and nonsteroidal antiinﬂamma-
tory drugs (NSAIDs) for the symptoms. Arthroplasty
and joint replacement often are required for heavy
weight–bearing joints and are used occasionally in the
TMJ. Occlusal adjustment and occlusal splints may
reduce symptoms by relieving the pressure on the joint
surfaces, and orofacial physiotherapy and hot or
cold packs may be helpful to relax involved muscles.
Arthroscopic lavage provides short-term pain relief in
many cases, and low-dose doxycycline (collagenase
inhibitor, antimatrix metalloproteinase) recently has
been shown to reduce symptoms. Glucosamine and
chondroitin sulfate, common therapies for large joint
arthritis, have shown some success in TMJ osteoar-
thritis patients.
Aggressive therapy might not be indicated for this
disease except in its most severe form. A recent 30-year
follow-up investigation found radiographic evidence of
continued joint destruction, but the clinical signs and
symptoms were no more severe than they had been
initially.
RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a chronic, presumably auto-
immune disorder characterized by nonsuppurative
inﬂammatory destruction of the joints. It may result
from a cross-reaction of antibodies generated against
hemolytic streptococci or other microorganisms, or it
may represent an antibody attack against bacterial cell `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 879
walls or viral capsule fragments deposited within the
synovium. The cause is still unknown, although some
examples show a familial pattern.
This disease affects 3% of people in the United States
to at least some degree, and approximately 200,000
new cases are diagnosed yearly. The TMJ eventually
becomes involved in 75% of patients, although the
involvement is usually so mild as to be clinically
insigniﬁcant.
In contrast to osteoarthritis (see previous topic),
rheumatoid arthritis begins as an attack against the
synovial membrane (synovitis). A reactive macro-
phage-laden ﬁbroblastic proliferation (pannus) from
the synovium creeps onto the joint surface. This re-
leases collagenases and other proteases, which destroy
the cartilage and underlying bone. Attempted remod-
eling by the damaged bone results in a characteristic
deformation of the joint.
CLINICAL AND RADIOGRAPHIC
FEATURES
Rheumatoid arthritis affects women three times more
frequently than men, although the condition in men is
usually diagnosed at a somewhat younger age (25 to 35
years) than in women (35 to 45 years). The onset and
course of the disease are extremely variable. For many
patients, only one or two joints become involved and
signiﬁcant pain or limitation of motion never develops.
In others, the disease rapidly progresses to debilitating
polyarthralgia.
Typically, the signs and symptoms become more
severe over time and include swelling, stiffness, pain,
joint deformity, and disability, with possible ﬁbrous or
bony fusion of opposing articular surfaces (ankylosis).
Periods of remission often are interspersed with
periods of exacerbation. Symmetrical involvement of
the small joints of the hands and feet almost always is
present, but it is not unusual for knees and elbows to
be affected. The hip joint, the joint most often affected
by osteoarthritis, is the joint least affected by rheuma-
toid arthritis. Twenty percent of patients have ﬁrm,
partially movable, nontender rheumatoid nodules
beneath the skin near the affected joint. These are
pathognomonic for the disease.
Joints involved with rheumatoid arthritis have a
characteristic “anvil” shape, with an irregular ﬂatten-
ing of the central articular surface and a splaying of the
lateral bone. Unlike the situation in osteoarthritis, nar-
rowing of the joint space is seldom seen, except when
ankylosis has occurred.
The TMJ is affected to some degree in more than
40% of persons with rheumatoid arthritis. When
present, TMJ involvement is usually bilateral and
occurs late in the disease. The signs and symptoms are
seldom as severe as in other joints and include stiffness,
crepitation, pain or ache, tenderness, or limitation
of mouth opening. Swelling is less obvious than with
other joints.
Frequently, the pain of TMJ rheumatoid arthritis is
not related to motion but rather to pressure on the
joint. Clenching the teeth on one side produces pain of
the contralateral joint. Similarly, subluxation or anky-
losis is less frequent in the TMJs than in other joints,
but gross destruction of the condylar heads may be so
severe that mandibular micrognathia causes a reced-
ing chin and malocclusion. Permanent TMJ sublux-
ation has been reported.
Radiographically, involved TMJs demonstrate a ﬂat-
tened condylar head with irregular surface features, an
irregular temporal fossa surface, perhaps with remod-
eling of the fossa itself, and anterior displacement of
the condyle. Several diagnostic techniques are avail-
able besides routine TMJ radiographs. CT scans, scan-
ning arthrography, and arthroscopy are excellent tools
for assessing TMJ damage. Thermography is used com-
monly in Europe to detect early disease. Ultrasonogra-
phy is valuable for larger joints but has been used little
in TMJ disease. Nuclear medicine scans that use scin-
tigraphy have, in recent years, been largely replaced by
MRI scans. The latter are sensitive and have become
the diagnostic tool of choice.
LABORATORY VALUES
Approximately 80% of patients with rheumatoid arthri-
tis exhibit signiﬁcant elevations of rheumatoid factor
(RF), an autoantibody thought to be directed toward an
altered host IgG antibody that is no longer recognized
by the body as “self.” In addition, antinuclear antibod-
ies (ANAs) can be detected in about 50% of the patients
with rheumatoid arthritis, although it is not diagnosti-
cally speciﬁc because it also may be associated with
other autoimmune diseases. During active phases of
the disease, almost all patients have an elevated eryth-
rocyte sedimentation rate. In addition, some affected
patients have mild anemia.
HISTOPATHOLOGIC FEATURES
Needle biopsy is the most popular technique for obtain-
ing diagnostic synovial material, but aspiration and
analysis of synovial ﬂuid from the affected joint fre-
quently are undertaken to rule out other forms of
arthritis. These techniques are seldom used for TMJ
involvement.
Microscopically, early cases of rheumatoid arthritis
demonstrate hyperplasia of the synovial lining cells
with deeper portions of the membrane showing
hyperemia, edema, and inﬁltration by lymphocytes, `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

880 ORAL AND MAXILLOFACIAL PATHOLOGY
macrophages, and occasional neutrophils. Neutrophils
are the predominant inﬂammatory cell in the synovial
ﬂuid. Older lesions show continued, often pronounced
synovial proliferation and edema, with cholesterol
crystals and fewer inﬂammatory cells. Typically, the
membrane protrudes into the joint space as villi or
ﬁngerlike projections. These projections occasion-
ally undergo necrosis, producing rice bodies—small
whitish villi fragments composed of cellular debris
admixed with ﬁbrin and collagen. When the TMJ is
severely involved, the meniscus is typically perforated
or replaced completely by ﬁbrous scar.
The rheumatoid nodule is represented by a moder-
ately well-demarcated area of amorphous, eosinophilic
necrosis surrounded by a thick layer of mononuclear
cells. The mononuclear cells closest to the amorphous
center are typically large and palisaded. Neutrophils
are frequently seen in the center.
TREATMENT AND PROGNOSIS
No cure exists for rheumatoid arthritis, and current
treatments strive only to suppress the process as much
as possible. The various therapies that are used are
largely empirical and aimed at nonspeciﬁc suppression
of the inﬂammatory or immunologic process in an
effort to attenuate not only the symptoms but also the
progressive damage to articular structures. Drug
therapy in early and mild cases consists of nonsteroidal
antiinﬂammatory drugs (NSAIDs), perhaps aided by
occasional corticosteroid injections into the joint. The
latter injections are used sparingly, however, because
frequent use is associated with additional degenerative
changes and ﬁbrous ankylosis.
Second-line medications often are required, and the
wide variability in responses to these drugs typically
results in an extended course of constantly changing
doses and agents in an effort to achieve optimal relief.
Systemic glucocorticoid therapy has been shown to be
effective in providing symptomatic relief for patients
with rheumatoid arthritis. A number of agents appear
to have the capacity to modify the course of rheuma-
toid arthritis, and these medications are referred to as
disease-modifying antirheumatic drugs. Agents such as
gold injections, D-penicillamine, sulfasalazine, the anti-
malarials, and methotrexate are included in this group.
Patients report clinical improvement with the use of
these medications; they also demonstrate an improve-
ment in serologic evidence of disease activity with
reductions in C-reactive protein, erythrocyte sedimen-
tation rate, and RF. Emerging evidence indicates that
the early and aggressive use of disease-modifying anti-
rheumatic drugs may actually retard the development
of bone erosions and potentially facilitate healing of
existing lesions. However, toxicity is a problem with all
of these agents, and at present, no one drug has dem-
onstrated a consistent advantage over the others. Meth-
otrexate, a folic acid antagonist, is the most frequently
used ﬁrst-line agent in the disease-modifying group.
The literature suggests that patients who fail or who
have shown a suboptimal response to disease-modulat-
ing therapy might beneﬁt from tumor necrosis factor-α
(TNF-α) neutralizing agents (e.g., etanercept and inﬂix-
imab), used alone or in combination with standard
disease-modulation algorithms.
Immunosuppressive drugs such as azathioprine,
cyclosporine, and cyclophosphamide appear to be
no more effective in the management of rheumatoid
arthritis than the previously mentioned disease-modu-
lating antirheumatic drugs, and the side effect proﬁle
of immunosuppressive therapy includes increased risk
for serious infections and potential predisposition to
the development of malignant neoplasms. Therefore,
immunosuppressive therapy should be reserved for
those patients who have failed all other efforts at disease
modulation.
Severely damaged joints may require surgical
replacement, with the goals of therapy being attenua-
tion of pain and reduction of disability. Total joint
replacement of the hips, knees, and shoulders are
reported to have the highest satisfaction rates associ-
ated with surgical management of these patients.
TEMPOROMANDIBULAR
JOINT DYSFUNCTION
Pain and dysfunction of the TMJ are common and have
been proposed to result from a wide variety of etiologic
factors, both traumatic and nontraumatic (Box 18-10).
The syndrome of signs and symptoms (pain, altered
function, joint noises) is termed temporomandibular
joint dysfunction (TMD). TMD is a problem of the
entire masticatory system: teeth, jaws, joints, and
muscles. All facets must be evaluated to arrive at the
most speciﬁc diagnosis and management protocol.
Because of the extreme complexity of this disease, the
present discussion is limited to a brief overview of those
facets of the disorder that are appropriate to the produc-
tion of pain.
Almost 15% of U.S. adults experience facial and
cervical pain, facial tenderness, and headache from
TMD, but fewer than 1% of those have symptoms
severe enough to warrant professional evaluation or
intervention.
CLINICAL AND RADIOGRAPHIC
FEATURES
TMD is seen primarily in middle-aged women, but it
may affect any age and either sex. Most patients have
some degree of pain, which is the primary reason for `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter 18 FACIAL PAIN AND NEUROMUSCULAR DISEASES 881
seeking professional help. The pain is usually localized
to the preauricular area but may radiate to the
temporal, frontal, or occipital areas. The pain may be a
headache, a ringing in the ears (tinnitus), an earache
(otalgia), or a toothache.
Nonarthritic inﬂammatory disorders of the TMJ are
characterized by continuous deep pain or ache. The
pain is evoked by palpation of the affected joint or by
mandibular movement, especially chewing and clench-
ing. Both TMJs may be involved, at the same time or at
differing times.
The pain may be associated more with the surround-
ing musculature and soft tissue than with the TMJ itself.
Muscle splinting can lead to involuntary CNS-induced
muscular contractions (myospasm), or the muscle
ﬁbers themselves may become inﬂamed (myositis).
Myofascial trigger point pain is common in TMD,
but it is seldom noted in other TMJ disorders. It is
characterized by circumscribed regions within the
muscle (“trigger points”) that elicit local or referred
pain on palpation and may be a source of constant deep
pain. In many instances, patients are aware only of the
referred pain and not the trigger points themselves.
The exact nature of the trigger points is not known, but
they seem similar to small areas of myospasm and can,
through their chronic nature, induce CNS excitatory
effects.
Derangements of the condyle and meniscus complex
are more often associated with dysfunction than with
joint pain (arthralgia). When present, the pain
associated with a deranged joint may be localized, non-
speciﬁc, or referred. It is not a reliable ﬁnding for diag-
nostic purposes. For TMD associated with internal
joint damage or derangement, CT and MRI provide
excellent diagnostic images of the TMJ. Transcranial
and cephalometric radiographic images are much less
detailed, but they are usually adequate and are used
more commonly. The bone itself frequently appears
normal, but a widened joint space, anteriorly displaced
meniscus, or altered meniscus shape are common
ﬁndings. Irregular joint surfaces with protuberances
(osteophytes) are more likely to relate to arthritis
than TMD (see previous two topics). Joint effu-
sions seen with MRI are useful markers of arthritic
degeneration.
TREATMENT AND PROGNOSIS
Therapies for TMD are numerous and should be rec-
ommended based on the exact pathogenesis of the
pain. Conservative treatments include simple rest or
immobilization of the joint, application of cold (usually
reserved for acute injuries) or heat, occlusal splints and
adjustment, and physical therapy. Various medications
also have been used for TMD with some success
(Box 18-11), although few TMD treatments have been
examined in a blinded, controlled fashion. Long-term
follow-up of large numbers of patients treated conser-
vatively indicates that 75% to 88% experience signiﬁ-
cant or complete reduction of symptoms.
Surgical intervention may be required for severely
affected joints, especially those with internal meniscal
derangements, condylar dislocation or fracture, anky-
losis, and degenerative or developmental deformities.
Usually, TMD is treated conservatively for several years
without improvement before surgery is attempted. For
joints with pain from anterior disk displacement
(with or without reduction), however, diskectomy is
Box 18-11
Medications Used to Treat the
Symptoms of Temporomandibular
Joint Dysfunction
● Aspirin
●Acetaminophen (with or without codeine)
●Other nonsteroidal antiinﬂammatory drugs (NSAIDs)
●Centrally acting muscle relaxants (methocarbamol,
chlorzoxazone)
●Benzodiazepine derivatives (diazepam,
chlordiazepoxide)
●Glucocorticoids (cortisone, prednisone)
Box 18-10
Classiﬁcation of Temporomandibular
Disorders
MUSCULAR DISORDERS
●Hyperactivity, spasm, and trismus
● Inﬂammation (myositis)
● Trauma
●Myofascial pain and ﬁbromyalgia
●Atrophy or hypertrophy
ARTHROGENIC DISORDERS
●Disc displacement (internal derangement)
●Hypomobility of the disc (adhesions or scars)
●Dislocation and subluxation
● Arthritis
● Infections
●Metabolic disease (gout, chondrocalcinosis)
● Capsulitis, synovitis
● Ankylosis (ﬁbrous, bony)
● Fracture
●Condylar hyperplasia, hypoplasia, aplasia
● Neoplasia `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
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882 ORAL AND MAXILLOFACIAL PATHOLOGY
recommended within 6 months of TMD diagnosis; for
those with ankylosis, surgery should occur even sooner.
The indications for surgery are strict. Of all patients
sent to a specialist for TMD surgery, fewer than 1%
actually have the surgery.
TEMPOROMANDIBULAR JOINT
ANKYLOSIS
Ankylosis refers literally to a “fusion” of body parts, in
this case the opposing components of a joint. The fusion
can be ﬁbrous or bony in nature—usually ﬁbrous when
the TMJ is involved. Joint infection, usually after trauma,
accounts for 50% of all TMJ ankylosis cases, but 30%
result from aseptic trauma. The remaining cases are
idiopathic or produced by rheumatoid arthritis.
The ankylosis may be intra-articular or extra-articu-
lar. Intra-articular ankylosis is characterized by the
destruction of the meniscus and the temporal fossa,
thickening and ﬂattening of the condylar head, and a
narrowing of the joint space. Opposing joint surfaces
then develop ﬁbrous adhesions that inhibit normal
movements and may become ossiﬁed. Fibrotic intra-
articular ankylosis is the most common type seen in
the TMJ, especially after trauma-induced hemorrhage
(hemarthrosis). Osseous ankylosis is more likely with
nonhemorrhagic infections of the joint.
Extra-articular involvement is less frequently seen
and produces an external ﬁbrous or osseous encapsula-
tion with minimal destruction of the joint itself.
CLINICAL FEATURES
TMJ ankylosis occurs predominantly in the ﬁrst decade
of life, and males and females are equally affected.
Almost all cases are unilateral. The condition results in
a gradually worsening inability to open the jaws, with
the mandible shifting toward the affected side on
opening. Pain, tenderness, and malocclusion may be
present, but this is not usually the case.
In severe examples, there is almost complete immo-
bilization of the mandible, and the mandible may pro-
trude forward as the excess tissues occupy the joint
space. In very young children, unilateral micrognathia
(hemifacial microsomia) may result from diminished
growth on the affected side. Malocclusion may be
severe in such cases.
HISTOPATHOLOGIC FEATURES
TMJ ankylosis is characterized by an excessive amount
of dense, rather avascular ﬁbrous connective tissue or
new bone formation. Intra-articular ankylosis demon-
strates irregular destruction of cartilage and bone with
a sparse lymphocytic inﬁltration.
TREATMENT AND PROGNOSIS
Surgical osteoplasty of the joint with removal of exces-
sive ﬁbrous or calciﬁc tissues is the treatment of choice
for TMJ ankylosis. For severe cases, complete joint
replacement may be necessary.
BIBLIOGRAPHY
Bell’s Palsy
Cook SP, Macartney KK, Rose CD et al: Lyme disease and
seventh nerve paralysis in children, Am J Otolaryngol 18:320-
323, 1997.
Danielidis V, Skevas A, Van Cauwenberge P et al: A comparative
study of age and degree of facial nerve recovery in patients
with Bell’s palsy, Eur Arch Otorhinolaryngol 256:520-522,
1999.
Friedman RA: The surgical management of Bell’s palsy: a review,
Am J Otol 21:139-144, 2000.
Furuta Y, Aizawa H, Ohtani F et al: Varicella-zoster virus DNA
level and facial paralysis in Ramsay Hunt syndrome, Ann Otol
Rhinol Laryngol 113(9):700-705, 2004
Jackson CG, von Doersten PG: The facial nerve: current trends
in diagnosis, treatment, and rehabilitation, Med Clin North Am
83:179-195, 1999.
Morgan M, Moffat M, Ritchie L et al: Is Bell’s palsy a reactivation
of varicella zoster virus? J Infect 30(1): 29-36, 1995.
Peitersen E: Bell’s palsy: the spontaneous course of 2,500 periph-
eral facial nerve palsies of different etiologies, Acta Otolaryn-
gol Suppl 549:4-30, 2002.
Ramsey MJ, Der Simonian R, Holtel MR et al: Corticosteroid
treatment for idiopathic facial nerve paralysis: a meta-analy-
sis, Laryngoscope 110:335-341, 2000.
Sussman GL, Yang WH, Steinberg S: Melkersson-Rosenthal syn-
drome: clinical, pathologic, and therapeutic considerations,
Ann Allergy 69:187-194, 1992.
Pretrigeminal and Trigeminal Neuralgia
Al-Din AS, Mirr, Davey R et al: Trigeminal cephalgias and facial
pain syndromes associated with autonomic dysfunction,
Cephalalgia 25(8):605-611, 2005.
Benoliel R, Sharav Y: SUNCT syndrome: case report and litera-
ture review, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
85:158-161, 1998.
Brabant S, Van Zundert J, Van Buyten JP: Pulsed radiofrequency
treatment of the gasserian ganglion in patients with essential tri-
geminus neuralgia: a retrospective study. Proceedings of the
World Pain Congress, San Francisco, 2000.
Brisman R: Trigeminal neuralgia and multiple sclerosis, Arch
Neurol 44:379-381, 1987.
Burchiel KJ, Slavin KV: On the natural history of trigeminal
neuralgia, Neurosurgery 46:152-155, 2000.
Evans RW, Graff-Radford SB, Bassiur JP: Pretrigeminal neural-
gia, Headache 45:242-244, 2005.
Fromm GH, Terrence CF, Maroon JCL: Trigeminal neuralgia-
current concepts regarding etiology and pathogenesis, Arch
Neurol 41:1204-1207, 1984.
Golby AJ, Norbash A, Silverberg GD: Trigeminal neuralgia result-
ing from infarction of the root entry zone of the trigeminal
nerve: case report, Neurosurgery 43:620-623, 1998.
Headache Classiﬁcation Subcommittee of the International
Headache Society: The international classiﬁcation of head-
ache disorders, ed 2, Cephalalgia 24(suppl 1):9-160, 2004. `ˆÌi`ÊÜˆÌ…ÊÌ…iÊ`i“œÊÛiÀÃˆœ˜ÊœvÊ
˜vˆÝÊ*ÀœÊ*Ê`ˆÌœÀÊ
/œÊÀi“œÛiÊÌ…ˆÃÊ˜œÌˆVi]ÊÛˆÃˆÌ\Ê
ÜÜÜ°ˆVi˜ˆ°Vœ“ÉÕ˜œVŽ°…Ì“

Chapter
18
F
ACIAL
P
AIN

AND
N
EUROMUSCULAR
D
ISEASES

883
Khan OA: Gabapentin relieves trigeminal neuralgia in multiple
sclerosis patients,
Neurology
51:611-614, 1998.
Mathews ES, Scrivani SJ: Percutaneous stereotactic radiofre-
quency thermal rhizotomy for the treatment of trigeminal
neuralgia,
Mt Sinai J Med
67:288-299, 2000.
Merrill RL, Graff-Radford SB: Trigeminal neuralgia: how to rule
out the wrong treatment,
J Am Dent Assoc
123:63-68, 1992.
Perkins GD: Trigeminal neuralgia,
Curr Treat Options Neurol

1:458-465, 1999.
Pollock BE, Foote RL, Stafford SL et al: Results of repeated
gamma knife radiosurgery for medically unresponsive tri-
geminal neuralgia,
J Neurosurg
93(suppl 3):162-164, 2000.
Sawaya RA: Trigeminal neuralgia associated with sinusitis,
ORL
J Otorhinolaryngol Relat Spec
62:160-163, 2000.
Schwartz AH: Trigeminal neuralgia in a patient with multiple
sclerosis and chronic inﬂ
ammatory demyelinating polyneu-
ropathy,
J Am Dent Assoc
136:469-476, 2005.
Tremont-Lukats IW, Megeff C, Backonja MM: Anticonvulsants
for neuropathic pain syndromes: mechanisms of action and
place in therapy,
Drugs
60:1029-1052, 2000.
Truini A, Galeotti F, Cruccu G: New insight into trigeminal neu-
ralgia,
J Headache Pain
6(4):237-239, 2005.
Glossopharyngeal Neuralgia
Ceylan S, Karakus A, Duru S et al: Glossopharyngeal neuralgia:
a study of 6 cases,
Neurosurg Rev
20:196-200, 1997.
Olesen J, Tfelt-Hansen P, Welch KMA:
The headaches
, ed 2, pp 921-
946, Philadelphia, 2000, Lippincott, Williams & Wilkins.
Rushton JG, Stevens C, Miller RH: Glossopharyngeal (vagoglos-
sopharyngeal) neuralgia: a study of 217 cases,
Arch Neurol

38:201-205, 1981.
Soh KB: The glossopharyngeal nerve, glossopharyngeal neuralgia
and the Eagle’s syndrome—current concepts and manage-
ment,
Singapore Med J
40:659-665, 1999.
Stevens JC: Cranial neuralgias,
J Craniomandib Disord
1:51-53,
1987.
Postherpetic Neuralgia
Bennett GJ: Hypotheses on the pathogenesis of herpes-associ-
ated pain,
Ann Neurol
35:538-541, 1994.
Donahue JG, Choo PW, Masson JE et al: The incidence of herpes
zoster,
Arch Intern Med
155:1605-1609, 1995.
Helgason S, Petursson G, Gudmundsson S et al: Prevalence of
postherpetic neuralgia after ﬁ
rst episode of herpes zoster:
prospective study with long term follow up,
BMJ
321(7264):
794-796, 2000.
Higa K, Mori M, Hirata K et al: Severity of skin lesions of herpes
zoster at the worst phase rather than age and involved region
most inﬂ
uences the duration of acute herpetic pain,
Pain

69:245-253, 1997.
Watson CPN, Gershon AA: Herpes zoster and postherpetic neu-
ralgia,
Pain Res Clin Management
11:90-93; 108-109, 2001.
Whitley RJ, Shukla S, Crooks RJ: The identiﬁ
cation of risk factors
associated with persistent pain following herpes zoster,
J
Infect Dis
178(suppl 1):S71-S75, 1998.
Atypical Facial Pain
DeNucci DJ, Chen CC, Sobiski C et al: The use of SPECT bone
scans to evaluate patients with idiopathic jaw pain,
Oral Surg
Oral Med Oral Pathol Oral Radiol Endod
90:750-757, 2000.
Fricton JR: Atypical orofacial pain disorders: a study of diagnostic
subtypes,
Curr Rev Pain
4:142-147, 2000.
Gouda JJ, Brown JA: Atypical facial pain and other pain syn-
dromes: differential diagnosis and treatment,
Neurosurg Clin
North Am
8:87-100, 1997.
Graff-Radford SB: Facial pain,
Curr Opin Neurol
13:291-296,
2000.
Graff-Radford SB, Ketelaer MC, Gratt BM et al: Thermographic
assessment of neuropathic facial pain,
J Orofac Pain
9:
138-146, 1995.
Headache Classiﬁ
cation Committee of the International Head-
ache Society: Classiﬁ
cation and diagnostic criteria for head-
ache disorders, cranial neuralgias and facial pain,
Cephalalgia

8:1-96, 1988.
Hampf G, Aalberg V, Sunden B: Assessment of patients suffering
from chronic orofacial pain of nonspeciﬁ
c origin,
J Cranio-
mandib Disord
4:30-34, 1990.
Lund JP, Lavigne GJ, Dubner R et al:
Orofacial pain: from basic
science to clinical management
, Chicago, 2001, Quintessence.
Marbach JJ, Hulbrock J, Hohn C et al: Incidence of phantom
tooth pain: an atypical facial neuralgia,
Oral Surg Oral Med
Oral Pathol
53:190-193, 1982.
Olesen J, Tfelt-Hansen P, Welch KMA:
The headaches
, ed 2,
pp 593-598, Philadelphia, 2000, Lippincott, Williams &
Wilkins.
Raskin NH:
Headache
, ed 2, pp 366-367, New York, 1998,
Churchill Livingstone.
Scully C, Porter S: Orofacial disease: update for the clinical team:
9. Orofacial pain,
Dent Update
26:410-417, 1999.
Sessle BJ: The neurobiology of facial and dental pain: present
knowledge, future directions,
J Dent Res
65:962-981, 1987.
Taha JM, Tew JM Jr: Honored guest presentation: therapeutic
decisions in facial pain,
Clin Neurosurg
46:410-431, 2000.
Turp JC, Gobetti JP: Trigeminal neuralgia versus atypical facial
pain: a review of the literature and case report,
Oral Surg Oral
Med Oral Pathol Oral Radiol Endod
81:424-432, 1996.
Woda A, Pionchon P: A uniﬁ
ed concept of idiopathic orofacial
pain: clinical features,
J Orofac Pain
13:172-195, 1999.
Neuralgia-Inducing Cavitational Osteonecrosis
Adams WR, Spolnick KJ, Bouquot JE: Maxillofacial osteonecrosis
in a patient with multiple facial pains,
J Oral Pathol Med

28:423-432, 1999.
Bouquot JE, LaMarche MG: Ischemic osteonecrosis under ﬁ
xed
partial denture pontics: radiographic and microscopic fea-
tures in 38 patients with chronic pain,
J Prosthet Dent
81:148-
158, 1999.
Bouquot JE, McMahon RE: Neuropathic pain in maxillofacial
osteonecrosis,
J Oral Maxillofac Surg
58:1003-1020, 2000.
Bouquot J, Wrobleski G, Fenton S: The most common osteone-
crosis? Prevalence of maxillofacial osteonecrosis (NICO),
J
Oral Pathol Med
29:345, 2000.
Glueck CJ, McMahon RE, Bouquot JE et al: Heterozygosity for
the Leiden mutation V gene, a common pathoetiology for
osteonecrosis of the jaw with thrombophilia augmented by
exogenous estrogens,
J Lab Clin Med
130:540-543, 1997.
Gruppo R, Glueck CJ, McMahon RE et al: The pathophysiology
of osteonecrosis of the jaw: anticardiolipin antibodies, throm-
bophilia, and hypoﬁ
brinolysis,
J Lab Clin Med
127:481-488,
1996.
Larheim TA, Westesson PL, Hicks DG et al: Osteonecrosis of the
temporomandibular joint: correlation of magnetic resonance
imaging and histology,
J Oral Maxillofac Surg
57:888-898,
1999.
McMahon RE, Adams W, Spolnik KJ: Diagnostic anesthesia for
referred trigeminal pain. Part 1,
Compendium
13:870-876,
1992.
Cluster Headache
Benoliel R, Sharav Y: Paroxysmal hemicrania: case studies and
review of the literature,
Oral Surg Oral Med Oral Pathol Oral
Radiol Endod
85:285-292, 1998.
Mathew NT: Cluster headache,
Semin Neurol
17:313-323,
1997.http://dentalebooks.com

884
O
RAL

AND
M
AXILLOFACIAL
P
ATHOLOGY
May A, Bahra A, Buchel C et al: PET and MRA ﬁ
ndings in cluster
headache and MRA in experimental pain,
Neurology
55:1328-
1335, 2000.
Olesen J, Tfelt-Hansen P, Welch KMA:
The headaches
, ed 2,
pp 675-740, Philadelphia, 2000, Lippincott, Williams &
Wilkins.
Penarrocha M, Bagan JV, Penarrocha MA et al: Cluster headache
and cocaine use,
Oral Surg Oral Med Oral Pathol Oral Radiol
Endod
90:271-274, 2000.
Salvesen R: Cluster headache,
Curr Treat Options Neurol
1:441-
449, 1999.
Silberstein SD, Niknam R, Rozen TD et al: Cluster headache with
aura,
Neurology
54:219-221, 2000.
Chronic Paroxysmal Hemicrania
Boes CJ, Doddick DW: Redeﬁ
ning the clinical spectrum of
chronic paroxysmal hemicrania: a review of 74 patients,
J
Headache Pain
42(8):699-708, 2002.
Goadsby PJ: Short-lasting primary headaches: focus on trigemi-
nal autonomic cephalgias and indomethacin-sensitive head-
aches,
Curr Opin Neurol
12(3):273-277, 1999.
Goadsby PJ, Lipton RB: A review of paroxysmal hemicranias,
SUNCT syndrome and other short-lasting headaches with
autonomic features, including new cases,
Brain
120(pt 1):193-
209, 1997.
Lance JW, Goadsby PJ:
Mechanism and management of headache
,
London, 1998, Butterworth-Heinemann.
Russell D: Paroxysmal hemicrania. In Olessen J, Goadsby PJ,
editors:
Cluster headache & related conditions
, pp 27-36, Oxford,
UK, 1999, Oxford University Press.
Migraine
Ambrosini A, de Noordhout AM, Sandor PS et al: Electrophysio-
logical studies in migraine: a comprehensive review of their
interest and limitations,
Cephalalgia
23(suppl 1):13-31, 2003.
Bolay H, Reuter U, Dunn AK et al: Intrinsic brain activity triggers
trigeminal meningeal afferents in a migraine model,
Nat Med

8:136-142, 2002.
Cady RK, Gutterman D, Saires JA et al: Responsiveness of non-
HIS migraine and tension-type headache to sumatriptan,
Cephalalgia
17:588-590, 1997.
Cologno D, Torelli P, Manzoni GC: Migraine with aura: a review
of 81 patients with 10-20 years’ follow-up,
Cephalalgia
18:690-
696, 1998.
Cutrer FM, O’Donnel A, del Rio MS: Functional neuroimaging:
enhanced understanding of migraine,
Neurology
55(suppl 2):
S36-S45, 2000.
Olesen J: Some clinical features of acute migraine attack: an
analysis of 750 patients,
Headache
18:268-271, 1978.
Olesen J, Tfelt-Hansen P, Welch KMA:
The headaches
, ed 2, pp 223-
542, Philadelphia, 2000, Lippincott, Williams & Wilkins.
Peatﬁ
eld RC: Migraine,
Curr Treat Options Neurol
1:450-457,
1999.
Silberstein SD, Lipton RB, Goadsby PJ:
Headache in clinical prac-
tice
, Oxford, UK, 1998, Isis Medical Media.
Ward TN: Providing relief from headache pain: current options
for acute and prophylactic therapy,
Postgrad Med
108:121-
128, 2000.
Woods RP, Iacoboni M, Mazziotta JC: Bilateral spreading cere-
bral hypoperfusion during spontaneous migraine headache,
N Engl J Med
331:1689-1692, 1994.
Temporal Arteritis
Blockmans D, Stroobants S, Maes A: Positron emission tomogra-
phy in giant cell arteritis and polymyalgia rheumatica: evi-
dence for inﬂ
ammation of the aortic arch,
Am J Med
108(3):246-249, 2000.
González-Gay MA, García-Porrúa C, Llorca J et al: Visual mani-
festations of giant cell arteritis. Trends and clinical spectrum
in 161 patients,
Medicine (Balt)
79:283-292, 2000.
Hunder GG: Giant cell arteritis,
Lupus
7:266-269, 1998.
Kleinegger CL, Lilly GE: Cranial arteritis: a medical emergency
with orofacial manifestations,
J Am Dent Assoc
130:1203-
1209, 1999.
Matteson EL, Gold KN, Bloch DA: Long-term survival of patients
with giant cell arteritis in the American College of Rheuma-
tology giant cell arteritis classiﬁ
cation criteria cohort,
Am J
Med
100:193-196, 1996.
Neff AG, Greifenstein EM: Giant cell arteritis update,
Semin
Ophthalmol
14:109-112, 1999.
Nesher G, Sonnenblick M, Friedlander Y: Analysis of steroid
related complications and mortality in temporal arteritis: a
15-year survey of 43 patients,
J Rheumatol
21:1283-1286,
1994.
Turbin RE, Kupersmith MJ: Giant cell arteritis,
Curr Treat Options
Neurol
1:49-56, 1999.
van der Wal JE, van der Waal I: Oral manifestations of giant cell
arteritis,
Mund Kiefer Gesichtschir
1:65-67, 1997.
Myasthenia Gravis
Anlar B: Juvenile myasthenia: diagnosis and treatment,
Paediatr
Drugs
2:161-169, 2000.
Daskalakis GJ, Papageorgiou IS, Petrogiannis ND et al: Myasthe-
nia gravis and pregnancy,
Eur J Obstet Gynecol Reprod Biol
89:201-204, 2000.
Iani C, Caramia M, Morosetti M et al: The treatment of severe
forms of myasthenia gravis,
Funct Neurol
13:231-237, 1998.
Lisak RP: Myasthenia gravis,
Curr Treat Options Neurol
1:239-250,
1999.
Mehta S: Neuromuscular disease causing acute respiratory
failure,
Respir Care
51:1016-1021; discussion 1021-1023,
2006.
Pascuzzi RM: Pearls and pitfalls in the diagnosis and manage-
ment of neuromuscular junction disorders,
Semin Neurol
21:425-440, 2001.
Robertson NP, Deans J, Compston DA: Myasthenia gravis: a
population based epidemiological study in Cambridgeshire,
UK,
J Neurol Neurosurg Psychiatry
65:492-496, 1998.
Sasakura Y, Kumasaka S, Takahashi T et al: Myasthenia gravis
associated with reduced masticatory function,
Int J Oral Maxil-
lofac Surg
29:381-383, 2000.
Scherer K, Bedlack RS, Simel DL: Does this patient have myas-
thenia gravis?
JAMA
293:1906-1914, 2005.
Weijnen FG, Kuks JB, van der Bilt A et al: Tongue force in
patients with myasthenia gravis,
Acta Neurol Scand
102:303-
308, 2000.
Motor Neuron Disease
Adams RD, Victor M, Ropper AH, editors:
Principles of neurology
,
ed 6, pp 1089-1094, New York, 1997, McGraw-Hill.
Bromberg MB: Pathogenesis of amyotrophic lateral sclerosis: a
critical review,
Curr Opin Neurol
12:581-588, 1999.
Francis K, Bach JR, DeLisa JA: Evaluation and rehabilitation of
patients with adult motor neuron disease,
Arch Phys Med
Rehabil
80:951-963, 1999.
Leighton SE, Burton MJ, Lund WS et al: Swallowing in motor
neurone disease,
J R Soc Med
87:801-805, 1994.
Rames CM, Newcombe RG, Harper PS et al: Risk estimates for
developing motor neuron disease in ﬁ
rst-degree relatives,
Clin Genet
47:13-16, 1995.
Ross MA: Acquired motor neuron disorders,
Neurol Clin
15:481-
500, 1997.
Strober JB, Tennekoon GI: Progressive spinal muscular atro-
phies,
J Child Neurol
14:691-695, 1999.http://dentalebooks.com

Chapter
18
F
ACIAL
P
AIN

AND
N
EUROMUSCULAR
D
ISEASES

885
Williams DB, Windebank AJ: Motor neuron disease (amyo-
trophic lateral sclerosis),
Mayo Clin Proc
66:54-82, 1991.
Wokke JH: Diseases that masquerade as motor neuron disease,
Lancet
347:1347-1348, 1996.
Wong PC, Rothstein JD, Price DL: The genetic and molecular
mechanisms of motor neuron disease,
Curr Opin Neurobiol

8:791-799, 1998.
Yapijakis C, Kapaki E, Boussious M et al: Prenatal diagnosis of
X-linked spinal and bulbar muscular atrophy in a Greek
family,
Prenat Diagn
16:262-265, 1996.
Burning Tongue Syndrome and Glossodynia
Bergdahl M, Bergdahl J: Burning mouth syndrome: preva-
lence and associated factors,
J Oral Pathol Med
28:350-354,
1999.
Bessho K, Okubo Y, Hori S et al: Effectiveness of kampo medi-
cine (sai-boku-to) in treatment of patients with glossodynia,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
86:682-686,
1998.
Bogetto F, Maina G, Ferro G et al: Psychiatric comorbidity in
patients with burning mouth syndrome,
Psychosom Med

60:378-385, 1998.
Brown RS, Krakow AM, Douglas T et al: “Scalded mouth syn-
drome” caused by angiotensin converting enzyme inhibitors:
two case reports,
Oral Surg Oral Med Oral Pathol Oral Radiol
Endod
83:665-667, 1997.
Formaker BK, Frank ME: Taste function in patients with oral
burning,
Chem Senses
25:575-581, 2000.
Grinspan D, Fernandez Blanco G, Allevato MA et al: Burning
mouth syndrome,
Int J Dermatol
34:483-487, 1995.
Grushka M, Bartoshuk LM: Burning mouth syndrome and oral
dysesthesias,
Can J Diagnos
99-109, June 2000.
Grushka M, Kawalec J, Epstein JB: Burning mouth syndrome:
evolving concepts,
Oral Maxillofac Surg Clin North Am
12:287-
295, 2000.
Grushka M, Sessle BJ: Burning mouth syndrome,
Dent Clin North
Am
35:171-184, 1991.
Haberland CM, Allen CM, Beck FM: Referral patterns, lesion
prevalence, and patient care parameters in a clinical oral
pathology service,
Oral Surg Oral Med Oral Pathol Oral Radiol
Endod
87:583-588, 1999.
Lamey PJ: Burning mouth syndrome,
Dermatol Clin
14:339-354,
1996.
Muzyka BC, De Rossi SS: A review of burning mouth syndrome,
Cutis
64:29-35, 1999.
Yanagisawa L, Bartoshuk LM, Catalanotto FA et al: Anesthesia of
the chorda tympani nerve and taste phantoms,
Physiol Behav

63:329-335, 1998.
Wesselmann U, Reich SG: The dynias,
Semin Neurol
16:63-74,
1996.
Dysgeusia and Hypogeusia
Ackerman BH, Kasbekar N: Disturbances of taste and smell
induced by drugs,
Pharmacotherapy
17:482-496, 1997.
Bromley SM: Smell and taste disorders: a primary care approach,
Am Fam Physician
61:427-436, 438, 2000.
Deem DA, Yen DM, Kreshak A et al: Spontaneous resolution of
dysgeusia,
Arch Otolaryngol Head Neck Surg
122:961-963,
1996.
Nelson GM: Biology of taste buds and the clinical problem of
taste loss,
Anat Rec
253:70-78, 1998.
Osaki T, Ohshima M, Tomita Y et al: Clinical and physiological
investigations in patients with taste abnormality,
J Oral Pathol
Med
25:38-43, 1996.
Schiffman SS, Graham BG, Suggs MS et al: Effect of psychotropic
drugs on taste responses in young and elderly persons,
Ann N
Y Acad Sci
855:732-777, 1998.
Schiffman SS, Zervakis J, Suggs MS et al: Effect of tricyclic anti-
depressants on taste responses in humans and gerbils,
Phar-
macol Biochem Behav
65:599-609, 2000.
Frey Syndrome
Bonanno PC, Palaia D, Rosenberg M et al: Prophylaxis against
Frey’s syndrome in parotid surgery,
Ann Plast Surg
44:498-
501, 2000.
Dulguerov P, Quinodoz D, Cosendai G et al: Frey syndrome
treatment with botulinum toxin,
Otolaryngol Head Neck Surg

122:821-827, 2000.
Kaddu S, Smolle J, Komericki P et al: Auriculotemporal (Frey)
syndrome in late childhood: an unusual variant presenting as
gustatory ﬂ
ushing mimicking food allergy,
Pediatr Dermatol

17:126-128, 2002.
Laskawi R, Drobik C, Schonebeck C: Up-to-date report of
botulinum toxin type A treatment in patients with gustatory
sweating (Frey’s syndrome),
Laryngoscope
108:381-384,
1998.
Laskawi R, Ellies M, Rodel R et al: Gustatory sweating: clinical
implications and etiologic aspects,
J Oral Maxillofac Surg

57:642-649, 1999.
Linder TE, Huber A, Schmid S: Frey’s syndrome after parotidec-
tomy: a retrospective and prospective analysis,
Laryngoscope

107:1496-1501, 1997.
Mellor TK: Frey’s syndrome following fracture of the mandibular
condyle: case report and literature review,
Injury
27:359-360,
1996.
Scrivani SJ, Keith DA et al: Posttraumatic gustatory neuralgia: a
clinical model of trigeminal neuropathic pain,
J Orofac Pain

12:287-292, 1998.
Shaw JE, Parker R, Hollis S et al: Gustatory sweating in diabetes
mellitus,
Diabet Med
13:1033-1037, 1996.
von Lindern JJ, Niederhagen B, Berge S et al: Frey syndrome,
Cancer
89:1659-1663, 2000.
Osteoarthritis
Dahlstrom L: Diagnoses among referrals to a Swedish clinic spe-
cialized in temporomandibular disorders,
Acta Odontol Scand

56:143-147, 1998.
de Bont LG, Boering G, Liem RS et al: Osteoarthritis and internal
derangement of the temporomandibular joint: a light micro-
scopic study,
J Oral Maxillofac Surg
44:634-643, 1986.
de Leeuw R, Boering G, van der Kuijl B et al: Hard and soft tissue
imaging of the temporomandibular joint 30 years after diag-
nosis of osteoarthrosis and internal derangement,
J Oral Max-
illofac Surg
54:1270-1280, 1996.
Dijkgraaf LC, Spijkervet FK, de Bont LG: Arthroscopic ﬁ
ndings
in osteoarthritic temporomandibular joints,
J Oral Maxillofac
Surg
57:255-268, 1999.
European Society of Osteoarthrology (ESOA): Joint destruction
in arthritis and osteoarthritis: 19th symposium of the ESOA,
Agents Actions
39(suppl):1-272, 1993.
Gynther GW, Holmlund AB, Reinholt FP et al: Temporoman-
dibular joint involvement in generalized osteoarthritis and
rheumatoid arthritis: a clinical, arthroscopic, histologic, and
immunohistochemical study,
Int J Oral Maxillofac Surg
26:10-
16, 1997.
Ong TK, Franklin CD: A clinical and histopathological study of
osteoarthrosis of the temporomandibular joint,
Br J Maxillofac
Surg
34:186-192, 1996.
Peyron JG, Altman RD: The epidemiology of osteoarthritis. In
Moskowitz RW, Howell DS, Goldberg VM, editors:
Osteoar-
thritis, diagnosis and medical/surgical management
, ed 2, pp
15-37, Philadelphia, 1992, Saunders.
Rodrigo JJ, Gershwin ME: Management of the orthopedic joint.
In Chapman MW, editor:
Chapman’s orthopaedic surgery
, ed 3, http://dentalebooks.com

886
O
RAL

AND
M
AXILLOFACIAL
P
ATHOLOGY
pp 2551-2572, Philadelphia, 2001, Lippincott, Williams &
Wilkins.
Rudisch A, Innerhofer K, Bertram S et al: Magnetic resonance
imaging ﬁ
ndings of internal derangement and effusion in
patients with unilateral joint pain,
Oral Surg Oral Med Oral
Pathol Oral Radiol Endod
92:566-571, 2001.
Sano T, Westesson PL, Larheim TA et al: Osteoarthritis and
abnormal bone marrow of the mandibular condyle,
Oral Surg
Oral Med Oral Pathol Oral Radiol Endod
87:243-252, 1999.
Takahashi T, Nagai H, Seki H et al: Relationship between joint
effusion, joint pain, and protein levels in joint lavage ﬂ
uid of
patients with internal derangement and osteoarthritis of the
temporomandibular joint,
J Oral Maxillofac Surg
57:1187-
1194, 1999.
Wiberg B, Wanman A: Signs of osteoarthrosis of the temporo-
mandibular joints in young patients: a clinical and radio-
graphic study,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod

86:158-164, 1998.
Rheumatoid Arthritis
Al-Mobireek AF, Darwazeh AM, Hassanin MB: Experimental
induction of rheumatoid arthritis in temporomandibular
joint of the guinea pig: a clinical and radiographic study,
Dentomaxillofac Radiol
29:286-290, 2000.
Ericson S, Lundberg M: Alterations in the temporomandibular
joint at various stages of rheumatoid arthritis,
Acta Rheum
Scand
13:257-274, 1967.
Gynther GW, Tronje G, Holmlund AB: Radiographic changes in
the temporomandibular joint in patients with generalized
osteoarthritis and rheumatoid arthritis,
Oral Surg Oral Med
Oral Pathol Oral Radiol Endod
81:613-618, 1996.
Hansson TL: Pathological aspects of arthritides and derange-
ments. In Sarnat BG, Laskin DM, editors:
The temporomandibu-
lar joint: a biological basis for clinical practice
, ed 4, pp 165-182,
Philadelphia, 1992, WB Saunders.
Harris ED: Pathogenesis of rheumatoid arthritis,
Am J Med
80:4-
10, 1986.
Larheim TA, Bjornland T: Arthrographic ﬁ
ndings in the tem-
poromandibular joint in patients with rheumatic disease,
J
Oral Maxillofac Surg
47:780-784, 1989.
Marbach JJ: Arthritis of the temporomandibular joints and facial
pain,
Bull Rheum Dis
27:918-921, 1976-1977.
Speculand B, Hensher R, Powell D: Total prosthetic replacement
of the TMJ: experience with two systems 1988-1997,
Br J Oral
Maxillofac Surg
38:360-369, 2000.
Voog U, Alstergren P, Eliasson S et al: Progression of radio-
graphic changes in the temporomandibular joints of patients
with rheumatoid arthritis in relation to inﬂ
ammatory markers
and mediators in blood,
Acta Odontol Scand
62:7-13, 2004.
Wenneberg B, Kononen M, Kallenberg A: Radiographic changes
in the temporomandibular joint of patients with rheumatoid
arthritis, psoriatic arthritis, and ankylosing spondylitis,
J Cra-
niomandib Disord
4:35-39, 1990.
Temporomandibular Joint Dysfunction
Adame CG, Monje F, Offnoz M et al: Effusion in magnetic reso-
nance imaging of the temporomandibular joint: a study of
123 joints,
J Oral Maxillofac Surg
56:314-318, 1998.
Burakoff RP, Kaplan AS: Temporomandibular disorders: current
concepts of epidemiology, classiﬁ
cation, and treatment,
J Pain
Symptom Manage
8:165-172, 1993.
Gaggl A, Schultes G, Santler G et al: Clinical and magnetic reso-
nance ﬁ
ndings in the temporomandibular joints of patients
before and after orthognathic surgery,
Br J Oral Maxillofac Surg

37:41-45, 1999.
Greene CS, Laskin DM: Long-term evaluation of treatment for
myofascial pain-dysfunction syndrome: a comparative analy-
sis,
J Am Dent Assoc
107:235-238, 1983.
Kaplan AS, Assael LA:
Temporomandibular disorders: diagnosis and
treatment
, Philadelphia, 1991, WB Saunders.
Laskin DM, Greene CS, Hylander WL:
Temporomandibular disor-
ders: an evidence-based approach to diagnosis and treatment
,
Chicago, 2006, Quintessence.
Lundh H, Westesson PL: Clinical signs of temporomandibular
joint internal derangement in adults: an epidemiologic study,
Oral Surg Oral Med Oral Pathol
72:637-641, 1991.
McQuary HJ, Tramer M, Nye BA et al: A systematic review of
antidepressants in neuropathic pain,
Pain
68:217-227,
1996.
Suvinen TI, Reade PC: Temporomandibular disorders: a critical
review of the nature of pain and its assessment,
J Orofac Pain

9:317-339, 1995.
Takahashi T, Nagai H, Seki H et al: Relationship between joint
effusion, joint pain, and protein levels in joint lavage ﬂ
uid of
patients with internal derangement and osteoarthritis of the
temporomandibular joint,
J Oral Maxillofac Surg
57:1187-
1194, 1999.
Vickers ER, Cousins MJ, Walker S et al: Analysis of 50 patients
with atypical odontalgia: a preliminary report on pharmaco-
logical procedures for diagnosis and treatment,
Oral Surg Oral
Med Oral Pathol Oral Radiol Endod
85:24-32, 1998.
Vickers ER, Cousins MJ, Woodhouse A: Pain description and
severity of chronic orofacial pain conditions,
Aust Dent J

43:403-409, 1998.
Westesson P-L, Yamamoto M, Sano T et al: Temporomandibular
joint. In Som PM, Curtin HD, editors:
Head and neck imaging
,
ed 4, pp 995-1053, St Louis, 2003, Mosby.
Widmark G: On surgical intervention in the temporomandibular
joint,
Swed Dent J
123(suppl):1-87, 1997.
Wright WJ Jr: Temporomandibular disorders: occurrence of
speciﬁ
c diagnoses and response to conservative manage-
ment: clinical observations,
J Craniomandib Disord
4:150-155,
1986.
Yatani H, Minakuchi H, Matsuka Y et al: The long-term effect of
occlusal therapy on self-administered treatment outcomes of
TMD,
J Orofacial Pain
12:75-88, 1998.
Temporomandibular Joint Ankylosis
Chidzonga MM: Temporomandibular joint ankylosis: review of
thirty-two cases,
Br J Oral Maxillofac Surg
14:136-138, 1999.
Freedus MS, William DZ, Doyle PK: Principles of treatment of
temporomandibular joint ankylosis,
J Oral Surg
33:757-765,
1975.
Koorbusch GF, Zeitler DL, Fotos PG et al: Psoriatic arthritis of
the temporomandibular joints with ankylosis,
Oral Surg Oral
Med Oral Pathol
71:267-274, 1991.
Manganello-Souza LC, Mariani PB: Temporomandibular joint
ankylosis: report of 14 cases,
Int J Oral Maxillofac Surg
32:
24-29, 2002.
Rowe NL: Ankylosis of the temporomandibular joint. Part 1,
J R
Coll Surg Edinb
27:67-79, 1982.
Rowe NL: Ankylosis of the temporomandibular joint. Part 2,
J R
Coll Surg Edinb
27:167-173, 1982.
Rowe NL: Ankylosis of the temporomandibular joint. Part 3,
J R
Coll Surg Edinb
27:209-218, 1982.
Salins PC: New perspectives in the management of cranioman-
dibular ankylosis,
Int J Oral Maxillofac Surg
29:337-340,
2000.
Sarma UC, Dave PK: Temporomandibular joint ankylosis: an
Indian experience,
Oral Surg Oral Med Oral Pathol
72:660-
664, 1991.
Su-Gwan K: Treatment of temporomandibular joint ankylosis
with temporalis muscle and fascia ﬂ
ap,
Int J Oral Maxillofac
Surg
30:189-193, 2001.http://dentalebooks.com

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19
Forensic Dentistry
EDWARD E. HERSCHAFT
CHAPTER OUTLINE
Record Management
Identiﬁ cation
Personal Recognition
Fingerprinting
Physical Anthropologic Examination of Bones and
Teeth
Serologic and Genetic (DNA) Comparison
Dental Evaluation
Bite Pattern Evidence
Basic Principles
●
Identiﬁ
cation of human remains, through the com-
parison of antemortem and postmortem dental infor-
mation, in cases that involve the death of an individual
or multiple deaths in mass fatality incident (MFI)
situations.
●
Collection and analysis of patterned marks (bite
marks) in inanimate material or injured tissue—this
evidence can be compared with, and potentially
related to, a speciﬁ
c human or animal dentition.
●
Recognition of the signs and symptoms of human
abuse (including intimate-partner violence [IPV],
elder abuse, and child abuse) and the dental health
care practitioner’s rights and responsibilities when
reporting such abuse.
●
Presentation of dental evidence as an expert witness
in identiﬁ
cation, bite mark, human abuse, malprac-
tice, fraud, and personal injury cases.
RECORD MANAGEMENT
The dental record is a legal document, owned by the
dentist or an incorporated dental practice, which con-
tains all subjective and objective information about the
patient. Initially, this information is secured when the
patient’s medical and dental history is obtained. Results
Forensic dentistry
, which is also referred to as
forensic
odontology
, is the area of dentistry concerned with the
correct management, examination, evaluation, and
presentation of dental evidence in criminal or civil
legal proceedings in the interest of justice. Thus the
forensic dentist must be knowledgeable in both den-
tistry and law.
Classically, forensic dentistry can be considered a
subspecialty of oral and maxillofacial pathology. This is
analogous to the relationship in medicine between
forensic pathology and pathology. The requirements of
forensic dental ﬁ
eld work, however, often demand an
interdisciplinary knowledge of dental science. This has
resulted in other dental specialists and general dentists
joining oral and maxillofacial pathologists in providing
legal authorities with dental expertise.
Regardless of background, forensic dentists assist
legal authorities by preparing dental evidence in the
following situations:
●
Management and maintenance of dental records
that comply with legal requirements to document all
unique dental information—these data are the foun-
dation on which dental identiﬁ
cation of the patient
is accomplished and potential malpractice litigation
is reduced.
Historical and Legal Issues
Characteristics of Bite Marks
Guidelines for Bite Mark Analysis
Human Abuse
Epidemiology and Classiﬁ cation
Signs and Symptoms
Role of Dentistry in Recognizing and Reporting Human
Abuse
Dentists as Expert Witnesses
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of the physical examination of the dentition and sup-
porting oral and paraoral structures are recorded.
In addition, the results of clinical laboratory tests,
study casts, photographs, and radiographs become
components of the record. With this database, the
dentist can develop a thorough assessment of all of the
patient’s medical and dental problems. Subsequent
documentation of this “problem list” facilitates the
development of a plan of treatment and prognosis for
the patient.
The treatment plan addresses the management of
both systemic and oral problems. It can then be peri-
odically revised and updated as problems resolve or as
new ones develop. Supplemental material, such as
dental laboratory authorizations, referral letters from
other practitioners, statements of informed consent,
written prescriptions, and insurance and ﬁ
nancial
statements, also is included and stored in the record.
The progress notes (i.e., daily log of actual treatment
rendered) should contain information about restor-
ative and therapeutic procedures provided. This infor-
mation should include documentation of the speciﬁ
c
brand of dental material used in restorative proce-
dures. This concept has forensic import because each
dental restorative product contains inorganic materi-
als, trace elements, and ﬁ
llers that are unique to that
product and can be detected by
x-ray ﬂ
uorescence

(XRF) technology even after incineration. The XRF
trace element and major element analysis of dental
remains may be useful as an adjunct to traditional
evaluation of dental information in some forensic set-
tings, including cremation and dismemberment cases
(Fig. 19-1).
Unusual physiologic and psychologic reactions and
the patient’s comments concerning therapy are entered
in the record. Summaries of telephone conversations
with patients, consultants, insurance company repre-
sentatives, or legal authorities should be noted. All
entries should be signed or initialed by recording per-
sonnel. Changes in the record should not be erased but
corrected by a single line drawn through the incorrect
material. This method permits the original entry to
remain readable and removes any questions concern-
ing fraudulent intent to alter recorded information.
It is becoming more common for dental records to
be maintained electronically, and numerous commer-
cial and individually designed computer software pro-
grams have been marketed to assist the dentist in
collecting and preserving the patient’s dental informa-
tion. The obvious advantage of computer-generated
dental records is that they can be easily networked and
transferred for routine professional consultation or
forensic cases requiring dental records for identiﬁ
ca-
tion. Issues related to patient privacy in this regard
are no different from those considered with paper
documents.
In the United States, the Privacy Rule governing the
use of protected health information (PHI) is regulated
under the federal Health Insurance Portability and
Accountability Act (HIPAA) of 1996. Despite the
establishment of the Privacy Rule, the ability and
necessity of forensic dentists, law enforcement person-
nel, medical examiners (MEs), and coroners to obtain
released antemortem dental and medical records for
forensic purposes was recognized and provided for in
the HIPAA legislation.
The potential charge of insurance fraud associated
with the enhancement of dental lesions or restorations
on computer-generated or scanned
digital radiogra-
phy
(DR) can be avoided if a clinician stores and main-
Fig. 19-1
The x-ray ﬂ
uorescence (XRF) spectrum from a particle recovered from a cremation
retort. The spectrum makes this a match for the restorative resin Four Seasons or Tetric
Ceram (Ivoclar, Amherst, NY).
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889
tains unaltered images. This is accomplished using
programs with unchangeable, secure tagged block ﬁ
le
extensions in their native ﬁ
le formats. When duplicates
or copies are required, working images should be
generated.
Computer-assisted management technology (e.g.
WinID3 dental comparison software bridged with the
Dexis digital radiography program) has been an asset
in expediting the comparison of antemortem and
postmortem dental record information in recent MFI
events, including the World Trade Center terrorist
attack, the Indian Ocean tsunami disaster, and the
Hurricane Katrina recovery effort. Additionally, soft-
ware such as Adobe Photoshop and Mideo Systems
casePACS, facilitates the superimposition of digi-
tally scanned radiographs and photographs for
comparison.
Whether preserved in written form or by using a
computer database, the principles of record manage-
ment describe a mechanism that ensures that dental
information, which may be required to resolve a foren-
sic problem, is properly maintained and retrievable.
Additionally, records preserved in this manner are reli-
able evidentiary material if subpoenaed in peer review
or malpractice litigation proceedings.
Time limits concerning how long records must be
retained vary among the states. As a rule, states mandate
that records be kept for 7 to 10 years. Federal legisla-
tion related to the problem of missing persons in the
United States requires that records of pediatric dental
patients be retained until the patient reaches the age
of majority.
IDENTIFICATION
Legal situations often revolve around the establishment
of a person’s proper identity. Any death not certiﬁ
ed by
an individual’s own physician must be referred to the
medical examiner (ME) or coroner for review. However,
cases requiring an
autopsy
to determine the time,
cause, and manner of death represent a small percent-
age of cases. When required, these tasks are the respon-
sibility of a coroner or ME. These ofﬁ
cials are charged
with the role of establishing identiﬁ
cation; determining
the cause, mechanism, and mode or manner of death;
and issuing a death certiﬁ
cate. Besides identiﬁ
cation
of the decedent, these key issues of death investigation
for the coroner or ME are deﬁ
ned according to the
following:
●

Cause of death.
The disease, injury, or chemical or
physical agent responsible for initiating the lethal
sequence of events (e.g., myocardial infarction,
cancer, bullet, knife, poison, ligature, lightning, infec-
tious agent)
●

Mechanism of death.
The pathologic process that
results in death (e.g., congestive heart failure, cardiac
arrhythmias, asphyxia, sepsis, exsanguination, renal
failure, and hepatic failure.)
●

Mode or manner of death.
According to the NASH
classiﬁ
cation, the mode or manner of death is
considered to be
N
atural,
A
ccidental,
S
uicide, or
H
omicide. Natural deaths are caused exclusively by
disease. Accidental deaths result from an environ-
mental or human tragedy (e.g., lightning strike,
vehicular incident).
●

Undetermined death.
Although the cause and
mechanism of death may be resolved, the manner or
mode may not be established because of decomposi-
tion, dismemberment, or postmortem destruction of
the remains by insects or feral animals.
The coroner is an elected ofﬁ
cial and, depending on
the laws of each state, does not necessarily have to be
a physician or have advanced training in death inves-
tigation. An ME is an appointed ofﬁ
cial who is a pathol-
ogist speciﬁ
cally trained in forensic medicine. Many
jurisdictions use forensic pathologists, and this trend
has contributed to the professionalizing of a posi-
tion increasingly involved with the interpretation of
advanced scientiﬁ
c techniques requiring knowledge of
toxicology, ballistics, pharmacology, and criminalistics,
as well as pathology.
A death certiﬁ
cate, identifying the decedent, is
required before probation of a will, release of life insur-
ance claims, or resolution of other affairs associated
with the settlement of an estate. Criminal cases involv-
ing homicide, suicide, and fraudulent misidentiﬁ
cation
may also require the expertise of forensic dentists and
other forensic scientists trained in identiﬁ
cation tech-
niques. These professionals act as consultants to the
coroner or ME and assist in this aspect of a death
investigation.
Besides analysis of the dentition, the most common
methods of identiﬁ
cation include personal recognition,
ﬁ
ngerprinting (friction ridge analysis), physical anthro-
pologic examination of bones, and serologic and genetic
(DNA) comparison techniques.
Additionally, the use of facial superimposition
techniques (when the teeth are visible) and facial
reconstruction techniques may also permit scientiﬁ
-
cally supported comparisons for identiﬁ
cation. Each
method has its advantages and disadvantages. However,
all rely on the principle that identiﬁ
cation is the posi-
tive correlation obtained by comparing known infor-
mation about a suspect or victim with unique facts
retrieved by physical examination of the suspect or
victim.
Regardless of the method used to identify a dece-
dent, the results of the antemortem and postmortem
data comparison lead to one of the following four
situations:
1.
Positive identiﬁ
cation.
There is sufﬁ
cient unique-
ness among the comparable items in the antemor-http://dentalebooks.com

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tem and postmortem databases, and no major
differences are observed.
2.
Presumptive (possible) identiﬁ
cation.
There are
commonalities among the comparable items in the
antemortem and postmortem databases; however,
enough information may be missing from either
source to prevent the establishment of a positive
identiﬁ
cation.
3.
Insufﬁ
cient identiﬁ
cation evidence.
There is
insufﬁ
cient supportive evidence available to com-
pare and arrive at a conclusion based on scientiﬁ
c
principles.
4.
Exclusion of identiﬁ
cation evidence.
Either
explainable or unexplainable discrepancies exist
among comparable items in the antemortem and
postmortem databases. This results in inconsisten-
cies that prevent the establishment of any identi-
ﬁ
cation. Exclusion may be just as important as a
determination of positive identiﬁ
cation.
PERSONAL RECOGNITION
Personal recognition is the least reliable method used
to identify an individual. It is often based on the visual
identiﬁ
cation of a decedent by a family member, friend,
or acquaintance. This process assesses artifactual mate-
rial, such as clothing, jewelry, keys, wallet contents,
luggage, other personal effects, scars, and tattoos to
determine identiﬁ
cation. Evidence in this type of iden-
tiﬁ
cation can be accidentally or purposely exchanged
between bodies. This can occur in MFI situations or
when there is criminal intent to create a misidentiﬁ
ca-
tion in cases of identity theft or alias associated with
criminal activity.
Even when a body is viewed shortly after death,
distraught relatives can inadvertently misidentify the
decedent. After the occurrence of postmortem changes
associated with soft tissue decomposition, insect and
burn artifact, or dismemberment, this method of iden-
tiﬁ
cation may be precluded (Figs. 19-2 and 19-3).
FINGERPRINTING
Anthropometry
was the ﬁ
rst “scientiﬁ
c” system police
used to identify criminals. The French law enforce-
ment ofﬁ
cer Alphonse Bertillon developed this system
in the latter part of the nineteenth century. The method
was unreliable and ﬂ
awed because it relied on biomet-
ric physical measurements of the head and body, indi-
vidual markings including scars and tattoos, and other
personal characteristics. Bertillon’s anthropometry
identiﬁ
cation process was eventually replaced by
analysis of the epidermal friction ridges of the
ﬁ
ngers, palms, and feet commonly referred to as
ﬁ
ngerprinting
.
By the beginning of the twentieth century, forensic
science had recognized that the ridgelike patterns on
the ﬁ
ngertips and palms are unique for each person.
These friction ridges are genetically determined, and
not even homozygous twins have the same patterns of
loops, arches, and whorls. A principal variation in the
ﬁ
ngerprints of twins is that they appear as mirror
images of each other. The variation in combinations of
the loops, arches, and whorls permits a scientiﬁ
c com-
parison of ﬁ
ngerprint records with the prints of an
unidentiﬁ
ed decedent.
Because the ﬁ
ngerprint pattern is inherited, it is a
static characteristic and remains unchanged through-
out life. This is an important advantage when one
compares ﬁ
ngerprint identiﬁ
cation with dental
identiﬁ
cation. The teeth and supporting structures
Fig. 19-2
Unrecognizable partially decomposed human
remains with a maxillary removable partial denture in place.
Notice that the skin tissue of the neck that has been
protected by the windbreaker jacket has not reached the
stage of decomposition of the tissues of the exposed face.
(Courtesy of Dr. Raymond D. Rawson.)
Fig. 19-3
A burn victim requiring identiﬁ
cation by dental,
DNA, or ﬁ
ngerprint methodology rather than personal
recognition.
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have ﬂ
uid characteristics. Dental patterns change as
teeth erupt, exfoliate, decay, become restored, and,
perhaps, are eventually extracted and replaced with
implants or other prosthetic devices.
Unlike dental records, which are principally retained
in private dental ofﬁ
ces in the Americas and Western
Europe, ﬁ
ngerprint information is maintained by
governmental agencies. Several states retain records of
noncriminals who work in sensitive occupations. In
this regard, Nevada has a ﬁ
ngerprint database for
employees in the gaming industry. The Criminal Justice
Information Services (CJIS) Division of the Federal
Bureau of Investigation (FBI) contains approximately
47 million ﬁ
ngerprint records in its Criminal Master
File. This is the largest biometric database in the world,
and it is retained within the Integrated Automated Fin-
gerprint Identiﬁ
cation System (IAFIS).
The establishment of the CJIS Division’s IAFIS ﬁ
les
permits automated computer data entry and search
capabilities for matching and retrieval of ﬁ
ngerprint
images. This information is available for electronic
exchange among law enforcement agencies for identi-
ﬁ
cation purposes. Included in the IAFIS database are
criminal and civil 10-print ﬁ
ngerprint records, latent
ﬁ
ngerprint services, and subject and criminal history
search capabilities. Information from this ﬁ
ngerprint
repository is shared with international legal agencies
such as Interpol and the Royal Canadian Mounted
Police.
Fingerprint nomenclature is standardized in IAFIS,
and all ﬁ
ngerprint experts use the same terminology
worldwide. This advantage is not observed in dental
identiﬁ
cation, in which numerous charting and tooth-
numbering systems are used. Because soft tissues
decompose shortly after death, the friction ridge pat-
terns within the epidermis may not be retrievable for
ﬁ
ngerprint comparison. This is the principal disadvan-
tage of ﬁ
ngerprint identiﬁ
cation.
PHYSICAL ANTHROPOLOGIC
EXAMINATION OF BONES AND TEETH
Forensic anthropologists and forensic dentists often
work together to resolve problems associated with
identiﬁ
cation. Both disciplines are concerned with
analysis of calciﬁ
ed structures of the body—bones and
teeth. Historically, this anatomic material has assisted
forensic anthropologists and dentists in determining
the race, age, and sex of a person (Table 19-1). These
characteristics have become less distinct in some popu-
lations as individuals from different cultures and races
have intermarried and blended these genetically deter-
mined features in their offspring.
Determination of the age of an individual is helpful
in cases involving limited population fatality incidents
in which the ages of the victims vary. Immigration ofﬁ
-
cials often deal with situations in which designation of
juvenile or adult is important when considering the
status of refugees or illegal aliens. In these settings the
assessment of dental evidence may provide resolution.
In addition to the study of osseous material, the
teeth can be evaluated clinically, radiographically, and
biochemically to determine the age of the decedent.
The basis for this analysis is related to progressive
S
EXUAL
C
HARACTERISTICS
Male Female
Size Large Small
Glabellar (supraorbital) ridges Pronounced Not developed
Mastoid process Large Small
Occipital area Pronounced muscle lines Minimal muscle lines
Mandible Larger, broader ramus Smaller
Forehead Steeper, slopes posteriorly Rounded, more vertical
Table

19-1

Skeletal Anthropologic Variations Associated with Racial and Sexual Characteristics of
the Skull
R
ACIAL
C
HARACTERISTICS
White Black Asian/Native American
Width Narrow Narrow Broad
Height High Low Intermediate
Proﬁ
le Straight Prognathic Intermediate
Orbit Triangular/teardrop Square Circular
Nasal opening Tapered Wide Rounded
Palate Narrow Wide Intermediatehttp://dentalebooks.com

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changes in forming and developing teeth, eruption pat-
terns, and levels of metabolically stable tissue factors,
including aspartic acid enantiomers. This information,
combined with analysis of the calciﬁ
cation centers of
the hand and wrist, can be used to estimate the precise
age of a person who is younger than 20 years of age.
Depending on the type of case being studied, several
techniques are available to estimate chronologic dental
age. In individuals younger than 20 years old, this is
most often accomplished through morphologic and
histologic analysis of dental and skeletal material.
Included in the methodology for this type of age evalu-
ation is the radiographic assessment of the calciﬁ
cation
stage of the third molars and analysis of ground sec-
tions of teeth for variations in the following patterns:
●
Attrition
●
Periodontal attachment
●
Secondary dentin
●
Cementum apposition
●
Root resorption
●
Transparency
There are variations in the calciﬁ
cation and erup-
tion patterns among various ethnic and cultural groups,
and studies have been undertaken to delineate these
differences further. After the third molars, long bones,
and bones of the wrist and hand are completely devel-
oped, evaluation of biochemical components of the
calciﬁ
ed structures and collagen is the most accurate
method for determining chronologic age.
Methods that rely on an analysis of the rate of race-
mization of the stereoisomers of aspartic acid in enamel
and dentin can be used to determine an accurate
chronologic age. This is related to the fact that the
change from the
L
-form of this amino acid to its mirror
image
D
-form occurs over time. Thus the ratio of the
L
- to
D
-forms of aspartic acid in the dentition is directly
related to the age of the individual. Often, anthropo-
logic and dental age analysis is helpful in arriving at a
presumptive identiﬁ
cation based on the criteria noted
previously.
Positive identiﬁ
cation may be achievable when the
skull and facial bones are used as a foundation to
reconstruct the facial soft tissues (Figs. 19-4 to 19-6).
Three-dimensional (3D) computer images, computed
tomography (CT) images, and radiographs have even
been used in the replication of the face of Europe’s
oldest mummiﬁ
ed human, a male dubbed Ötzi, whose
5300-year-old remains were removed from glacial ice
in the Ötztal Alps on the Austrian-Italian border.
With knowledge of the anatomic relationships
between the skull and face, antemortem facial photo-
graphs or radiographs can be superimposed for com-
parison with the skull of an unknown. Video
superimposition with two television cameras and an
electronic mixing device has been used successfully to
Fig. 19-4
Reconstruction of the facial soft tissue uses
predetermined, standard anthropologic thickness
measurements for speciﬁ
c points around the face. These
measurements are based on variables that are related to
racial and sexual characteristics.
(Courtesy of Dr. Cleve Smith.)
Fig. 19-5
The soft tissue thickness points can be connected
with sculpting clay or digitized on a computer screen. The
ultimate result of these techniques is a re-creation of the
contour of the soft tissue features that permits a visual
identiﬁ
cation.
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overlay a photograph of a human face on an image of
a skull for identiﬁ
cation. The development of computer
software programs capable of superimposition has
further facilitated the process.
The anterior dentition of the skull can be overlayed
and compared with a smiling antemortem photograph.
The shapes and positions of the individual teeth and
their relationships to each other have been considered
distinctive enough features on which to base identiﬁ
ca-
tion, as have certain signiﬁ
cant cranial and facial land-
marks, including the orbits, nasal openings, malar
eminence, and chin. Prosthetic joint replacements,
intraosseous and dental implants, and radiographic
signs of prior bone fracture are other anthropologic
ﬁ
ndings that can be used to facilitate identiﬁ
cation.
Additionally, prosthetic devices, implanted deﬁ
bril-
lators and pacemakers, and dental and osseous implants
are designated with individual identiﬁ
cation code
numbers provided by their manufacturers. These codes
can be visualized in the various devices and are useful
in identifying individuals in cremation and dismem-
berment scenarios when the teeth and ﬁ
ngerprints are
not available for evaluation.
SEROLOGIC AND GENETIC (DNA)
COMPARISON
Every individual is unique by virtue of his or her chro-
mosomal DNA—a polymer structured as a double helix
and composed of four different nucleotides. The poly-
morphic sequencing of these nucleotides along the two
strands of the DNA molecule accounts for the genetic
diversity of all living things. This “ultimate identiﬁ
ca-
tion material” was ﬁ
rst used forensically to obtain a
conviction in a criminal case in 1986, and DNA com-
parison has since become an accepted forensic method
to resolve problems of identiﬁ
cation.
Before 1986, comparison of antigenic markers
found on red blood cells (RBCs) and in body ﬂ
uids of
secretors of these markers among the human popula-
tion was traditionally used as a means of exculpatory
(exclusionary) evidence. Because the ABH antigenic
surface markers of RBCs are not discriminatory, this
type of evidence was primarily used to exclude a
suspect or victim when negative comparative results
were achieved. Positive comparisons were justiﬁ
ed
only to place the suspect or victim in a population of
individuals having similar serologic antigens.
Although DNA has become the principal biologic
substance used to effect a positive identiﬁ
cation, anti-
genic surface markers A, B, and H of the ABO blood
group system, as well as various components of the
rhesus (Rh) and Lewis systems, continue to be accepted
for medicolegal comparison. The ability to secrete the
ABH antigens in saliva and other body ﬂ
uids is geneti-
cally determined, and more than 80% of individuals
are secretors. With appropriate laboratory tests, even
dried samples of ﬂ
uid and blood can be analyzed for
these markers.
DNA found in human cells is composed of chromo-
somal and mitochondrial DNA (mtDNA). Two copies
of chromosomal DNA are incorporated into the nuclei
of a person’s cells by DNA provided from both parents.
However, hundreds of copies of mtDNA are contained
in the cytoplasm of these cells. This DNA is only
maternally transferred and can be isolated from cells
without nuclei such as RBCs. Unlike nuclear DNA,
mtDNA is single stranded and circular. Because there
is no mixing of sequence types from generation to gen-
eration in maternally transferred mtDNA, it can be
compared with that of distant maternal relatives to
effect iden tiﬁ
cation when other reference sources are
unavailable.
Restriction fragment length polymorphism (RFLP)
and polymerase chain reaction (PCR) analyses are the
principal laboratory techniques used to compare and
evaluate fragments of DNA material from a suspect or
victim’s biologic forensic specimens (e.g., semen,
vaginal ﬂ
uid, teeth, soft tissues, saliva). Both are
Fig. 19-6
The width of the mouth is related to the
interpupillary distance. The length and shape of the nose are
determined by the relationship between the inferior and
superior nasal spines. If known, then the addition of a speciﬁ
c
hairstyle, eyeglasses, and eye color can further individualize a
facial reconstruction.
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extremely accurate, precise, and reproducible; these
methods are used when the conditions of the sample
DNA presented dictate the need for their respective
advantages.
RFLP methods result in splitting source DNA into
thousands of fragments using “biologic scissors” known
as
restriction enzymes
. Fragment size varies among indi-
viduals related to the variable number of tandem
repeats (VNTR) of base pairs. These short segments of
DNA contain a number of repeat units that differ
among individuals. After gel separation of the frag-
ments and transfer to a nylon mesh, speciﬁ
c DNA
fragments are identiﬁ
ed using oligonucleotides labeled
with radioisotopes. Analysis of a series of different
VNTR loci permits generation of an individual DNA
proﬁ
le.
A match of four or more VNTR loci is consistent
with a positive match between DNA evidence gathered
from suspect, victim, or crime scene evidence. The
RFLP method requires large amounts of high molecu-
lar weight DNA, a major disadvantage. Small DNA
samples (
<
100 ng) or degraded evidence in which the
DNA has become denatured because of extreme heat
or pH variation requires an analytic method other than
RFLP.
The evaluation of minute quantities of DNA or DNA
that has undergone degradation can be accomplished
with the highly sensitive PCR test. Using this labo-
ratory technique, smaller VNTR loci of a speciﬁ
c DNA
sequence can be ampliﬁ
ed into enough copies for suf-
ﬁ
cient analysis. Because of its high degree of sensiti-
vity, PCR analysis has been used to evaluate small
amounts of DNA from a suspect’s clothing left at the
scene of a crime, as well as from bone fragments from
the Vietnam War. DNA ampliﬁ
cation of microsatellite
loci (referred to as
STRs
) and minisatellite loci (or
LTRs
)
using PCR, is referred to as
AmpFLP analysis
.
The hard and soft tissues of the oral cavity and saliva
are often good sources for DNA material. However, if
the teeth or other hard structures of the mouth are to
be used for the collection of DNA evidence, then the
identiﬁ
cation value of these structures should be con-
sidered (beyond their ability to yield a harvest DNA).
A tooth or jaw fragment capriciously destroyed can
result in the loss of valuable radiographic and anatomic
sources for eventual dental identiﬁ
cation. Besides the
obvious source of DNA from human tissues, the foren-
sic dentist often considers the evaluation of chewed
gum, cigarette remains, licked envelopes, stamps, or
similar inanimate objects as potential sources for DNA
evidence using PCR analysis described previously.
Passage of the DNA Identiﬁ
cation Act of 1994 and
the establishment of the FBI’s National DNA Index
System (NDIS) in 1998 have facilitated the exchange
and comparison of DNA proﬁ
les among federal, state,
and local crime laboratories in the United States. This
is accomplished electronically through the FBI Labora-
tory’s Combined DNA Index System (CODIS). Through
the CODIS computer program’s forensic and offender
indexes, biologic evidence from crime scenes can be
linked to DNA proﬁ
les of individuals convicted of sex
offenses and other felonies. As of March 2007, the total
number of DNA proﬁ
les contained in the CODIS data-
bases was more than 4.5 million. More than 47,000
successful comparisons (“hits”) were made among
cases in which the CODIS system was activated. This
represents a 98% success rate linking DNA from a
crime scene with similar material from the convicted
offender proﬁ
les.
The U.S. Department of Defense has initiated a
policy of obtaining DNA samples on all military per-
sonnel. This DNA “ﬁ
ngerprint” has signiﬁ
cantly
reduced the possibility of another unknown soldier
among future military casualties. Despite the positive
effects of DNA evidence in resolving questions of iden-
tity, the technique is not without controversy. Chal-
lenges have been made by population geneticists,
concerned about random matching and variations
among racial subgroups.
DENTAL EVALUATION
BASIC PRINCIPLES
In an identiﬁ
cation case, the principal advantage of
dental evidence is that, like other hard tissue, it is often
preserved indeﬁ
nitely after death. Although the status
of a person’s teeth changes throughout life, the combi-
nation of decayed, missing, and ﬁ
lled teeth is measur-
able, reproducible, and comparable at any ﬁ
xed point
in time. Therefore, like the comparison of unique pat-
terns in a ﬁ
ngerprint, a scientiﬁ
c, objective analysis
of antemortem and postmortem dental variables is
achievable.
The presence and position of individual teeth and
the respective anatomic, restorative, and pathologic
components provide the database for the antemortem
and postmortem comparison (Fig. 19-7). The pattern
of the palatal ridge, ridges on the lip surface, and radio-
graphic outline of the maxillary and frontal sinuses are
also considered unique. In addition, the legal commu-
nity accepts the fact that dentists can recognize proce-
dures that they have performed.
Problems associated with dental identiﬁ
cation infor-
mation are often related to acquiring and interpreting
antemortem records. Most antemortem dental records
are retrieved from private-sector dental providers.
However, dental records may be recovered from insur-
ance carriers, dental schools, hospitals, clinics, state
and federal prisons, military ﬁ
les, and the FBI National
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To initiate a request for antemortem records, a puta-
tive (suspected) identiﬁ
cation is required. Reports of
missing and unidentiﬁ
ed persons, obtained from law
enforcement agencies, are the principal source for this
material. Thousands of victims who cannot be identi-
ﬁ
ed by ﬁ
ngerprint methods remain uniden-
tiﬁ
ed because a putative identiﬁ
cation has not been
established.
The FBI-NCIC computer registry of missing and
unidentiﬁ
ed persons was established to help rectify
this problem. This computer system maintains demo-
graphic, dental, and medical information on missing
persons. It attempts to match these data with similar
facts obtained from unidentiﬁ
ed bodies. The latter
information is submitted by various investigative and
legal agencies. Potentially, the otherwise unidentiﬁ
able
victims of random violence, serial homicides, terrorist
acts, and child abduction can now be identiﬁ
ed without
the need to determine a putative identiﬁ
cation. A dis-
advantage of the NCIC computer identiﬁ
cation system
is that it does not have the capability to identify possi-
ble decedents based solely on dental information.
The National Dental Image Repository (NDIR) has
been established to address this issue. Law enforce-
ment agencies can voluntarily post supplemental dental
images related to NCIC Missing, Unidentiﬁ
ed, and
Wanted Person records on the NDIR secure website.
Thus access, retrieval, and review of dental information
by qualiﬁ
ed forensic odontologists who are members
of the NDIR Review Panel can facilitate dental
comparisons. The NDIR website is located at Law
Enforcement Online (LEO) at http://cgate.leo.gov. This
repository permits law enforcement, criminal justice,
and public safety authorities to maintain a national and
international method of electronic communication,
education, and sharing of dental information.
The Armed Forces, Department of Veterans Affairs,
and many states require that identifying markings be
placed on removable dental prostheses (Fig. 19-8). The
American Dental Association also supports this policy.
It is an attempt to provide a basis for identiﬁ
cation
among the substantial population of completely or par-
tially edentulous individuals in the United States.
Identifying markings in dental prostheses are impor-
tant because even if dental records of an edentulous
person can be obtained, they may not reﬂ
ect the current
status of the ridges and alveolar bone. Commonly used
information for identifying marking in removable
dental prostheses includes the person’s name, driver’s
license number, and/or other identiﬁ
cation number.
Even when a suspected identiﬁ
cation is achieved,
it may still be difﬁ
cult to secure antemortem dental
records. The family or acquaintances of the victim may
not know where dental treatment was sought. Review-
ing the victim’s canceled bank checks or medical
deductions on tax records may be helpful in locating
antemortem dental records in such cases.
Although records obtained from institutional or
governmental dental facilities routinely indicate all
restored teeth, this is not true of charts forwarded from
private dentists. In these instances, previously restored
teeth often are not charted unless the current dentist
intends to re-treat them. Therefore, in these records,
the antemortem radiographs and progress notes
become the principal sources for dental information.
Unfortunately, the nomenclature associated with
dental charting systems is not standardized (Table
19-2). In 1984, the American Dental Association
Fig. 19-7
The combination of decayed, missing, and ﬁ
lled
teeth, along with unique anatomic and pathologic ﬁ
ndings,
provides the database for comparison in a dental
identiﬁ
cation. Note the microdont in the maxillary left
quadrant.
Fig. 19-8
Denture identiﬁ
cation is accomplished by
inserting a typed name or code number (i.e., Social Security
number, hospital patient number) in an area of the denture
that will not interfere with the aesthetics of the prosthesis.
This procedure is performed in the laboratory during the ﬁ
nal
acrylic pack. Information can also be engraved in the
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adopted the Universal Tooth Numbering System. All
insurance companies, the Armed Forces, dental
schools, and most dentists in the United States now use
this system. It should be used in all forensic dental
cases.
In the Universal Numbering System, a consecutive
number from 1 to 32 is assigned to the adult dentition.
It begins with the maxillary right third molar and ends
with the mandibular right third molar. The deciduous
dentition is identiﬁ
ed by letters from A to T, beginning
with the maxillary right deciduous second molar and
ending with the mandibular right deciduous second
molar. Thus the quadrants are identiﬁ
ed in a clockwise
direction, beginning with the maxillary right.
Other tooth numbering methods include the Zsig-
mondy/Palmer System and the Federation Dentaire
Internationale (FDI) Two-Digit System. Each uses a dif-
ferent coding technique to identify dental quadrants
and speciﬁ
c teeth.
The Zsigmondy/Palmer System stresses the ana-
tomic likeness of the eight tooth types in each sym-
bolically identiﬁ
ed dental quadrant. Homologous
permanent teeth are assigned the same number from
1 to 8. Deciduous teeth are assigned letters
A

through
E.
The FDI Two-Digit System is endorsed by the World
Health Organization (WHO) and is used in most devel-
oped countries, except the United States. The ﬁ
rst digit
represents the quadrant. Quadrants 1 to 4 are assigned
for permanent teeth; 5 to 8 represent quadrants for
the primary dentition. As in the Universal Numbering
System, the quadrants are identiﬁ
ed in a clock-
wise direction, beginning with the maxillary right. The
second digit designates the permanent tooth type from
1 to 8, or deciduous tooth type from 1 to 5.
Thus in the Universal Numbering System, tooth 12
is the maxillary left ﬁ
rst bicuspid. In the FDI Two-Digit
System, tooth 12 (one-two) is the maxillary right lateral
incisor. In the Zsigmondy/Palmer System, all lateral
incisors are designated with a No. 2 code. The position
of a speciﬁ
c No. 2 tooth is diagrammatically indicated
by a symbolic quadrant.
Unless the forensic dentist knows which system has
been used to encode the teeth in the antemortem
record, all teeth should be referred to by their actual
names. This method will prevent errors because all
dentists use the same anatomic nomenclature when
referring to individual teeth.
Dental identiﬁ
cation problems may be further com-
pounded because dental radiographs can be mounted
and viewed from right to left or vice versa. Intraoral
radiographic duplicating ﬁ
lm does not contain a raised
dot to assist the dentist in orienting the ﬁ
lm for mount-
ing. The lack of this orienting device can lead to
transposition of dental evidence and potential misiden-
tiﬁ
cation based on an incorrect comparison. Panoramic
radiographic duplicating ﬁ
lm, however, does contain a
series of notches on one side to indicate that the ﬁ
lm
is not an original.
With the advent of aesthetic materials for posterior
restorations and the reduction in the incidence of
caries, it may be difﬁ
cult for the forensic dentist to
determine whether restorations are present by simple
visual assessment of the teeth. In addition, the postmor-
tem dental evaluation is often performed in an autopsy
room, temporary morgue, or funeral home. In these
locations, proper lighting and access to dental instru-
ments, which can facilitate analysis of the oral
structures, are not readily available for detailed
examination.
Often, there are additional demands for immediacy
in providing a coroner, ME, or other legal agent with
the results of a dental identiﬁ
cation. These demands
further compound the forensic dentist’s technical and
Table

19-2
Dental Numbering Systems
P
ERMANENT
T
EETH
Maxillary Right
Mandibular Right
Maxillary Left
Mandibular Left
UNIVERSAL NUMBERING SYSTEM
1 2 3 4 5 6 7 8 910111213141516
32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17
ZSIGMONDY/PALMER SYSTEM
87654321 12345678
87654321 12345678
FEDERATION DENTAIRE INTERNATIONALE
TWO-DIGIT SYSTEM
18 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28
48 47 46 45 44 43 42 41 31 32 33 34 35 36 37 38
D
ECIDUOUS
T
EETH
UNIVERSAL NUMBERING SYSTEM
ABCDE F GHI J
TSRQPONMLK
ALTERNATE UNIVERSAL NUMBERING SYSTEM
4D 5D 6D 7D 8D 9D 10D 11D 12D 13D
29D 28D 27D 26D 25D 24D 23D 22D 21D 20D
ZSIGMONDY/PALMER SYSTEM
E DCBA ABCDE
E DCBA ABCDE
FEDERATION DENTAIRE INTERNATIONALE
TWO-DIGIT SYSTEM
55 54 53 52 51 61 62 63 64 65
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stress-related problems while performing the tasks
related to this discipline. Because of the previous
caveats, the forensic dentist should prepare an equip-
ment kit (Box 19-1). The kit should be portable, con-
taining instruments and supplies speciﬁ
cally required
for the performance of dental procedures in an autopsy
room environment.
GUIDELINES FOR DENTAL IDENTIFICATION
Although dental information can support the identiﬁ
-
cation of a visually recognizable body, identiﬁ
cation of
dental remains is especially helpful when a decedent
is skeletonized, decomposed, burned, or dismembered.
Because each of these forensic situations presents dif-
ferent technical problems to the dentist, Body Identiﬁ
-
cation Guidelines have been established by the
American Board of Forensic Odontology (ABFO). The
purpose of delineating these criteria is to assist dentists
in comparing antemortem and postmortem dental
information. Furthermore, the possibility of misidenti-
ﬁ
cation is reduced in both routine and mass-disaster
cases.
Under the Body Identiﬁ
cation Guidelines, provi-
sions are made for the following:
●
Examination of the postmortem dental remains in
compliance with infection control and Occupa-
tional Safety and Health Administration (OSHA)
requirements
●
Examination of antemortem dental records
●
Comparison of all dental and paradental information
from the two databases
●
Development of a written report listing conclusions
and an opinion regarding the strength of the identi-
ﬁ
cation, for example positive, presumptive, in-
sufﬁ
cient, or exculpatory (Exculpatory evidence is
favorable to the defendant in a criminal trial, clear-
ing the defendant of guilt.)
P
OSTMORTEM
E
XAMINATION
The postmortem dental evidence is gathered by photo-
graphic, radiographic, and charting techniques. All
records should include the case number, date, demo-
graphic and anthropologic information, the name of
the authority that is requesting the dental examination,
the location of the examination, and the name of the
examining dentist.
Photographs should be taken of full head and face
views. Images of the occlusal planes of both dental
arches and individual views of unusual pathologic or
restorative ﬁ
ndings are also obtained. A single-lens
reﬂ
ex (SLR), 35-mm, ﬁ
lm-based or digital camera and
appropriate electronic ﬂ
ash and lens systems for close-
up photography should be used. Routinely, both color
and black-and-white exposures are recommended for
use in each case.
Dental impressions and jaw resection may also be
required after the initial full head photographs have
been obtained. If requested by the coroner or ME, then
the dental specimens from the autopsy may have to be
retained and preserved in a 10% formalin solution.
The guidelines for body identiﬁ
cation recognize that
the dentist and dental auxiliary personnel involved in
performing forensic dental procedures do so at the
request and direction of a legal authority, such as a
coroner or ME. Therefore, it is only with the permission
of these individuals that techniques involving postmor-
tem facial dissection or jaw resection are performed
by the forensic dentist to achieve complete access to
dental tissues.
These measures are used most often in decomposed,
dismembered, or incinerated bodies to make postmor-
tem dental charting and radiographic examination
easier. Resection or soft tissue dissection may be neces-
sary in visually recognizable bodies when the oral
cavity is inaccessible because of rigor mortis.
When the jaws are removed with a reciprocating
(Stryker) saw or osteotome and mallet, a Le Fort I frac-
ture of the maxilla is created. The dissection instru-
ments are placed above the inferior nasal spine and
malar processes to ensure that the apices of the maxil-
lary teeth are not transected. Similarly, if the mandible
is not removed by disarticulation, then cuts into the
mandibular rami should be high enough to prevent
damage to impacted third molars.
While obtaining postmortem radiographic evidence,
the forensic dentist may encounter technical obstacles
Box
19-1
Suggested Instrument Kit for
Forensic Identiﬁ
cation
Dental explorers Photographic mirrors
Dental mirrors SLR ﬁ
lm-based camera
Periodontal probes Digital camera
Bite blocks Photographic ﬁ
lm, digital
Tissue scissors memory card
Osteotome Radiographic ﬁ
lm and digital
Rubber air/water syringe sensors
Cotton swabs Rubber, latex, and nitrile gloves
Gauze Tissue forceps
Flashlight or headlamp Tissue clamp
Specimen containers Tongue clamp
Scalpels and blades Disclosing solution
Cheek retractors Stryker saw
ABFO No. 2 ruler Writing instruments
Bone mallet Case labels
Appropriate charts
Masks and HEPA ﬁ
lters
ABFO
, American Board of Forensic Odontology;
SLR
, single-lens reﬂ ex;
HEPA
, high-efﬁ ciency particulate air.http://dentalebooks.com

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that need to be addressed. It often is difﬁ
cult to place
intraoral radiographic ﬁ
lm or digital radiographic
sensors securely against the mandible or maxilla of a
deceased individual. A modiﬁ
ed Rinn XCP self-sup-
porting ﬁ
lm holder, which does not require active par-
ticipation from the examinee, has been developed for
postmortem identiﬁ
cation. Because all dental evidence
may eventually be required to be relinquished in court,
the use of double-pack intraoral radiographs permits
the forensic dentist to retain a set of ﬁ
lms. Digital radio-
graphic exposure and storage of images precludes this
problem.
When the jaws cannot be resected, postmortem
changes in rigor mortis cases and in bodies that are
partially decomposed may prevent the positioning
of intraoral periapical radiographic ﬁ
lms or digital
sensors. Occlusal ﬁ
lms, 5
×
7 lateral plates, and pan-
oramic radiographs are often used in these situations.
Additionally, charting of dental evidence in fourth-
degree burn cases, in which charring of soft tissues
results in contraction of the muscles of mastication,
may preclude the placement of these devices. With the
coroner or ME’s permission, the entire skull can be
removed from the rest of the remains and placed in a
panoramic radiographic machine.
Fifth-degree burn cases result in cremation (some-
times referred to as
cremains
). Dental evidence may
be lost or compromised in these cases as temperatures
range between 870° and 980° C (1600° and 1800° F).
Most cremated skeletal and dental remains are struc-
turally recognizable, and it is only the processing of
these structures in commercial crematoria that creates
the ash most associated with this process. Cremated
bones and teeth are fragile, crumble easily, and require
extreme care when handled.
Fragmentation of dental structures in dismember-
ment cases and total loss of soft tissues in skeletonized
remains necessitate alterations in routine radiation
exposure settings. Generally, when radiographs of this
type of material are taken, 10-mA and 65-kVp expo-
sure settings are used. Because there is little or no soft
tissue, standard exposure times or impulse settings are
halved to prevent overexposure of the radiograph.
The maxilla can be split along the midsagittal suture,
and each half can be placed horizontally on an occlusal
ﬁ
lm. This projection can be used to simulate antemor-
tem panoramic radiographs or bite-wing views. Similar
exposures can be obtained from the mandible by
mounting the jaw on the edge of a table or bracket tray
and placing an occlusal ﬁ
lm under the supporting half.
Exposures of the opposite side of the arch are made
by simply ﬂ
ipping the mandible and repeating the
procedure.
The charting (odontogram) of the postmortem den-
tition should provide for situations in which teeth are
missing after death. If such a discrepancy remains
unexplained, then it may preclude the positive identi-
ﬁ
cation of the body. Scavenging animals or poor inves-
tigation of a crime or disaster scene can cause
postmortem loss of teeth. Environmental conditions at
or around the time of death, such as tidal action in a
saltwater drowning, can also contribute to perimortem
loss of teeth. When teeth are lost in this manner, the
crest of the alveolar bone remains intact. In addition,
there is no reossiﬁ
cation of the socket (Fig. 19-9). This
pattern is inconsistent with what is observed after
extraction of a tooth.
Postmortem tooth loss is associated with decom-
position of the periodontal ligament. Thus the tooth
simply falls out when the body is moved by animals or
during crime scene recovery efforts. When this phe-
nomenon occurs and is recognized, the charting
abbreviation MPPA (missing postmortem, present
antemortem) is used in that tooth’s position in the
dental odontogram.
A
NTEMORTEM
R
ECORD
E
XAMINATION
Antemortem records are usually obtained directly
from the police, coroner, or ME. Before accepting this
evidence, the forensic dentist should determine that
the records indicate the name of the person to be iden-
tiﬁ
ed and the name and address of the submitting
dentist. In addition, most jurisdictions require an evi-
dence transfer document to be signed. This form indi-
cates that the continuity of evidence has been
maintained and speciﬁ
es who is currently in posses-
sion of the material.
Several antemortem records of the same person
may be submitted from different dental practices for
Fig. 19-9
Postmortem tooth loss results in an alveolar
socket with unfractured margins and no reossiﬁ
cation. In this
example, teeth Nos. 7, 9, 10, and 11 represent postmortem
tooth loss. Tooth No. 2 is a result of antemortem loss. Teeth
Nos. 4, 8, and 13 were found near the body and reinserted
into their respective sockets.http://dentalebooks.com

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comparison with postmortem dental evidence. It is not
uncommon for the general dental records of a dece-
dent and those obtained from the oral and maxillofa-
cial surgeon, endodontist, orthodontist, and other
dental specialty practices to be forwarded for forensic
analysis. Even if only one antemortem record is sent,
then the forensic dentist should rechart all information
obtained from the radiographs, progress notes, and
odontograms on a standardized form. This record
should be identical to the one on which the postmor-
tem information was documented. All of this material
should be appropriately labeled as the antemortem
record.
The use of computer software, such as the WinID3
program, in mass-disaster situations accomplishes this
same principle by entering all antemortem and post-
mortem dental information into the respective identi-
ﬁ
cation program. Besides making the comparison of
records easier to manage, the creation of similar ante-
mortem and postmortem analytic material is easier to
present in court.
C
OMPARISON

OF
A
NTEMORTEM

AND
P
OSTMORTEM

R
ECORDS

AND
W
RITTEN
C
ONCLUSIONS
After all dental information has been collected from
the antemortem and postmortem databases, it is com-
pared for similarities and discrepancies. Comparison
of dental evidence is unique among the techniques
used to identify a decedent. A positive identiﬁ
cation
may still be established, even when some reconcilable
discrepancies are observed.
Furthermore, the forensic dentist must routinely
rely on the belief that antemortem records are truly
those of the person they are purported to represent.
The latter problem is best exempliﬁ
ed by the contro-
versy associated with the antemortem dental records
used to identify the bodies of Adolph Hitler and Eva
Braun. Until recently, there was uncertainty concern-
ing the reliability of those records. This uncertainty was
based on the possibility that the records had been falsi-
ﬁ
ed to encourage the misidentiﬁ
cation of Hitler and
his wife.
The case demonstrated in Fig. 19-10 shows that all
teeth, restorations, and anatomic structures are identi-
cal, except that deciduous tooth K is still present in the
antemortem radiograph. Tooth No. 20 is erupted in the
postmortem ﬁ
lm. This difference could not support a
positive identiﬁ
cation if it were a component of ﬁ
nger-
print or DNA evidence. The facts that the deciduous
tooth has exfoliated and the permanent tooth erupted
before death are acceptable discrepancies in compa-
rable dental evidence.
Comparison of dental evidence is often complicated
by the quality of the evidence submitted. The physical
status of the postmortem dental material can be
compromised when teeth have fractured or are avulsed
secondary to trauma. Often, only fragments of the jaws
may be presented for comparison, and there may have
been postmortem loss of teeth.
Dental restorations can be separated from the teeth
or melted in a ﬁ
re. Acrylic restorative material melts in
temperatures less than 540° C (1000° F), gold and
amalgam melt at 870° C (1600° F), and porcelain
can withstand temperatures greater than 1100° C
(2010° F). In addition, extreme temperature in a ﬁ
re
can cause the teeth to explode or appear shrunken.
Although the principal role of the dentition of a ﬁ
re
victim is to provide data for identiﬁ
cation, studies indi-
cate that morphologic and microscopic tissue altera-
tions of the teeth may assist forensic scientists, such as
arson investigators, in determining temperature and
duration of exposure to ﬁ
re.
The problems associated with incomplete antemor-
tem records are compounded when radiographs are of
poor quality as a result of exposure and developing
errors. Mischarted information in the antemortem
record can also be considered a reconcilable discrep-
ancy. This error often occurs when teeth have been
extracted and adjoining teeth have moved into the
position of the extraction site. Restorations may be
inadvertently indicated on the wrong tooth when the
clinician is charting or entering information into the
progress record.
Regardless of the difﬁ
culties encountered when
dental evidence is compared, the ﬁ
nal conclusions
must be based on an objective analysis of the data pre-
sented. The conclusions must be supportable and
defensible when they are presented under oath in a
court of law.
DENTISTRY’S ROLE IN MULTIPLE (MASS)
FATALITY INCIDENT IDENTIFICATION
The term
multiple (mass) fatality incident
(MFI) evokes
images of a chaotic event, initiated by a destructive
Fig. 19-10
Antemortem and postmortem radiographs
demonstrating the ﬂ
uid, changing nature of dental
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force, which results in numerous deaths necessitating
identiﬁ
cation. These mass disaster events can be clas-
siﬁ
ed in one of three ways:
1. Natural
2. Accidental
3. Criminal (e.g., serial homicide, mass suicide, acts
of terrorism)
Each type of MFI event results in the death of
numerous victims. However, the problems faced by the
forensic dental team responsible for identifying the
decedents may vary, depending on the type of mass
disaster.
N
ATURAL
D
ISASTERS
Natural mass disasters include earthquakes, tornadoes,
hurricanes, volcanic eruptions, ﬁ
re storms, tsunamis,
and ﬂ
oods. These may occur over relatively short
periods or may be protracted over days or weeks.
Victims may be scattered throughout broad areas, ex-
tending for miles. In addition, many victims in natural
MFI situations may be unknowns who cannot be pre-
sumptively identiﬁ
ed. Several countries or states can be
affected, as in the 2004 Indian Ocean tsunami event.
Transients, homeless individuals, and tourists who
are visiting an area involved in a natural MFI are often
difﬁ
cult to identify.
In a natural disaster, the principal problem for the
dental identiﬁ
cation team is that the environmental
infrastructure is often compromised. For example,
after Hurricane Katrina, medical and dental ofﬁ
ces
and hospital facilities containing antemortem records
had been destroyed by tornado activity and ﬂ
ooding.
In addition, communication lines and roads were
damaged, preventing the retrieval of most available
antemortem records. All of these factors delayed or
precluded the prompt identiﬁ
cation of many victims.
A
CCIDENTS
Accidental MFI events are most often associated with
transportation accidents, ﬁ
res, industrial and mining
accidents, and military accidents. These situations
usually occur over short time periods and are associ-
ated with closed populations (e.g., airplane, bus, or
train passengers; mine or factory workers).
Airlines maintain passenger logs of individuals who
are registered on speciﬁ
c ﬂ
ights. However, it has been
estimated that at any given time as many as 10% of air
travelers may purchase their tickets using an alias for
identiﬁ
cation. The mining company, mill, or industrial
plant can document those who have reported for work.
In these examples, the victims of accidents should logi-
cally come from the closed population of employees
on that shift. Therefore, antemortem records are ﬁ
rst
solicited from the families and health care providers
of these individuals. Another source of medical and
dental records in these cases is the occupational
health ﬁ
les of workers, which are maintained by the
employer.
Problems can be associated with the identiﬁ
cation
of victims of industrial and military accidents because
these populations may be of similar age, sex, and eth-
nicity. Commonly, individuals working in industrial or
military settings wear similar clothing. Thus military
uniforms and protective industrial clothing decrease
the potential use of personal recognition as an identi-
ﬁ
cation aid in these cases.
C
RIMINAL
D
ISASTERS
Unlike natural and accidental MFIs, criminal mass
disasters involving death may occur over extremely
long time periods and wide ranges of territory (e.g.,
different cities or states). This was the pattern of the
rapes and murders committed by Ted Bundy, whose
victims included young women residing in states from
Washington to Florida from 1974 to 1978. The remains
of the victims of serial killers can be hidden, as in the
Green River homicides in the Paciﬁ
c Northwest and
the murders of young men committed by John Wayne
Gacey in Chicago. Dismemberment and mutilation of
victims is exempliﬁ
ed by the Jeffrey Dahmer case.
Dental structures in these situations may not always be
available for postmortem review.
Law enforcement agencies are often unaware of the
victims of serial killers from other jurisdictions. Each
agency may be investigating an individual homicide
without recognizing a pattern of broader criminal
involvement. Until the development of the FBI-NCIC
computer registry, coordinated efforts at identiﬁ
cation
were hampered.
The rise in national and international terrorism in
the twenty-ﬁ
rst century has changed the paradigm
associated with the traditional participation of the
dental profession in an MFI setting. Until recently,
forensic odontologists and other dental professionals
were simply tasked as experts in the identiﬁ
cation of
the decedents. Currently, there are ongoing efforts
within organized dentistry to develop effective
responses to acts of bioterrorism. These efforts are
exempliﬁ
ed by the profession’s encouragement of leg-
islation authorizing dental professionals, in federally
declared emergencies, to perform various procedures
that are routinely not within the practice of the profes-
sion. Under these provisions, dentists registered and
trained in emerging medical diseases, bioterrorism,
and emergency medical care would be indemniﬁ
ed for
actions taken in the performance of these services.
Acts of terrorism may include exposure to biologic
agents, chemical toxins, and the discharge of nuclear
devices. Thus the dentist involved in MFI recovery and
identiﬁ
cation after an act of terrorism may additionally http://dentalebooks.com

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be required to assist medical workers in providing care
for the injured. In these scenarios, dentists must con-
sider their personal safety and that of their families.
Civil defense and emergency preparedness organiza-
tional plans are beginning to include dentists among
those charged with triaging the injured. Additional
roles for the dental professional in future acts of bioter-
rorism and nuclear or chemical attack include provid-
ing ﬁ
rst aid care and immunizations to injured and
exposed survivors.
R
ESPONSIBILITIES
In the United States, the National Response Plan (NRP)
provides a comprehensive, risk-based, emergency
management plan to respond to any hazardous event.
The NRP establishes guidelines to manage domestic
response to radiological, technical, natural, or terrorist
incidents by developing 12 emergency services func-
tions and delineating the agencies charged with per-
forming speciﬁ
c tasks in a response.
As part of the presidential directive that created the
U.S. Department of Homeland Security after the Sep-
tember 11, 2001 terrorist attacks, the National Inci-
dent Management System (NIMS) was also developed.
The overall objective of this system is coordination of
governmental agencies, nongovernmental organiza-
tions, and the private sector in the resolution of nation-
ally signiﬁ
cant incidents.
Regardless of the type of MFI, the local coroner or
ME is ultimately responsible for performing the autop-
sies and identifying the victims. In accidents that
involve modes of public transportation, the National
Transportation Safety Board (NTSB) is empowered to
investigate and determine the cause of the crash. Other
agencies with jurisdiction at a disaster scene may rep-
resent local police, public safety, and funeral home
personnel. In addition, there may be representatives of
the Federal Emergency Management Agency (FEMA),
members of the FBI ﬁ
ngerprint team, members of the
clergy, or personnel with the Disaster Mortuary Opera-
tional Response Team (DMORT) or Disaster Medical
Assistance Team (DMAT).
Although DMORT and DMAT units include dental
personnel, these teams may not be mobilized in all
MFIs. In these situations, forensic dentists and support
staff responsible for identiﬁ
cation or care of the injured
should also be organized into teams. Several state
dental associations (including California, Washington,
Michigan, New York, South Carolina, Nevada, and
Iowa) have developed, supplied, and trained such
groups in preparation for emergencies requiring their
expertise. Training sessions include mock MFI exer-
cises. These drills can prepare the dental team members
for dealing with the technical problems of cases involv-
ing multiple fatalities.
In addition, training sessions can be used to counsel
the dental team and to inform members of the post-
traumatic stress often associated with this type of foren-
sic work. This delayed stress is a result of the sensory
and psychologic insults encountered by the dentist,
hygienist, or dental assistant who is dealing with human
death on a large scale.
During an MFI the National Disaster Medical System
(NDMS), under its emergency support functions, is
authorized and has responsibility to assist local authori-
ties by establishing temporary morgue facilities; identify-
ing victims using scientiﬁ
c techniques; and processing,
preparing, and disposing of victims’ remains to families,
funeral homes, or proper legal representatives. This
mission has been accomplished through the develop-
ment of 10 regional DMORTs administered by the
Department of Health and Human Services. Each
DMORT is composed of funeral directors, MEs, coro-
ners, pathologists, forensic anthropologists, medical
records technicians and transcribers, ﬁ
ngerprint special-
ists, forensic dentists, dental hygienists, dental assistants,
radiology technicians, mental health specialists, com-
puter professionals, administrative support staff, and
security and investigative personnel. These individuals
are private citizens, each with a speciﬁ
c ﬁ
eld of expertise,
who are mobilized during a disaster. The licensure and
certiﬁ
cation of the DMORT members is recognized by all
states because they are considered temporary federal
employees during the emergency response.
Working with the authorization of the coroner or
ME, a local dental disaster team or dental component
of a DMORT is responsible for antemortem record
assembly and interpretation, postmortem physical and
dental radiographic examination, and ﬁ
nal compari-
son of dental information. These are the same princi-
ples used to establish an individual identiﬁ
cation. Yet,
when numerous victims need to be identiﬁ
ed in a
short time, problems of identiﬁ
cation are compounded
exponentially.
Dividing the team into subsections responsible for
each of the three identiﬁ
cation domains permits a divi-
sion of labor among the team members. This division
reduces errors in identiﬁ
cation, in that speciﬁ
c tasks in
the identiﬁ
cation process are assigned to separate sub-
sections. A chain of command should be established,
and the team leader of each shift should be directly
responsible to the coroner or ME. This person is the
only member of the team authorized to release the
results of the dental identiﬁ
cation process to appropri-
ate investigative agencies.
T
ECHNOLOGIC
A
IDS

IN
M
ULTIPLE
F
ATALITY

I
NCIDENT
A
NALYSIS
Advances in photographic, radiographic, and computer
technology have provided the forensic dental team http://dentalebooks.com

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with additional resources to enable recovery, docu-
mentation, storage, and comparison of forensic dental
evidence in MFIs, as well as in other situations requir-
ing forensic dental expertise (e.g., bite mark analysis,
documentation of human abuse). Among these
advances are developments in the following:
●

Digital photography.
The basic digital camera used
for forensic evidence documentation should include
a through-the-lens (TTL), light-metering, SLR, 35-
mm digital camera body with interchangeable lenses
or an adjustable lens capable of normal range (30
to 50 mm) to macro range (90 to 100 mm) focal
length. A removable ﬂ
ash memory card with ade-
quate storage capacity is also required. The Scientiﬁ
c
Working Group on Imaging Technology (SWGIT)
imaging guidelines provide the forensic odonto-
logist with information regarding the limitations and
parameters imposed by the judicial system regarding
the manipulation and presentation of digital photo-
graphic evidence.
●

Digital radiography
(
DR) equipment.
Electroni-
cally generated and stored radiographic imaging can
be accomplished by the following:
●
Scanning normally processed radiographic ﬁ
lm
into a computer
●
Using a phosphor substrate shaped and used like
radiographic ﬁ
lm to expose and scan radiographic
information into the computer by a special propri-
etary device
●
Using a sensor sized and shaped like a radio-
graphic ﬁ
lm that is made of a scintillation
screen and a charge-coupled device (CCD) or
complementary metal oxide semiconductor
(CMOS)
●

Direct digital radiography (DDR).
When ener-
gized by radiation, this device creates a direct image
on the pixels of its CCD or CMOS. This radiographic
image is then sent to a computer through wire or
wireless technology. Thus because of its ability to
save time, DDR technology is recommended for
clinical and forensic casework. Additionally, DDR
procedures reduce exposure times by requiring 90%
less radiation than that required to expose a standard
type D ﬁ
lm radiograph and 50% less radiation than
that required in exposure of type E ﬁ
lm radiographs.
The parameters by which the quality of a radiograph
is evaluated include resolution and contrast sensitiv-
ity. Image resolution describes the detail an image
holds. In ﬁ
lm-based radiographs, this is expressed as
a function of how close lines can be to each other and
still be visibly distinguished. Digital imaging mea-
sures resolution as pixel counts. The contrast sensi-
tivity is a measure of the smallest percentage change
in an object’s base thickness (density) that can be
detected in a radiograph. The high resolution of the
image produced by the DDR sensor is one of its most
advantageous properties.
●

Cone-beam computed tomography (CBCT).

CBCT provides a 3D imaging modality to collect a
complete maxillomandibular-facial anatomic volume
of data. Computer software can be used to analyze
the obtained image, and the diagnostic interpreta-
tion provided can be used for treatment planning,
assessment of pathologic conditions, and evaluation
of dental implants. Application of CBCT in forensic
dental situations can overcome intraoral access prob-
lems with some specimens (e.g., fourth-degree burn
cases).
●

Portable hand-held x-ray generation devices
(e.g., Nomad manufactured by Aribex, and
MinXray HF70DUL Type A).
The forensic dentist
is able to expose ﬁ
lm or digital radiographs quickly
and effortlessly with a battery-powered unit that can
be carried to the body on the gurney in the morgue.
Additional applications for the use of these devices
in the dental ofﬁ
ce include exposure of radiographs
on pediatric or sedated patients or those having end-
odontic therapy.
●

X-ray ﬂ
uorescence
(
XRF) methodology.
As dis-
cussed previously, analysis of dental materials in cre-
mation and other difﬁ
cult forensic identiﬁ
cation
cases may be facilitated by analysis of specimens
with this technology.
●

Computer software technology.
The advent of
computer software has assisted MFI dental identiﬁ
-
cation teams in ﬁ
ling, storing, sorting, and matching
bits of antemortem and postmortem information.
Computer assistance has proved beneﬁ
cial in disas-
ters involving hundreds of victims. Commonly used
programs include the following:
●
The FBI-NCIC program, based on the California
Dental Identiﬁ
cation System, developed by Dr.
Norman Sperber and Dr. Robert Siegel (San
Diego, Calif.)
●
CAPMI-4 (Computer-Assisted Postmortem identi-
ﬁ
cation—version 4.0), developed by Dr. Lewis
Lorton of the U.S. Army Institute of Dental Re-
search and maintained by the Armed Forces Insti-
tute of Pathology (It was ﬁ
rst used in 1985 in
support of the Arrow Air-U.S. military charter avia-
tion runway accident in Gander, Newfoundland.)
●
WinID3 dental comparison software, developed
by Dr. James McGivney (St. Louis, Mo.) (Bridged
with the Dexis DR program, WinID3 facilitated
comparison of antemortem and postmortem
dental records in Hurricane Katrina recovery
efforts and various transportation and industrial
MFI events.)
Each of these computer software systems is user
friendly, can be run on readily available and accessible http://dentalebooks.com

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hardware, is automated and capable of networking,
and relies on objective data entry. The use of these
computer software programs in MFI situations reduces
the time and effort that had to be expended in past
events. Before their use, an examiner in the dental
identiﬁ
cation team walked along tables with a post-
mortem record comparing the dental data and radio-
graphs at each station containing an antemortem
record.
Despite the fact that these technologic advances
have facilitated forensic casework, the caveat for the
forensic dentist remains that identiﬁ
cation is the result
of human thought processes and not the highly techni-
cal supportive procedures that provide the material
being evaluated. To arrive at correct comparative con-
clusions based on the evidence, individual dental
team members must evaluate the computer-generated
matches for deﬁ
nitive identiﬁ
cation.
BITE PATTERN EVIDENCE
BASIC PRINCIPLES
A bite mark is a patterned injury or surface disturbance
produced by teeth on an individual’s skin or inanimate
object. Analysis of this type of evidence presumes that
the dentition of the biter (animal or human) is unique
and can be compared scientiﬁ
cally and related to the
resultant pattern mark on the surface of a victim or
object. Although studies indicate the uniqueness of the
human dentition, the debate among forensic odontolo-
gists relates to the ability of these unique features to be
transferred into skin, which is acknowledged as a poor
impression material.
Despite the controversies related to this type of
forensic evidence, 70% of respondents to a survey
among specialists in the ﬁ
eld indicated that trained
forensic odontologists could positively identify a suspect
from a bite mark on skin. Thus issues related to the
validity, reliability, and admissibility of bite mark evi-
dence continues to rest with the judicial system and its
various rules pertaining to the introduction of scientiﬁ
c
evidence in court.
Victims of mammalian animal bites account for
most bite injuries reported annually. Bite-related inju-
ries represent approximately 1% of all hospital emer-
gency visits that require medical attention. Of these,
nearly 370,000 were associated with dog bites in 2001.
The second and third most likely mammalian biters
are cats and humans, respectively. Each represents
from 5% to 20% of cases reporting to urban emergency
rooms.
As the habitats of wild animals in North America
continue to recede, humans are more likely to come
in contact with these dangerous carnivores. This is
reﬂ
ected in the increase in attacks on humans by
mountain lions and brown, black, and grizzly bears,
resulting in biting injuries or death from biting and
clawing.
Animal bites may be observed postmortem when a
body has not been buried or discovered quickly. Com-
monly, insect bites are made by ants and roaches,
which leave pattern injuries that can be mistakenly
interpreted as antemortem trauma (Fig. 19-11). Post-
mortem bites from rats and scavenging dogs and cats
are often avulsive and of narrower or smaller diameter
than human bites.
Injuries caused by human bites are routinely related
to either aggressive or sexual behavior. Ironically, it is
not uncommon for the perpetrator of an aggressive act
to be bitten by the victim (as a means of self-defense).
In children, biting is a form of expression that occurs
when verbal communication fails. Biting injuries in
children can result from playground altercations or
sports competition. They are common among children
who attend day care centers.
Self-inﬂ
icted bites are observed in
Lesch-Nyhan
syndrome
. This syndrome is an X-linked, recessively
transmitted disease manifesting insensitivity to pain
and self-mutilation (among other signs) by chewing
away the lips. This disease is rare, and self-inﬂ
icted
bites are more commonly seen in adults and children
who are victims of physical abuse or sexual assault.
These individuals may bite their own forearms or
hands in anguish or to prevent themselves from crying
out while they are being traumatized.
Injuries resulting from animal or human bites may
become septic or may progress to systemic infections.
Secondary bacterial infections are more commonly
Fig. 19-11
Insect bites on the skin that mimic the pattern
injury associated with bite mark trauma. In a decedent, this
pattern may additionally be mistakenly interpreted as
antemortem trauma.
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associated with human bites than with animal
bites, although 30% to 50% of cat bites become infected
because bacteria are injected into the puncture wounds
inﬂ
icted by their needlelike teeth. Infectious complica-
tions include tetanus, tuberculosis, syphilis, actinomy-
cosis, cat-scratch disease (caused by
Bartonella henselae
),
and those infectious complications related to strepto-
coccal and staphylococcal organisms. Anaerobic organ-
isms associated with bite injuries may eventually result
in complications such as septic arthritis, tenosynovitis,
meningitis, and infections of the lymphatic system.
Viral complications, including hepatitis B virus,
herpes simplex, and cytomegalovirus, have resulted
from transmission through human bites. The human
immunodeﬁ
ciency virus (HIV) can also potentially be
transmitted through the exchange of blood and saliva
in a bite injury. The risk of seroconversion from this
mode of HIV transmission, however, is believed to be
extremely low. An immunocompromised individual
who is already infected with the HIV virus is at
increased risk of secondary infection when bitten by a
cat.
Rabies
is the most serious infectious complication
that results from mammalian animal bites. It is often
necessary to identify the speciﬁ
c offending animal for
rabies control or potential litigation. This identiﬁ
cation
is not routinely done by matching the animal’s teeth to
the pattern injury. When humans bite, however, the
marks left in injured tissue or inanimate objects are
often analyzed and compared with the alleged perpe-
trator’s dentition.
HISTORICAL AND LEGAL ISSUES
References to biting during acts of passion or aggres-
sion can be found in the
Bible, Kama Sutra
, and Old
English law. In colonial America, the Reverend George
Burroughs was charged with the crime of biting one of
the women accused of witchcraft during the Salem,
Massachusetts, witch hunt incidents in 1692. He was
hanged for this offense. Bite mark evidence was pro-
vided in expert dental testimony in the 1870 Ohio trial
of Ansil L. Robinson, who was accused of murdering
his mistress. Although the defendant was eventually
acquitted, the expert dental presentation by Dr.
Jonathan Taft became a benchmark for future experts
in the discipline.
The concept of accepting evidence related to the
analysis of patterns created by the dentition was ﬁ
rst
accepted by the appellate level courts of the United
States justice system in 1954. At that time,
Doyle v. State
of Texas
became the ﬁ
rst modern case in which a crimi-
nal conviction was based on evidence relating a sus-
pect’s dentition to pattern marks in an inanimate object
(a piece of cheese). Because of the
Doyle
case, more
than 260 decisions involving bite mark evidence have
been entered into the case law records of the appellate
courts of the United States.
The legal community has recognized tool mark and
ﬁ
ngerprint pattern analysis as scientiﬁ
cally acceptable
forensic disciplines for some time. The evidence pre-
sented by experts in these areas has been accepted in
20% of state courts under the
Frye
standard
(Frye v.
United States)
, and the remaining 80% of state courts
and all federal courts under the Federal Rules of Evi-
dence 702-705. These are special rules dealing with
the admissibility of scientiﬁ
c evidence in the American
judicial system. Thus they are also applicable to bite
mark information.
The
Frye
test had been the standard for scientiﬁ
c
admissibility in most state and federal courts since
1923. The three components of scientiﬁ
c evidence
admissibility that are considered under the
Frye
test
include the following:
1. The scientiﬁ
c principle must be recognizable.
2. The scientiﬁ
c principle must be sufﬁ
ciently
established.
3. The scientiﬁ
c principle must have gained general
acceptance within the scientiﬁ
c discipline to
which it belongs.
Among the three requirements, only the concept of
“general acceptance” must be met to satisfy the
Frye

test of admissibility.
In 1993 the U.S. Supreme Court ruled on the admis-
sibility of scientiﬁ
c evidence in
Daubert v. Merrell Dow
Pharmaceuticals
. It was the Court’s decision in this case
that the general acceptance aspect of the
Frye
test
should no longer be the sole, determining factor used
in considering admissibility of scientiﬁ
c evidence.
Essentially, the Court replaced this principle with one
that stresses scientiﬁ
c validity. This decision removes
the responsibility of determining sound scientiﬁ
c evi-
dence from the scientiﬁ
c community in which it has
gained general acceptance.
Instead, the
Daubert
ruling gives great latitude to the
trial judge in considering the admissibility of scientiﬁ
c
evidence. Trial judges often have limited knowledge of
scientiﬁ
c methodology; however, under
Daubert
they
are required to determine if the weight and admissibil-
ity of expert testimony is not only scientiﬁ
cally valid but
also relevant and germane to the issues in individual
cases. Thus the results of the Supreme Court’s decision
in
Daubert
are to make the judge a “gatekeeper” and
the expert witness a provider of scientiﬁ
cally valid
evidence.
The general acceptance concept is no longer the
sole determinant of admissibility in
Daubert
. It becomes
one of several factors that must be met for scientiﬁ
c
evidence to be admissible. These factors include the
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●
Techniques used must be testable and tested.
●
Peer review and publication of results are not
required but may persuade the judge in admitting
evidence.
●
Standards should be established for evaluation of the
scientiﬁ
c methods and error rates associated with
the techniques used.
●
Consideration is given to acceptance of scientiﬁ
c
principles that have gained general acceptance
within the scientiﬁ
c discipline to which they
belong.
Because it is reasonable to consider the teeth as
cutting or mashing tools, the basis for accepting bite
pattern evidence can be supported on the same scien-
tiﬁ
c principles used to evaluate tool marks. In addition,
studies indicate that, like ﬁ
ngerprints, the human den-
tition is unique for each person. Variations in size,
wear, and fractures; position in the dental arch;
diastemata; and restored surfaces contribute to this
principle.
Thus bite mark evidence is admissible under the
Frye
standard and Federal Rules of Evidence as deter-
mined by the
Daubert
decision. Although some legal
experts believe the Federal Rules of Evidence provide
better guidelines for admissibility decisions, no chal-
lenge to the scientiﬁ
c basis of bite mark evidence has
been successful under either set of standards.
CHARACTERISTICS OF BITE MARKS
To evaluate a pattern mark, its characteristics must
be recognizable and distinguishable. Reasonably, the
mark should be consistent with the face of the instru-
ment from which it was generated. Speciﬁ
c teeth can
create representative patterns that are recognizable.
These individual marks are described as internal char-
acteristics of the entire bite mark. Human incisors
make rectangular marks. Depending on the amount of
attrition observed on the incisal edge of the cuspid, this
surface may be associated with point or triangular pat-
terns. Unlike mandibular bicuspid teeth, which have
a diminutive lingual cusp, maxillary bicuspids often
mark in a pattern that resembles a “ﬁ
gure eight.”
Class characteristics of a human bite mark are
related to the shapes that are created when groups of
teeth from both dental arches are impressed into a
bitten surface. Round, ovoid, or elliptical patterns are
usually observed, but variations may be associated with
tapered, square, and
U
-shaped arches. When only one
arch contacts a surface, a crescent pattern may be
formed. The greatest dimensions of an adult human
bite mark do not usually exceed 4 cm (Fig. 19-12).
Internal and class characteristics of bite patterns are
generated by groups of speciﬁ
c teeth. The dynamics of
occlusion and muscle function must also be accounted
for when variations in internal and class characteristics
of a bite mark are considered. Such variations can be
caused by malocclusion, individual tooth mobility asso-
ciated with periodontal disease, and movement of
facial muscles during biting.
Class II malocclusion can cause the palatal surfaces
of the maxillary anterior teeth, rather than their incisal
edges, to contact the material being bitten. Shieldlike
imprints of the palatal surfaces are generated in the
bite mark rather than the rectangular patterns rou-
tinely associated with these teeth.
Aberrant muscle forces associated with tongue
thrusting can alter the way the teeth contact a bitten
surface. Temporomandibular joint dysfunction (TMD)
can also contribute to variations in bite patterns. TMD
can be associated with midline shifts or inability to
achieve maximum opening while biting.
When bitten, many inanimate objects tend to act
like dental-impression material, retaining the marks of
the teeth. Such cases have involved bite marks in foods,
chewing gum, paper toweling, and a roll of masking
tape. Unlike inanimate material, the skin is a dynamic
tissue that can change after it is injured. Swelling,
caused by the acute inﬂ
ammatory response of the
tissue, can distort and affect the interpretation of the
pattern. Bleeding into the area of a bite mark can mask
the pattern.
The age of an injury is the time elapsed from its
inﬂ
iction to the analysis of the damaged tissue. Reliable
determination of the age of antemortem skin injuries
requires histopathologic and histochemical analysis to
Fig. 19-12
A bite mark pattern demonstrating the internal
and class characteristics associated with impressions made
by the human dentition. An ecchymotic area in the center of
the ovoid pattern is observed, which is not always related to
the sucking action of a sexual bite. Therefore, this ﬁ
nding
should not be overinterpreted to imply sexual intent on the
part of the biter. The impressions made by the teeth of the
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relate the injury to the time of the alleged incident
(Table 19-3). Color changes in the bitten tissue, associ-
ated with the degradation of hemoglobin from lysed
RBCs, can be used only to broadly estimate the time of
occurrence and qualify the age of a bruise as recent or
old. Environmental factors, including seasonal tem-
perature, location of the body, and presence or absence
of clothing, may additionally act as important variables
requiring consideration when attempting to determine
the age of injury patterns.
Contusions and areas of ecchymosis are not unusual
in bite marks made in living tissue. The absence of
bleeding into the injury may imply that it was inﬂ
icted
after death. Additional postmortem soft tissue changes
that can affect the quality of a bite pattern injury and
its eventual weight as evidence include artifacts created
by lividity (caused by the settling of blood pigments
in dependent body areas), decomposition, and
embalming.
Bite marks from sexual attacks are commonly found
on the neck, breasts, arms, buttocks, genitalia, and
thighs. Axillary bites and bite patterns on the back,
shoulder, penis, and scrotum are often associated with
homosexual activity. Abused children may be bitten in
areas of the face, particularly the cheek, ear, and nose.
Assailants also can be bitten. The analysis of these bite
pattern injuries is just as incriminating as those found
on the victim of a violent act.
A review of 778 bite mark injuries concerning the
anatomic locations most often bitten, victim and biter
demographics, the type of crimes in which biting
occurred, and legal disposition of cases revealed the
following information:
●
Females were bitten more often than males.
●
Perpetrators were male more often than female.
●
The most common sites bitten were the arms. Bites
in these locations occurred more commonly among
males.
●
Females were bitten on the breast more often than
males. This location accounted for the second most
commonly bitten area of the body.
●
The type of crime and the age of the victim were
related to patterns in location, distribution, and
number of bites.
GUIDELINES FOR BITE MARK ANALYSIS
In 1984 the American Board of Forensic Odontology
(ABFO) established Guidelines for Bite Mark Analy-
sis. Additional workshops held in 1993 and 1994
provided further insight into the techniques available
to recover, store, analyze, and evaluate bite mark evi-
dence based on the Guidelines. After the workshops,
the ABFO Bite Mark Methodology Guidelines were
revised in 1995. The development and revision of the
Guidelines created a scientiﬁ
c approach to the descrip-
tion of the bite mark, collection of evidence from suspect
and victim, and subsequent analysis of the evidence.
The guidelines do not mandate speciﬁ
c analytic
methods for comparison. Through their careful use,
however, the quality of the investigation and conclu-
sions based on bite mark evidence follow customary
Table

19-3

Histopathologic and Clinical Changes Used to Monitor the Time Elapsed (Aging) in Skin
Injuries Associated with Bite Marks
Time
Predominant Cellular
Inﬁ
ltrate and Deposits Healing Variable Clinical Color
HOURS
4-8 Polymorphonuclear leukocytes with a
peripheral front
Red-blue-purple
12 Polymorphonuclear leukocytes
16-24 Macrophages peak Blue-black
24-36 Polymorphonuclear leukocytes peak Peripheral ﬁ
broblasts
DAYS
1-3 Central necrosis
3
+
Hemosiderin Green-blue
4 Collagen ﬁ
bers
4-5 Capillary growth Brown-yellow-green
6 Lymphocytes peak at periphery
10-14 Granulation tissue Tan-yellowhttp://dentalebooks.com

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procedures. Thus with these guidelines, it should be
possible to determine the weight of bite mark evi-
dence required to establish the validity of bite mark
comparison.
DESCRIPTION OF THE BITE MARK
Demographic information (i.e., age, race, sex, and name
of the victim; examination date; referring agency; case
number) is obtained in cases involving both living and
deceased victims. The names of the forensic dental
examiner and referring agency contact person should
also be included.
The location of the bite is then described. Attention
is directed to the anatomic location, surface contour,
and tissue characteristics of the bitten area. Underlying
structures, such as bone or fat, may inﬂ
uence the ana-
lytic quality of the pattern injury. Relative skin mobility
is also evaluated.
The shape, color, size, and type of injury are recorded.
Metric measurements of the horizontal and vertical
dimensions of the bite mark are determined. Irregu-
larities and variations from the standard round, ovoid,
and crescent shapes associated with human bite marks
are noted. Injury types include abrasion, laceration,
ecchymotic and petechial hemorrhage, incision, and
avulsion. Artifactual injuries, such as proximate stab
and bullet wounds, should be recorded because these
may distort the pattern by separating anatomic cleav-
age lines of the skin
(Langer’s lines)
.
EVIDENCE COLLECTION
E
XAMINATION

OF

THE
V
ICTIM

AND

THE
S
USPECT
Both the victim and the suspect are examined, and
evidence from each is gathered for comparative study
and evaluation. Collection of evidence must be per-
formed in a manner that protects the rights of the
person who is providing the evidence and that permits
the eventual acceptance of the evidence in court.
A standard health history and informed consent are
obtained before any evidence recovery procedure
regarding the suspect is performed. An intraoral and
extraoral examination of the suspect is completed,
which includes dental charting, soft tissue and tongue
evaluation, and probing of the periodontium. There-
fore, knowledge of the medical history of the suspect
relative to systemic problems associated with cardio-
vascular disease, allergy, seizure disorder, diabetes, or
requirements for antibiotic prophylaxis has medicole-
gal importance in forensic casework, as well as in tra-
ditional patient evaluation.
A search warrant, court order, or legal consent may
be required before evidence is collected from a suspect.
A speciﬁ
c list of the dental-related evidence desired
should be recorded in the legal document. This list
usually includes facial and oral photographs, impres-
sions of the teeth, occlusal registrations and bite exem-
plars, and saliva samples. These documents protect the
rights of the suspect against unreasonable search and
seizure and provide for due process, as guaranteed by
the Fourth and Fourteenth Amendments, respectively,
to the U.S. Constitution.
Bite marks are considered similar to such physical
evidence as ﬁ
ngerprints, hair, blood, and semen
samples, as well as to sobriety tests. Therefore, this
material is not protected under provisions of the Fifth
Amendment, which deals with self-incrimination.
P
HOTOGRAPHY
Because evidence associated with bite marks, human
abuse, and sexual and physical assault is transitory,
there is an immediacy associated with the collection of
physical evidence in these cases. Initial photographs of
the pattern mark should be taken before any investiga-
tive procedures that may alter the pristine bite mark
evidence (e.g., touching, removing, impressing, swab-
bing, cleansing).
Ideally, standard visible-light photographic tech-
niques include the use of a 35-mm, SLR, ﬁ
lm or digital
camera with a ﬂ
at-ﬁ
eld macro lens and dedicated elec-
tronic ﬂ
ash. Numerous images using different camera
and lighting positions, exposure settings, and color and
black-and-white exposures should be obtained. If ﬁ
lm
is used, the submission of this evidence for develop-
ment should strictly follow protocols for evidence pres-
ervation and maintenance of the chain of custody.
Additional legal considerations and protocols related
to the documentation of image enhancement, restora-
tion, compression, and analysis have been established
for digital bite mark images.
Orientation positions and close-up views with a ref-
erence scale are required. A reference scale permits
the bite mark images to be measured and prepared
as life-size (i.e., 1:1) representations of the pattern
injury. Ultimately, these images can then be compared
with casts and other exemplars obtained from the
suspect. The scale should be stabilized and positioned
next to, and in the same plane as, the bite mark to
eliminate potential distortion artifacts in the resultant
images. It should never be hand-held. Omitting the
scale from at least one view documents that no
marks or other injuries have been intentionally hidden
by it.
The ABFO No. 2 reference scale (Lightning Powder
Company, Inc; Salem, Ore.) was developed for use in
bite mark photography (Fig. 19-13). This standardized,
accurate scale has become the gold standard in bite
mark photographic analysis. Variations of it have even-
tually come to be used in all varieties of forensic case-
work requiring accurate measurement of evidence at
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This instrument contains two metric scales, an 18%
color gray scale, three circular symbols, and rectifying
grids. Each of these components is used to account for
photographic distortions, which can negate the value
of the photographic evidence. Techniques using Adobe
Photoshop and Mideo Systems casePACS computer
software have been used to rectify distortions observed
in the ABFO No. 2 reference scale and ultimately
to eliminate these from a bite mark image being
analyzed.
With living victims, serial pictures are taken over
several days. This series provides documentation of the
color changes associated with healing of the wound. In
addition, special advanced photographic techniques,
using nonvisible energy sources at the extremes of the
electromagnetic spectrum and ﬂ
uorescent alternative
light sources, can be used to identify latent images of
the teeth that may remain after the bite mark has clini-
cally disappeared. These techniques require special
ﬁ
lms and illumination sources, bracketing of aperture
(f-stop) openings, variations in shutter speeds, and/or
lens ﬁ
lters to work within the desired wavelengths and
include the following (Table 19-4):
●

Reﬂ
ective ultraviolet (UV) photography.
This
technique enhances the bite mark image by selec-
tively identifying photoactive
chromophores
such
as melanin and hemoglobin pigment in the superﬁ
-
cial layers of the injured tissue. Variations in the
amount of these natural light–absorbing organic pig-
ments in the traumatized tissue are observable in
images exposed with this energy source. This is based
on the ﬂ
uorescence created when the skin is exposed
to UV light in the 200- to 400-nm wavelength range.
Although there may be focusing problems associated
with UV photography and exposures
must
be made
with a tripod-mounted camera, the fact that this
technique may permit recovery of latent evidence,
even months after all clinical signs of a bite
mark injury have disappeared, makes the effort
worthwhile.
●

Infrared (IR) photography.
Tungsten lamps and
quartz-halogen lamps are good sources of IR radia-
tion when attempting to expose IR images from
unﬁ
ltered light sources. To expose images speciﬁ
-
cally within the IR wavelengths of 750 to 1000 nm,
a ﬁ
lter must be placed in front of the lens to absorb
Table

19-4

Comparison of Photographic Electromagnetic Energy Spectrum Sources and Their
Forensic Imaging Capabilities
Visible Light UV Light IR Light ALI Fluorescence
Light wavelength 400-700 nm 200-400 nm 700-1000 nm 450 nm
Filter None Kodak
Wratten Filter No. 18A gel
(visibly opaque glass ﬁ
lter)
Kodak
gel 87
Kodak
gel 15
TARGET PIGMENT OR MATERIAL
Hemoglobin in pattern injuries and
vessels
++ ++
Melanin
++ +
Tattoos
++ ++
Ink variations in document forgeries
++
Gunshot residues
++
Latent ﬁ
ngerprints
+
Serologic ﬂ
uids (saliva, semen, blood)
+
Residual ﬁ
bers
+
UV
, Ultraviolet;
IR
, infrared;
ALI
, alternate light imaging.
Fig. 19-13
The American Board of Forensic Odontology
(ABFO) No. 2 Reference Scale.http://dentalebooks.com

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visible light. The Kodak 87 gel ﬁ
lter accomplishes
this task by limiting all transmittance of light except
at the designated wavelengths. Additionally, IR pho-
tography requires that the camera lens be refocused
(focus shift) after initial focusing under visible light
and before exposure of the image. Like alternate light
source photography, the focal plane for IR photogra-
phy lies below the skin surface. The deeper focal
depth permits visualization of faded tattoos and
wound damage within a blood stain. This technique
is not the best for identifying individual characteris-
tics in bite mark injuries.
●

Alternate light source (alternate light imaging
[ALI]) photography.
This technique is also referred
to as
ﬂ
uorescent photography
. It is advantageous in
assisting investigators to locate and document evi-
dence involving the presence of ink residues, ﬁ
nger-
print patterns, and the chromophores previously
indicated. ALI enhances visualization of pigments
derived from chromophores that may be found
within evidence involving latent serologic ﬂ
uids and
subdermal bruises or pattern injuries of victims of
violent or sexual crimes. ALI techniques illuminate
deeper tissue targets by using a predominantly mono-
chromatic band of light between the wavelengths of
430 and 460 nm. To accomplish the visualization of
the weak ﬂ
uorescent glow from the desired pig-
ments, ALI photography must be performed by elim-
inating all other sources of light from striking the
imaging surface (ﬁ
lm or digital sensor). This requires
that ALI techniques be performed in total darkness
with yellow ﬁ
lters such as the Kodak gelatin No. 15.
Because longer exposure times are also required,
images exposed using ALI
must
be made with a
tripod-mounted camera.
As previously stated, photographs of the suspect
should involve the same attention to technical quality
control. Extraoral, intraoral, and occlusal photographs
are taken. Additional images of wax or acrylic test bites
and measurements of maximum interincisal opening
are also recorded.
S
ALIVA
E
VIDENCE
Although the forensic dentist is concerned principally
with the analysis of the physical evidence associated
with a bite mark, biologic evidence in the form of sero-
logic and DNA material is also of probative impor-
tance. Collection of saliva trace evidence from the
surface of the bite injury of the victim is performed
before other evidence-gathering manipulation of the
injury. There is an increase in the yield of recovered
DNA for analysis when this procedure is carried out
according to the two-swab protocol developed by Dr.
David Sweet and others at the Bureau of Legal
Dentistry, University of British Columbia.
Using this technique, a saliva sample is collected by
ﬁ
rst rubbing the bitten area with a cotton swab that has
been moistened in sterile, distilled water. The swab
should contain no preservatives. The bite mark is sub-
sequently rolled with a second, dry, cotton swab. Both
samples can be considered a single exhibit because
they have been collected from the center of the pattern
injury. They are placed in an evidence box and permit-
ted to air-dry before submission to the laboratory. No
control swabs are required from adjacent areas of the
victim’s skin.
DNA from the victim of a bite mark injury should
be obtained from whole blood samples or buccal swabs.
Additionally, autopsy tissue samples can be obtained
from decedent victims. All samples can be used for
DNA comparison with bodily ﬂ
uid or tissue samples
obtained from the suspect.
Because a victim may be bitten through the cloth-
ing, areas of garments that approximate a bite pattern
injury should also be retained and evaluated for
saliva. Many victims of sexual abuse wash the area of
a bite mark before reporting for treatment. This is
unfortunate because biologic evidence associated with
DNA recovery can be lost. In this regard, emergency
room personnel should be trained to recognize poten-
tial bite mark injuries and instructed not to wash or
disinfect these areas until saliva evidence can be
obtained.
I
MPRESSIONS

AND
S
TUDY
C
ASTS
When a bite injury exhibits indentations that can be
related to the dentition of an alleged biter, accurate,
3D, life-sized exemplars (casts) can be obtained from
molds of the area. Dental impression materials are
used to create the molds that are then reinforced to
prevent dimensional changes and distortions.
The Guidelines for Bite Mark Analysis deliberately
do not dictate which impression materials should be
used to create exemplars of a bite mark. Low- and
medium-viscosity vinyl polysiloxane (VPS) impression
materials are dimensionally stable, meet American
Dental Association speciﬁ
cations, and are all accept-
able. Hydrocolloid, polysulﬁ
de, polyether, and alginate
materials are not recommended because of problems
associated with long-term stability.
Orthopedic cast materials, heavy-body VPS materi-
als, and nonexothermic resins have been used to create
the rigid, stable trays for bite mark impressions. All
impression trays and study casts should be appropri-
ately labeled with demographic information for the
speciﬁ
c case. Additionally, anatomic direction markers
should be added to the impression tray before its
removal from the skin surface. This will ensure that the
impression is correctly oriented relative to the actual
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Original impression trays and study casts are
retained for eventual presentation in court. Working
casts and models should be duplicated from the origi-
nal impression or master casts. It is recommended that
master casts be poured in type IV stone, according to
the manufacturer’s speciﬁ
cations, and that these casts
remain pristine.
T
ISSUE
S
AMPLES
Tissue samples of a bite mark can be retained from
decedents. With the permission of the ME or coroner,
the epidermis, dermis, and underlying muscle and
adipose tissue can be removed for transillumination
analysis. Before excision, an acrylic ring or stent
must be secured within 1 inch of the borders of the
injured tissue sample. The ring or stent prevents shrink-
age and distortion of the specimen when it is placed
into a 4% formalin solution for ﬁ
xation. The acrylic
material is bound to the skin surface with cyanoacry-
late and sutures (Fig. 19-14). These tissues samples
can be transilluminated by backlighting. This process
permits observation of the pattern injury in the bruised
skin by a manner that is not possible when the tissue
is
in situ.
EVIDENCE ANALYSIS
The responsibility of comparing the photographs of the
bite pattern injury with the dentition of the suspect
rests with the forensic dentist. As an expert in the anal-
ysis of these patterns, this person objectively evaluates
the evidence. The forensic dentist ﬁ
rst determines
whether the pattern is truly a result of biting or whe-
ther it is an artifact. Patterns of blood splatter around
a wound, other tool marks, or insect artifacts unrelated
to the teeth may be mistaken for bite marks in
photographs provided for evaluation by crime scene
investigators, police, and emergency room or autopsy
personnel.
Once it is established that the pattern is related to
the teeth, it can be matched to the suspect’s dentition
for inclusion or exclusionary purposes. An expert
opinion is then made according to the results of the
relationship of the bite pattern and suspect’s teeth.
To accomplish these goals, the dentist uses numer-
ous methods that have been accepted in the courts.
Images of the bite mark and the teeth can be digitized
in a computer. This information can then be enhanced
and subsequently overlaid for matching purposes.
Clear overlays of the chewing surfaces of the teeth
can be made by simply tracing these surfaces on a
sheet of transparent acetate. Placing the incisal edges
of the study casts on the glass of an ofﬁ
ce photocopier
and duplicating on special paper achieves the same
end. A similar effect is obtained by placing an opaque
powder, such as barium sulfate, into wax or acrylic test
bites and by obtaining radiographs of these exemplars.
All of these overlays are then superimposed over the
bite mark for comparison (Figs. 19-15 and 19-16). This
process can also be accomplished using various com-
puter programs to create a transparent computer-
generated image of the dental casts of the alleged
biter. These hollow outline images can then be super-
imposed over an equally standardized image of the
bite pattern (Fig. 19-17).
A recent study indicates that there are limitations to
the accuracy of the various overlay techniques. It has
been suggested that subjective, hand-traced overlay
methods be discontinued. Among the other techniques,
Fig. 19-14
An experimental bite pattern injury on a
cadaver. This bite mark has had an acrylic stent glued and
sutured around its circumference before dissection and
ﬁ
xation in 4% formalin.
(Courtesy of Dr. E. Steven Smith.)
Fig. 19-15
An overlay of the maxillary cast of a suspect’s
dentition on a photograph of a bite pattern injury. Note the
diastema between the central incisor teeth. The distal incisal
surfaces of the lateral incisor teeth are not in the plane of
occlusion.http://dentalebooks.com

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computer-generated bite mark overlays are the most
reproducible and accurate for analysis. The area of the
biting edges of the teeth is best measured using over-
lays constructed from radiopaque material in wax
dental impressions. Photocopiers, calibrated to create
100% images, are best used to record tooth rotation.
In court, bite mark evidence must be able to with-
stand legal challenges based on its scientiﬁ
c validity
and the credibility of the expert witness who presents
the evidence. This is true regardless of the techniques
used to retrieve, compare, and determine a conclusion
based on the evidence. When the Guidelines for
Bite Mark Analysis are used, such challenges can be
minimized.
HUMAN ABUSE
EPIDEMIOLOGY AND CLASSIFICATION
Dental professionals are likely to encounter more
victims of physical, neglective, sexual, and psychologic
abuse as the scope of the problems associated with
violent human behavior become more recognized and
openly discussed. Currently in the United States, statis-
tics reveal more than 3 million cases of child abuse, 2
million cases of elder abuse, and 4 million victims of
intimate partner violence (IPV) annually.
Child abuse is the nonaccidental, physical, mental,
emotional, or sexual trauma; exploitation; or neglect
endured by a child younger than 18 years of age while
under the care of a responsible person, such as a parent,
sibling, babysitter, teacher, or other person acting
in
loco parentis
. Elder abuse and abuse of the disabled are
similar in all regards, except that they deal with geriat-
ric victims or individuals who are physically and/or
mentally impaired or disabled. These populations often
require special care or have been institutionalized.
Victims of IPV are unique and differ from those of
child, elder, or disabled abuse because they often have
autonomy to choose their circumstances. Unlike the
abused child, or geriatric or disabled resident in a
nursing home, the abused intimate partner can make
choices to leave the traumatic, violent environment.
Of the 3 million cases of alleged child abuse or
neglect investigated by state and local child protective
services (CPS) in the United States in 2004, 872,000
children were determined to be victims of child mal-
treatment and 1490 cases resulted in death. The
National Child Abuse and Neglect Data System
(NCANDS) is a federally sponsored program directed
by the Department of Health and Human Services to
collect and analyze annual data on child abuse and
neglect.
Recognizing the global problem, in 2006 the United
Nations released the ﬁ
rst
UN Secretary-General’s Study
on Violence Against Children
. This document addresses
violence against children in the home, school, work-
place, community, and other settings. The project is the
“ﬁ
rst comprehensive, global study conducted by the
United Nations on all forms of violence against chil-
dren” (Box 19-2).
Victims and their abusers come from all racial,
ethnic, religious, socioeconomic, and educational back-
grounds. Reports concerning the distribution of cases
among the different types of abuse vary widely. Up to
70% of child abuse cases may be the result of physical
Fig. 19-16
A repositioned overlay of the maxillary cast of a
suspect’s dentition on a photograph of a bite pattern injury
(same case as depicted in Fig. 19-15). The drag marks,
diastema space, and mesial contact points of the lateral
incisor teeth become apparent in the pattern.
(From Nuckles DB,
Herschaft EE, Whatmough LN: Forensic odontology in solving crimes: dental
techniques and bite mark evidence,
Gen Dent
42:210-214, 1994.)
Fig. 19-17
On the left side, dental casts of an alleged
suspect are being scanned and scaled to 1:1 before digitizing
their image. The right half of the illustration shows three
photographs of bite marks on the victim. Transparent
overlays of the teeth of the alleged suspect have been
digitally superimposed over 1:1 digital images of the victim’s
bite mark using a software program developed by Mideo
Systems, Inc.
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trauma. Some studies relate 15% to 25% of the cases to
sexual abuse and 50% to neglect. Neglective abuse is
subclassiﬁ
ed by the caretaker’s neglect of the child’s
medical, dental, and safety needs; physical well-being;
or education. Intentional drugging or poisoning and
failure to thrive are additional types of maltreatment
classiﬁ
ed as abusive.
Many abusive individuals were themselves abused
as children. Criminal charges are often lodged against
an abusing caretaker. It is recognized, however, that
counseling and psychologic and emotional support can
also help to stabilize a violent, dysfunctional family
unit.
SIGNS AND SYMPTOMS
Regardless of the overall statistical variations in sub-
classiﬁ
cation of the problem of abuse, the dentist is
most likely to encounter physical and sexual abuse, as
well as health care and safety neglect among pediatric,
older adult, and disabled dental patients. Of the chil-
dren and older adults who are physically abused, 50%
manifest orofacial and scalp injuries (Figs. 19-18 and
19-19). These unexplained injuries are inappropriately
reported by the caretaker or are inconsistent with the
history provided. Abusive trauma to the face and mouth
includes the following:
●
Laceration of the labial or lingual frenum, which
results from a blow to the lip or forceful feeding
●
Repeated fracture or the avulsion of teeth
●
Zygomatic arch and nasal fractures
●
Bilateral contusions of the lip commissures from
the placement of a gag
●
Bilateral periorbital ecchymoses (raccoon mask)
●
Traumatic alopecia secondary to grabbing the
head hair of the victim while throwing them
Pattern injuries can be associated with the semicir-
cular or crescent shape of bite marks. Other instru-
ments that contact the skin may leave parallel linear
patterns; these include injuries made by a hanger,
strap, belt, or ruler. Multiple parallel lines are associ-
ated with ﬁ
nger marks after an open-handed slap. Mul-
tiple circular, punched out, or ulcerated areas are
caused by intentional burning with a cigarette or cigar.
Loop patterns are created by electrical cord, rope, and
wire (Figs. 19-20 and 19-21).
Box
19-2
Epidemiological, Statistical Overview
of the
UN Secretary-General’s Study
on Violence Against Children
●
Almost 53,000 children died worldwide in 2002 as
a result of homicide.
●
Up to 80% to 98% of children suffer physical punish-
ment in their homes, with one third or more experi-
encing severe physical punishment resulting from
the use of implements.
●
150 million girls and 73 million boys younger than
18 years experienced forced sexual intercourse or
other forms of sexual violence during 2002.
●
Between 100 and 140 million girls and women in
the world have undergone some form of female
genital mutilation/cutting. In sub-Saharan Africa,
Egypt, and the Sudan, 3 million girls and women are
subjected to genital mutilation/cutting every year.
●
In 2004, 218 million children were involved in
child labor. Among these, 126 million did hazardous
work.
●
Estimates from 2000 suggest that 1.8 million chil-
dren were forced into prostitution and pornography,
and 1.2 million were victims of trafﬁ
cking.
Fig. 19-18
An avulsed tooth, a fractured tooth, and a torn
labial frenum associated with oral facial injuries in physical
child abuse.
Fig. 19-19
Bilateral periorbital ecchymoses (raccoon mask)
and fractured nasal bone in a 77-year-old white female
victim of physical elder abuse.
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Other characteristics of child and elder abuse inju-
ries are related to their multiplicity and repetitive
nature. They often appear in various stages of resolu-
tion. Some injuries are acute; others are healing or
even scarred. Therefore, the dentist should examine
the skin of the pediatric, geriatric, or disabled dental
patient. Suspicion of abuse is increased when the child
or older patient appears overdressed for seasonal con-
ditions; overdressing may be an attempt to mask or
hide the physical signs of abuse.
By adulthood, 10% of men and 25% of women are
the victims of sexual abuse. Oral infections associated
with sexually transmitted diseases (STDs) are obviously
signs of sexual abuse when they are observed in a
minor. Erythematous or petechial lesions of the palate
or ulceration of the sublingual area should be noted
because these ﬁ
ndings can result from the physical
trauma associated with performing fellatio or cunnilin-
gus (see page 307).
Among siblings, nursing or “baby bottle caries” is a
sign of neglective abuse and indicates the caretaker’s
inattention to the dental needs of the children. When
infants and toddlers are placed to bed with a nursing
bottle ﬁ
lled with cariogenic solutions (e.g., milk, soft
drinks, sweet juices), the maxillary incisors are bathed
in the sugary solution and can manifest severe caries.
The mandibular teeth, protected from the cariogenic
material by the position of the tongue and nipple during
sucking, are spared the destructive effects, and the
child takes on the appearance of a pseudoprognathism
or pseudo-Class III malocclusion (Fig., 19-22).
The dentist may become aware of other abusive
behavior directed to a child or older patient by a
responsible caretaker. Abusive behavior can involve
refusal or delay in seeking treatment for serious medical
or dental problems, abandonment, refusal to cooperate
with planned treatment, and failure to return to the
same physician or dentist for treatment.
ROLE OF DENTISTRY IN RECOGNIZING
AND REPORTING HUMAN ABUSE
Awareness of the signs and symptoms of abuse among
individuals of all ages should be a goal for every dentist.
As a component of the dental relicensure process, New
York state requires documentation of continuing edu-
cation credits in the area of child abuse recognition
and the dental professional’s responsibility to report
such cases.
By statute, all states require that dental personnel,
other health care professionals, teachers, and day care
and nursing home employees report suspected cases of
child and elder abuse. Unfortunately, the reporting of
IPV is limited in most jurisdictions to cases involving
the use of a weapon while committing a violent act.
Fig. 19-20
Multiple circular ulcerated injuries are
associated with intentional burns from a cigarette. When a
child is accidentally burned by a cigarette, only one elliptic
ulcer is observed.
Fig. 19-21
Parallel linear (“railroad track”) patterns are
associated with blows to the skin with such straight-edged
objects as a belt, a hanger, an electrical cord, and a ruler.
Fig. 19-22
Pseudoprognathism or pseudo-Class III
malocclusion observed in a neglected child with nursing
bottle (baby bottle) decay.
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Although the dentist has no legal requirement to report
IPV in these areas, the American Dental Association’s
Principles of Ethics and Code of Professional Conduct
indicate a responsibility on behalf of dental profession-
als to intercede in cases involving family violence.
The agency to which the report is made varies
among the different jurisdictions. Commonly, the
police, social service, child welfare, senior services
agencies, or family services departments are the gov-
ernmental ofﬁ
ces designated to accept reports. When
a report is made in good faith, the dentist is immune
from any counterprosecution or civil liability that
might stem from a false report. Failure to report is
considered a misdemeanor in most states. In addition,
the dentist may be subject to license revocation or
malpractice litigation by failing to make a report.
When a dentist determines that a report of child or
elder abuse should be made, documentation of the
physical evidence to support the charge is mandatory.
All evidence is collected according to the principles
described for identiﬁ
cation and bite mark cases.
Descriptions of the injuries and their locations, sup-
porting photographs and radiographs, and information
stating the basis for suspicion of abuse are included in
the report. When abuse is considered, the dentist
should examine the patient and assess the problem
separately from the abusive caregiver. Parental consent
is not required to obtain appropriate physical evidence
from victims younger than the age of majority.
DENTISTS AS EXPERT WITNESSES
Observational, or lay, witnesses testify only to the facts
known to them. They are referred to as
witnesses of
fact
. Such witnesses are permitted to make inferences
about physical facts based on ordinary experience. The
witness of fact is not entitled to present hearsay evi-
dence related by another person.
The judicial system recognizes that people with a
scientiﬁ
c background or specialized ﬁ
eld of study that
is admissible under the
Frye
rule or Federal Rules of
Evidence can provide the courts with analyses or expla-
nations relative to that discipline. The facts and opin-
ions offered by such a witness are beyond the scope of
information that could be expected to be provided by
a lay person or witness of fact. A witness who is quali-
ﬁ
ed to testify under this standard is acknowledged as
an “expert.”
Members of the dental profession are experts. They
are qualiﬁ
ed to testify by the judge, who bases his or
her opinion on educational background, dental and
forensic expertise, publications, and other professional
qualiﬁ
cations. Dentists who have additional training in
one of the dental specialties may be called on to present
speciﬁ
c information from that discipline.
Dental experts assist attorneys and, ultimately, the
triers of fact (judges and juries) in understanding the
scope and complexities of dental science and practice
in relation to questions of law. The dentist should not
become an advocate for either side in a case but should
strive to be an educator and friend of the court.
As experts, dentists may be required to testify in civil
litigation cases that involve the following situations:
●

Malpractice based on negligence.
This category
includes battery (e.g., extraction of the wrong tooth);
misdiagnosis; and failure to diagnose, refer, or inform.
All of these actions fall outside the standard of care
for the profession.
●

Personal injury.
Temporomandibular joint (TMJ)
damage or dental trauma suffered in vehicular,
home, sports, recreational, and work-related acci-
dents fall under this category.
●

Dental fraud.
Charging for materials or procedures
that were not used or performed are examples of
fraud.
●

Identiﬁ
cation of multiple fatality incident
victims.
In criminal court, dental expertise is requested in
identiﬁ
cation of homicide victims and in bite mark and
human abuse cases.
Dentists are often unfamiliar with, and may be
intimidated by, the adversarial nature of courtroom
procedure and protocol. When presenting evidence,
the dental expert should remember that his or her role
in the legal process is to help the trier of fact under-
stand the dental issues in the case. To this end, and as
a scientist, the dental expert witness should present the
evidence conﬁ
dently, accurately, and objectively, relat-
ing information in nontechnical terms.
When cross-examined by the opposing attorney, the
dental expert witness should remain composed and
conﬁ
dent. As an expert, the dentist has the right to
refer to records and exemplars prepared for the case.
The dentist is entitled to read and review any books or
articles proffered by the opposing attorney with the
intent of discrediting the testimony.
Pretrial preparation is required if the dental expert
and the attorney who has retained his or her services
are to develop the evidence to be presented in court.
Both must be aware of the strengths and weaknesses
of the material and decide how best to provide the jury
with this information. Adequate time must be allotted
to prepare exhibits for court. It is also advantageous to
attempt to determine the position that will be taken by
dental experts called by the opposing side.
SUMMARY
Each practitioner has a responsibility to understand
the forensic implications associated with the practice
of his or her profession. This understanding should http://dentalebooks.com

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915
include more than ethics and jurisprudence, which
were traditionally the only aspects of knowledge of the
law acquired by dental professionals. Appreciation
of forensic dental problems involving body identiﬁ
ca-
tion permits clinicians to maintain legally acceptable
records and assist legal authorities in the identiﬁ
cation
of victims of multiple fatality incidents and crimes.
The pursuit of justice in cases of rape, homicide, and
human abuse often relies on dental testimony to inter-
pret bite pattern injuries. The development of UV and
IR wavelength photographic techniques and equip-
ment has given forensic dentists the opportunity to
provide objective scientiﬁ
c evidence in these types of
cases. Evidence gathered using these resources can be
analyzed and assessed with computer software, labora-
tory, and clinical procedures that also enhance the
forensic odontologist’s ability to interpret results.
The reliance of the legal community on the dental
profession to continue to provide expertise in civil and
criminal proceedings ensures that forensic dentistry
will remain a viable component of the forensic sciences
and the practice of dentistry.
BIBLIOGRAPHY
Arany S, Ohtani S, Yoshioka N et al: Age estimation from aspartic
racemization of root dentin by internal standard method,
Forensic Sci Int
141:127-130, 2004.
Austin-Smith D, Maples WR: The reliability of skull/photograph
superimposition individual identiﬁ
cation,
J Forensic Sci

39:446-455, 1994.
Barsley RE: Forensic and legal issues in oral diagnosis,
Dent Clin
North Am
37:143-144, 1993.
Berger MA: Evidentiary framework. In Cecil JS et al:
Shepard’s
reference manual on scientiﬁ
c evidence
, pp 39-117, New York,
1994, McGraw-Hill.
Blankenship JA, Mincer HH, Anderson KM et al: Third molar
development in the estimation of chronologic age in Ameri-
can blacks as compared with whites,
J Forensic Sci
52:428-
433, 2007.
Bowers CM, Johansen RJ: Photographic evidence protocol: the
use of digital imaging methods to rectify angular distortion
and create life size reproductions of bite mark evidence,
J
Forensic Sci
47:179-186, 2002.
Bush MA, Bush PJ, Miller RG: Detection and classiﬁ
cation of
composite resins in incinerated teeth for forensic purposes,
J
Forensic Sci
51:636-642, 2006.
Bush MA, Miller RG, Prutsman-Pfeiffer J et al: Identiﬁ
cation
through XRF analysis of dental restorative resin materials: a
comprehensive study of non-cremated, and processed cre-
mated individuals,
J Forensic Sci
52:157-165, 2007.
Child Abuse Prevention and Treatment Act of 1974 (PL93-247),
DHEW Pub No 78-30137, 42 USCS Section 5106 g (4),
Washington, DC, 1988.
Chiodo GT, Tolle SW, Tilden VP: The dentist and family vio-
lence,
Gen Dent
46:20-25, 1998.
CODIS, Combined DNA Index System. Available at http://www.
fbi.gov/hq/lab/codis/clickmap.htm. Accessed January 15,
2008.
Cottone JA, Standish SM:
Outline of forensic dentistry
, Chicago,
1982, Year Book Medical Publishers.
Covell K:
The rights of children part three: child sexual exploitation and
the age of consent,
2006. Available at http://aboutkidshealth.
ca/News/The-Rights-of-Children-Part-Three-Child-sexual-
exploitation-and-the-age-of-consent.aspx?articleID
=
8226
&categoryID
=
news-type. Accessed February 8, 2008.
da Fonseca MA, Feigal RJ, ten Bensel RW: Dental aspects of
1248 cases of child maltreatment on ﬁ
le at a major county
hospital,
Pediatr Dent
14:152-157, 1992.
Daubert v Merrell Dow Pharmaceuticals Inc
, 113 S Ct 2786, 2798,
1993.
DiMaio DJ, DiMaio VJM:
Forensic pathology
, Boca Raton, 1993,
CRC Press.
Dorion RBJ, editor:
Bitemark evidence
, New York, 2005, Marcel
Dekker.
Doyle v State
, 159 Tex C R 310, 263 S W 2d 779, January 20,
1954.
Epstein JB, Scully C: Mammalian bites: risk and management,
Am J Dent
5:167-172, 1992.
Freeman AJ, Senn DR, Arendt DM: Seven hundred seventy eight
bite marks: analysis by anatomical location, victim and biter
demographics, type of crime, and legal disposition,
J Forensic
Sci
50:1436-1443, 2005.
Frair J, West MH: Ultraviolet forensic photography,
Kodak Tech
Bits
2:311, 1989.
Frye v United States
, 293 F 1013 DC Cir, 1923.
Golden GS: Lessons learned from the WTC disaster: a ﬁ
rst-
person account,
J Can Dent Assoc
32:675-680, 2004.
Golden GS: Use of alternative light source illumination in bite
mark photography,
J Forensic Sci
39:815-823, 1994.
Gorlin RJ, Cohen MM, Levin LS:
Syndromes of the head and neck
,
ed 3, New York, 1990, Oxford University Press.
Gustafson G: Age determination on teeth,
J Am Dent Assoc

41:445-454, 1950.
Herschaft EE, Alder ME, Ord DK et al, editors:
American Society
of Forensic Odontology—manual of forensic odontology
, ed 4,
Albany, NY, 2007, ImPress Printing.
Hopper J:
Child abuse, statistics, research, and resources
, 2007. Avail-
able at http://www.jimhopper.com/abstats/. Accessed on Feb-
ruary 8, 2008.
Hyzer WG, Krauss TC: The bitemark standard reference scale
ABFO no. 2,
J Forensic Sci
33:498-506, 1988.
IAFIS:
Integrated automated ﬁ
ngerprint identiﬁ
cation
system,
2005. Available at http://www.fbi.gov/hq/cjisd/iaﬁ
s.
htm#main. Accessed February 7, 2008.
Jakush J: Forensic dentistry,
J Am Dent Assoc
119:355-368,
1989.
Kim YK, Kho HS, Lee KH: Age estimation by occlusal wear,
J
Forensic Sci
45:303-309, 2000.
Lewis LM, Levine MD, Dribben WH: Bites and stings. In Dale
DC, Federman DD, editors:
Interdisciplinary medicine,
New
York, 2000, WebMD Inc.
Mincer HH, Harris EF, Berryman HE: The ABFO study of third
molar development and its use as an estimator of chronologi-
cal age,
J Forensic Sci
38:379-390, 1993.
Moenssens AA, Inbau FE, Slam JE:
Scientiﬁ
c evidence in criminal
cases
, ed 3, Mineola, NY, 1986, Foundation Press.
Myers SL, Williams JM, Hodges JS: Effects of extreme heat on
teeth with implications for histologic processing,
J Forensic Sci

44:805-809, 1999.
Oeschger MP, Hubar JS: Modiﬁ
ed intraoral ﬁ
lm holders
for postmortem identiﬁ
cation,
J Forensic Sci
44:846-848,
1999.
Ohtani S, Yamamoto T: Strategy for the estimation of chronologi-
cal age using the aspartic acid racemization method with http://dentalebooks.com

916
O
RAL

AND
M
AXILLOFACIAL
P
ATHOLOGY
special reference to coefﬁ
cient of correlation between D/L
ratios and ages,
J Forensic Sci
50:1020-1027, 2005.
Pierce L: Early history of bite marks. In Averill D, editor:
Manual
of forensic odontology
, ed 2, pp 127-128, Colorado Springs,
1991, American Society of Forensic Odontology.
Pitluck HM:
Bite mark case management and legal considerations
update.
Presentation at the UNLV School of Dental Medicine,
Bite Mark Course, Las Vegas, 1999.
Pretty IA: A web-based survey of odontologists’ opinions con-
cerning bite mark analysis,
J Forensic Sci
48:1117-1120,
2003.
Pretty IA, Sweet D: The scientiﬁ
c basis for human bite mark
analysis—a critical review,
Sci Justice
41:85-92, 2001.
Ramsland K:
The C.S.I. effect
, New York, 2006, Berkley Publishing
Group.
Regan JD, Parrish JA:
The science of photomedicine
, New York,
1982, Plenum Press.
Roberts D: The iceman: lone voyager from the copper age,
Natl
Geogr Mag
183:36-67, 1993.
Sanger RG, Bross DC:
Clinical management of child abuse and
neglect: a guide for the professional
, Chicago, 1984, Quintes-
sence Publishing.
Schrader BA, Senn DR: Dental identiﬁ
cation of human remains
from orthopedic metallic ﬁ
xation devices,
Proceedings of the
American Academy of Forensic Sciences
7:198, 2006.
Scientiﬁ
c Working Group on Imaging Technology (SWGIT),
International Association for Identiﬁ
cation. Available at
http://www.theiai.org/guidelines/swgit/index.php. Accessed
February 7, 2008.
Sinclair K, McKechnie VM: DNA extraction from stamps and
envelope ﬂ
aps using QIA amp and QIA shredder,
J Forensic
Sci
45:229-230, 2000.
Smith ES, Rawson RD:
Proceedings of the First National Symposium
on Dentistry’s Role and Responsibility in Mass Disaster Identiﬁ
ca-
tion
, Chicago, 1988, American Dental Association.
Soomer H, Ranta H, Lincoln MJ et al: Reliability and validity of
eight dental age estimation methods for adults,
J Forensic Sci

48:149-152, 2003
Spitz WU, Spitz DJ:
Spitz and Fischer’s medicolegal investigation of
death: guidelines for the application of pathology to criminal inves-
tigation
, ed 4, Springﬁ
eld, Ill, 2006, Charles C Thomas.
Standish SM, Stimson PG: Forensic dentistry: legal obligations
and methods of identiﬁ
cation for the practitioner,
Dent Clin
North Am
21:1-196, 1977.
Sweet DJ, Bowers CM: Accuracy of bite mark overlays: a
comparison of ﬁ
ve common methods to produce exem-
plars from a suspect’s dentition,
J Forensic Sci
43:362-367,
1998.
Sweet D, Lorente M, Lorente JA et al: An improved method to
recover saliva from human skin: the double swab technique,
J Forensic Sci
42:320-322, 1997.
Vale GL: Identiﬁ
cation by dental evidence: basic and beyond,
J
Can Dent Assoc
32:665-672, 2004.
Vale GL et al: Guidelines for bite mark analysis,
J Am Dent Assoc

112:383-386, 1986.
Warnick AJ:
Forensic dental identiﬁ
cation team manual
, Detroit,
1989, Detroit Dental Association.
Wright FD, Golden G: Forensic photography. In Stimson P,
Mertz C, editors:
Forensic dentistry
, Boca Raton, Fla, 1997,
CRC Press.
Zarkowski P: Bite mark evidence: its worth in the eyes of the
expert,
J Law Ethics Dent
1:47-57, 1988.http://dentalebooks.com

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APPENDIX
Differential Diagnosis of Oral and Maxillofacial Diseases
The most important aspect of patient care is the accu-
rate diagnosis of the patient’s disease. Unfortunately,
the clinical presentation of many disease processes can
be strikingly similar, despite their vast differences in
etiology and pathogenesis. Because treatment and, ulti-
mately, prognosis are based on the diagnosis, the diag-
nostic process is critical in optimal patient management.
This appendix provides some guidelines for expediting
and facilitating the diagnostic process from a clinical
perspective.
The ﬁ
rst step in gathering information is the acquisi-
tion of a thorough history of the disease process. This
step typically includes items such as the onset, severity,
location, duration, character, and course of the signs
and symptoms being experienced by the patient. Addi-
tional information regarding medical, social, and family
history may be necessary. With this information, the
clinician can often start the process of formulating a
list of possible diagnoses, even before performing an
examination.
The information obtained during the clinical exami-
nation is also important because many lesions have
characteristic appearances. By evaluating these char-
acteristics in conjunction with the patient’s history,
often the clinician can narrow the list of diag-
nostic possibilities. This list, known as a
differential
diagnosis
, essentially includes possible pathologic enti-
ties, usually ranked in order from most likely to least
likely.
DEFINITIONS
To better describe the appearances of lesions and
communicate these features to colleagues, the
clinician should be familiar with the following
terms:
Macule.
Focal area of color change that is not ele-
vated or depressed in relation to its surroundings.
Papule.
Solid, raised lesion that is less than 5 mm
in diameter.
Nodule.
Solid, raised lesion that is greater than
5 mm in diameter.
Sessile.
Describing a tumor or growth whose base
is the widest part of the lesion.
Pedunculated.
Describing a tumor or growth
whose base is narrower than the widest part of the
lesion.
Papillary.
Describing a tumor or growth exhibiting
numerous surface projections.
Verrucous.
Describing a tumor or growth exhibit-
ing a rough, warty surface.
Vesicle.
Superﬁ
cial blister, 5 mm or less in diame-
ter, usually ﬁ
lled with clear ﬂ
uid.
Bulla.
Large blister, greater than 5 mm in
diameter.
Pustule.
Blister ﬁ
lled with purulent exudate.
Ulcer.
Lesion characterized by loss of the surface
epithelium and frequently some of the underlying
connective tissue. It often appears depressed or
excavated.
Erosion.
Superﬁ
cial lesion, often arising secon-
dary to rupture of a vesicle or bulla, that is char-
acterized by partial or total loss of the surface
epithelium.
Fissure.
Narrow, slitlike ulceration or groove.
Plaque.
Lesion that is slightly elevated and is ﬂ
at
on its surface.
Petechia.
Round, pinpoint area of hemorrhage.
Ecchymosis.
Nonelevated area of hemorrhage,
larger than a petechia.
Telangiectasia.
Vascular lesion caused by dilata-
tion of a small, superﬁ
cial blood vessel.
Cyst.
Pathologic epithelium-lined cavity, often ﬁ
lled
with liquid or semi-solid contents.
Unilocular.
Describing a radiolucent lesion having
a single compartment.
Multilocular.
Describing a radiolucent lesion
having several or many compartments.
By using these terms, the clinician can describe the
characteristics of lesions efﬁ
ciently and uniformly.
Applying these clinical descriptors to the lesions also
can help categorize them with respect to the differen-
tial diagnosis. By adding additional characteristics such
as prevalence, patient race or nationality, patient
age at diagnosis, patient sex, and sites of predilection,
the clinician can hone the differential diagnosis list
considerably.
HOW TO USE THIS APPENDIX
This appendix is designed to help the clinician formu-
late a differential diagnosis by organizing and catego-
rizing disease entities according to their most prominent
or identiﬁ
able clinical features. Under each “clinical
feature” heading is a list of lesions with that clinical
feature as a prominent component. Diseases are listed
according to estimated frequency relative to similar
diseases or lesions.
The most common lesions are marked with triple
asterisks (
***
), less common lesions are marked with
double asterisks (
**
), and rare lesions are marked with
a single asterisk (
*
). Such estimated frequency indica-http://dentalebooks.com

918
A
PPENDIX
tors should not be compared between lists; they are
intended only for the single differential diagnosis list
in which they occur.
Clinical features that most readily distinguish the
lesions are listed with each disease process to help
focus the clinician’s search for the most accurate
diagnosis. Finally, the corresponding page number in
the book is provided for each disease entity so that
the reader can refer to the text for a more detailed
discussion.http://dentalebooks.com

INDEX TO THE APPENDIX: DIFFERENTIAL DIAGNOSIS LISTS
PART 4:
RADIOGRAPHIC PATHOLOGY
A. Unilocular Radiolucencies:
Pericoronal Location 929
B. Unilocular Radiolucencies:
Periapical Location 929
C. Unilocular Radiolucencies:
Other Locations 929
D. Multilocular Radiolucencies 930
E. Radiolucencies: Poorly Deﬁ
ned or
Ragged Borders 930
F. Radiolucencies: Multifocal or Generalized 931
G. Radiopacities: Well-Demarcated Borders 931
H. Radiopacities: Poorly Demarcated Borders 931
I. Radiopacities: Multifocal or Generalized 932
J. Mixed Radiolucent/Radiopaque Lesions:
Well-Demarcated Borders 932
K. Mixed Radiolucent/Radiopaque Lesions:
Poorly Demarcated Borders 932
L. Mixed Radiolucent/Radiopaque Lesions:
Multifocal or Generalized 933
M. Unique Radiographic Appearances:
“Ground Glass” (Frosted Glass)
Radiopacities 933
N. Unique Radiographic Appearances:
“Cotton Wool” Radiopacities 933
O. Unique Radiographic Appearances:
“Sunburst” Radiopacities 933
P. Unique Radiographic Appearances:
“Onion-Skin” Radiopacities 933
Q. Soft Tissue Radiopacities 933
PART 5:
PATHOLOGY OF TEETH
A. Hyperdontia (Extra Teeth) 934
B. Hypodontia (Missing Teeth) 934
C. Macrodontia (Larger Than Normal Teeth) 934
D. Microdontia (Smaller Than Normal Teeth) 934
E. Malformed Crown 934
F. Enamel Loss After Tooth Formation 935
G. Extrinsic Staining of Teeth 935
H. Intrinsic Discoloration (“Staining”) of Teeth 935
I. Abnormally Shaped Roots 935
J. Enlarged Pulp Chamber or Canal 936
K. Pulpal Calciﬁ
cation 936
L. Thickened Periodontal Ligament 936
M. Generalized Loss of Lamina Dura 936
N. Premature Exfoliation of Teeth 936
PART 1:
MUCOSAL AND SOFT TISSUE
PATHOLOGY: COLOR CHANGES
A. White Lesions: Can Be Scraped Off 920
B. White Lesions: Cannot Be Scraped Off 920
C. White and Red Lesions 921
D. Red Lesions 921
E. Petechial, Ecchymotic, and
Telangiectatic Lesions 921
F. Blue and/or Purple Lesions 922
G. Brown, Gray, and/or Black Lesions 922
H. Yellow Lesions 923
PART 2:
MUCOSAL AND SOFT TISSUE
PATHOLOGY: SURFACE
ALTERATIONS
A. Vesiculoerosive and Ulcerative Lesions:
Acute (Short Duration and Sudden Onset) 924
B. Vesiculoerosive and Ulcerative Lesions:
Chronic (Long Duration) 924
C. Papillary Growths: Focal or Diffuse 925
PART 3:
MUCOSAL AND SOFT TISSUE
PATHOLOGY: MASSES OR
ENLARGEMENTS
A. Soft Tissue Masses (Lumps and Bumps):
Lower Lip 926
B. Soft Tissue Masses (Lumps and Bumps):
Upper Lip 926
C. Soft Tissue Masses (Lumps and Bumps):
Buccal Mucosa 926
D. Soft Tissue Masses (Lumps and Bumps):
Gingiva/Alveolar Mucosa 926
E. Soft Tissue Masses (Lumps and Bumps):
Floor of Mouth 927
F. Soft Tissue Masses (Lumps and Bumps):
Tongue 927
G. Soft Tissue Masses (Lumps and Bumps):
Hard or Soft Palate 927
H. Soft Tissue Masses (Lumps and Bumps):
Multiple Lesions 928
I. Soft Tissue Masses (Lumps and Bumps):
Midline Neck Lesions 928
J. Soft Tissue Masses (Lumps and Bumps):
Lateral Neck Lesions 928
K. Generalized Gingival Enlargement 928
919http://dentalebooks.com

PART 1: MUCOSAL AND SOFT TISSUE PATHOLOGY: COLOR CHANGES
Frequency
of Occurrence Lesion or Condition Comments or Special Characteristics Page
A. WHITE LESIONS: CAN BE SCRAPED OFF
*** White coated tongue May be scraped off slightly, with difﬁ
culty 13
*** Pseudomembranous
candidiasis
“Milk curd” or “cottage cheese” appearance; may leave red
base when rubbed off
213
*** Morsicatio Surface may appear to be peeling off 286
** Thermal burn Example: pizza burn 289
** Sloughing traumatic
lesion
Example: cotton roll “burn” 293
** Toothpaste or mouthwash
reaction
Filmy whiteness; leaves normal appearing mucosa when rubbed
off
350
** Chemical burn Example: aspirin burn secondary to direct application for
toothache
291
* Secondary syphilis Mucous patch; may be only partially scraped off 188
* Diphtheria Gray-white pseudomembrane of oropharynx 186
B. WHITE LESIONS: CANNOT BE SCRAPED OFF
*** Linea alba Buccal mucosa along occlusal plane 285
*** Leukoedema Primarily in blacks; milky white alteration of buccal mucosa
bilaterally; disappears when stretched
8
*** Leukoplakia May show benign hyperkeratosis, epithelial dysplasia, or
invasive carcinoma
388
*** Tobacco pouch keratosis Usually in mandibular vestibule; associated with use of snuff or
chewing tobacco
398
*** Actinic cheilosis Pale, gray-white, scaly alteration of lower lip; usually in older
men with history of chronic sun exposure; precancerous
405
*** Lichen planus Wickham’s striae; typically bilateral on buccal mucosa 782
*** Morsicatio Most common on anterior buccal mucosa, labial mucosa, and
lateral border of tongue; exhibits ragged surface
286
*** White coated tongue Diffuse involvement of dorsal tongue 13
** Nicotine stomatitis Usually associated with pipe smoking; occurs on hard palate 403
* Hairy leukoplakia Usually lateral border of tongue; rough surface with vertical
ﬁ
ssures; usually associated with HIV infection
268
* Hyperplastic candidiasis Most commonly affects anterior buccal mucosa 217
* Lupus erythematosus Most common on buccal mucosa; may mimic lichen planus or
leukoplakia; associated skin lesions usually present
794
* Skin graft History of previous surgery —
* Submucous ﬁ
brosis More common in South Asia; associated with betel quid
chewing
401
* White sponge nevus Hereditary; onset in childhood; generalized lesions, especially
buccal mucosa
743
* Hereditary benign
intraepithelial
dyskeratosis
Hereditary; onset in childhood; generalized lesions, especially
buccal mucosa; ocular involvement possible
744
* Pachyonychia congenita Hereditary; onset in childhood; most common on dorsal tongue
and areas of trauma; nail, palmar, and plantar changes also
present
745
* Dyskeratosis congenita Hereditary; onset in childhood; dystrophic nail changes 746
* Tertiary syphilis Syphilitic glossitis 190
* Uremic stomatitis Renal failure 851
920http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

OF
O
RAL

AND
M
AXILLOFACIAL
D
ISEASES

921
Frequency
of Occurrence Lesion or Condition Comments or Special Characteristics Page
C. WHITE AND RED LESIONS
*** Erythema migrans Geographic tongue; continually changing pattern; rarely
involves other oral mucosal sites
779
*** Candidiasis White component may be rubbed off 213
*** Lichen planus Atrophic or erosive forms; Wickham’s striae; typically bilateral
on buccal mucosa
782
** Burns Examples: pizza burn, aspirin burn, other chemical burns; white
component may be rubbed off
289
** Actinic cheilosis Pale, gray-white and red alteration to lower lip; usually in older
men with history of chronic sun exposure
405
** Nicotine stomatitis Usually associated with pipe smoking; occurs on hard palate 403
** Erythroleukoplakia Usually shows epithelial dysplasia or carcinoma 392
** Cinnamon reaction Related to cinnamon ﬂ
avored gum; typically on buccal mucosa
and lateral tongue
352
* Lupus erythematosus Most common on buccal mucosa; may mimic lichen planus or
leukoplakia; associated skin lesions usually present
794
* Scarlet fever Secondary to
β
-hemolytic streptococcal infection; strawberry/
raspberry tongue
184
* Verruciform xanthoma Most common on gingiva and hard palate; surface may be
papillary
372
D. RED LESIONS
*** Pharyngitis Examples: strep throat, viral pharyngitis 183
*** Traumatic erythema Caused by local irritation —
*** Denture stomatitis Denture-bearing palatal mucosa 216
*** Erythematous candidiasis Example: central papillary atrophy (median rhomboid glossitis) 215
*** Erythema migrans Geographic tongue (cases with absence of white borders);
continually changing pattern; rarely involves other mucosal
sites
779
*** Angular cheilitis Erythema and cracking at labial commissures 216
** Thermal burns Example: caused by hot liquids 289
** Erythroplakia Usually shows epithelial dysplasia or carcinoma 397
* Anemia Atrophic, red tongue; can be due to pernicious anemia, iron-
deﬁ
ciency anemia, hypovitaminosis B
827
* Hemangioma Develops in younger patients; may blanch; may show bluish
hue
538
* Lupus erythematosus Usually with associated skin lesions 794
* Scarlet fever Secondary to
β
-hemolytic streptococcal infection; strawberry/
raspberry tongue
184
* Plasma cell gingivitis Allergic reaction usually related to ﬂ
avoring agents 159
* Radiation mucositis Patient currently undergoing radiotherapy 294
E. PETECHIAL, ECCHYMOTIC, AND TELANGIECTATIC LESIONS
*** Nonspeciﬁ
c trauma History of injury to lesional site 305
** Upper respiratory
infections
Soft palate petechiae 306
* Infectious mononucleosis S
oft palate petechiae; tonsillitis and/or pharyngitis may be present
253
* Idiopathic
thrombocytopenic
purpura
Areas of trauma; gingival bleeding possibly present 585
* Trauma from fellatio Posterior palatal petechiae or ecchymosis 307
* Hemophilia Hereditary; childhood onset; gingival bleeding may be present 573
* Leukemia Caused by secondary thrombocytopenia; gingival bleeding may
be present
587

Continuedhttp://dentalebooks.com

922
A
PPENDIX
Frequency
of Occurrence Lesion or Condition Comments or Special Characteristics Page
E. PETECHIAL, ECCHYMOTIC, AND TELANGIECTATIC LESIONS—cont’d
* Hereditary hemorrhagic Multiple, pinhead-sized telangiectasias; possible history of
nosebleeds or gastrointestinal bleeding
754
* CREST syndrome Multiple, pinhead-sized telangiectasias;
C
alcinosis cutis,
R
aynaud’s phenomenon,
E
sophageal motility defect,
S
clerodactyly,
T
elangiectasias
801
F. BLUE AND/OR PURPLE LESIONS
*** Varicosities Especially after 45 years of age; most common on ventral
tongue and lips
15
*** Submucosal hemorrhage Also see Appendix List, Part 1, E. (previous topic)
Petechial, Ecchymotic, and Telangiectatic Lesions
305
*** Amalgam tattoo Most common on gingiva; blue-gray; radiopaque amalgam
particles sometimes discovered on radiographs
308
*** Mucocele Especially on lower labial mucosa; typically pale blue; cyclic
swelling and rupturing often exhibited
454
** Eruption cyst Overlying an erupting tooth 682
** Salivary duct cyst Usually pale blue 457
** Hemangioma Usually red-purple; may blanch under pressure; onset in
younger patients
538
** Ranula Pale blue, ﬂ
uctuant swelling of lateral ﬂ
oor of mouth 456
** Kaposi’s sarcoma Especially in AIDS patients; usually purple; most common on
palate and maxillary gingiva
270
* Nasopalatine duct cyst Midline of anterior palate 28
* Salivary gland tumors Especially mucoepidermoid carcinoma and pleomorphic
adenoma; usually pale blue; most common on posterior
lateral palate
Chapter 11
* Gingival cyst of the adult Most common in mandibular bicuspid-cuspid region 692
* Blue nevus Most common on hard palate 386
* Malignant melanoma Most common on hard palate and maxillary gingiva; may show
mixture of deep blue, brown, black, and other colors
433
G. BROWN, GRAY, AND/OR BLACK LESIONS
*** Racial pigmentation Most common on attached gingiva in darker complexioned
patients
—
*** Amalgam tattoo Most common on gingiva; usually slate-gray to black; opaque
amalgam particles may be found on radiographs
308
*** Black/brown hairy tongue Discoloration and elongation of ﬁ
liform papillae 13
** Melanotic macule Brown; most common on lower lip 379
** Smoker’s melanosis Most common on anterior facial gingiva 316
** Non-amalgam tattoos Example: graphite from pencil 308
* Melanocytic nevus Most common on hard palate; can be ﬂ
at or raised 382
* Malignant melanoma Most common on hard palate and maxillary gingiva; may show
mixture of deep blue, brown, black, and other colors
433
* Oral melanoacanthoma Rapidly enlarging pigmented lesion; usually occurs in blacks 380
* Drug ingestion Examples: chloroquine, chlorpromazine, minocycline; especially
on hard palate
317
* Peutz-Jeghers syndrome Freckle-like lesions of vermilion and perioral skin; intestinal
polyps; hereditary
753
* Addison’s disease Chronic adrenal insufﬁ
ciency; associated with bronzing of skin 841
* Neuroﬁ
bromatosis type I
Café au lait
pigmentation; cutaneous neuroﬁ
bromas
529
* McCune-Albright
syndrome
Café au lait
pigmentation; polyostotic ﬁ
brous dysplasia;
endocrine disorders
636
* Heavy metal poisoning Typically along marginal gingiva (e.g., lead, bismuth, silver) 313
* Melanotic
neuroectodermal tumor
of infancy
Anterior maxilla; destroys underlying bone 533 http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

OF
O
RAL

AND
M
AXILLOFACIAL
D
ISEASES

923
Frequency
of Occurrence Lesion or Condition Comments or Special Characteristics Page
H. YELLOW LESIONS
*** Fordyce granules Sebaceous glands; usually multiple submucosal papules on
buccal mucosa or upper lip vermilion
7
** Superﬁ
cial abscess Example: parulis from nonvital tooth 136
** Accessory lymphoid
aggregate
Most common in oropharynx and ﬂ
oor of mouth; may exhibit
orange hue
572
** Lymphoepithelial cyst Most common on lingual and palatine tonsils, and ﬂ
oor of
mouth; may be yellow-white
37
** Lipoma Most common on buccal mucosa; soft to palpation 523
* Jaundice Generalized discoloration, especially involving soft palate and
ﬂ
oor of mouth; sclera usually affected also
821
* Verruciform xanthoma Most common on gingiva and hard palate; surface may be
rough or papillary
372
* Pyostomatitis vegetans “Snail-track” pustules; associated with inﬂ
ammatory bowel
disease
850 http://dentalebooks.com

PART 2: MUCOSAL AND SOFT TISSUE PATHOLOGY: SURFACE ALTERATIONS
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
A. VESICULOEROSIVE AND ULCERATIVE LESIONS: ACUTE (SHORT DURATION AND SUDDEN ONSET)
*** Traumatic ulcer Mild-to-moderate pain; history of local trauma 287
*** Aphthous stomatitis Extremely painful; may be single or multiple; nonkeratinized
movable mucosa; often recurs
331
*** Recurrent herpes labialis Vermilion and labial skin; begins as multiple vesicles; often
recurs
243
** Primary herpetic
gingivostomatitis
Fever and malaise; children and young adults; multiple vesicles;
gingiva consistently affected
241
** Necrotizing ulcerative
gingivitis (NUG)
Painful destruction of gingival papillae; fetid odor; mostly in
teenagers and young adults
157
** Mucosal burns Chemical or thermal 289
** Recurrent intraoral herpes
simplex
Gingiva or hard palate (except in immunocompromised); focal
cluster of vesicles and shallow ulcers
244
** Allergic reactions Example: Caused by topical medications or dental materials;
erythema and vesicles
350
** Erythema multiforme Predominantly in children and young adults; multiple blisters
and ulcers; often crusting, hemorrhagic lip lesions; may have
associated “target” skin lesions or involvement of ocular and
genital mucosa (Stevens-Johnson syndrome)
776
** Herpangina Especially in children; multiple small ulcers on soft palate and
tonsillar pillars
257
* Varicella (chickenpox) Associated with skin eruption; few oral vesicles and ulcers;
usually in children
248
* Herpes zoster Unilateral involvement along nerve distribution; usually middle-
aged and older adults; painful vesicles and ulcers
250
* Hand-foot-and-mouth
disease
Especially in children; multiple vesicles and ulcers; associated
vesicles on hands and feet
257
* Necrotizing
sialometaplasia
Usually posterior lateral hard palate; prior swelling may be
present; deep crater-like ulcer; may be only minimal pain
471
* Anesthetic necrosis Usually at site of palatal injection 303
* Primary syphilis Chancre at site of inoculation; usually painless with clean ulcer
bed
188
* Behçet’s syndrome Aphthous-like ulcers; genital ulcers and ocular inﬂ
ammation 336
B. VESICULOEROSIVE AND ULCERATIVE LESIONS: CHRONIC (LONG DURATION)
*** Erosive lichen planus Associated with white striae; usually in middle-aged and older
adults; most common on buccal mucosa and gingiva
(“desquamative gingivitis”)
785
** Squamous cell carcinoma Usually in middle-aged and older adults; usually indurated and
may have rolled border; may be painless
409
** Mucous membrane
pemphigoid
Most common in middle-aged and older women; most
commonly presents as a “desquamative gingivitis”; may
involve ocular and genital mucosa
771
** Traumatic granuloma Solitary, non-healing ulcer 287
* Lupus erythematosus May have associated red and white change; usually with skin
involvement
794
* Pemphigus vulgaris Usually in middle-aged and older patients; multiple oral blisters
and ulcers usually precede skin lesions
765
* Deep fungal infections Examples: histoplasmosis, blastomycosis; may be painless Chapter 6
* Tuberculosis Associated mass may be present; may be painless 195
* Sarcoidosis May be associated with erythematous macules or plaques; may
be painless
338
924http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

OF
O
RAL

AND
M
AXILLOFACIAL
D
ISEASES

925
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
B. VESICULOEROSIVE AND ULCERATIVE LESIONS: CHRONIC (LONG DURATION)—cont’d
* Epidermolysis bullosa Hereditary (except epidermolysis bullosa acquisita); onset in
infancy and childhood; multiple skin and oral blisters or
ulcers in areas of trauma; may result in extensive scarring
761
* Pyostomatitis vegetans Yellowish “snail-track” pustules; associated with inﬂ
ammatory
bowel disease
850
* Wegener’s granulomatosis Usually palatal ulceration and destruction; associated lung and
kidney involvement may be present; may show “strawberry
gingivitis”
345
* Extranodal NK/T-cell
lymphoma, nasal-type
(midline lethal
granuloma)
Palatal lymphoma with ulceration and destruction of underlying
bone; may be painless
602
* Noma Gangrenous necrosis secondary to necrotizing ulcerative
gingivitis; usually in malnourished children or
immunocompromised individuals
201
* Tertiary syphilis Gumma; associated mass may be present; may be painless; may
perforate palate
190
C. PAPILLARY GROWTHS: FOCAL OR DIFFUSE
*** Hairy tongue Usually brown or black discoloration; hyperkeratotic elongation
of ﬁ
liform papillae on posterior dorsal tongue
13
*** Papilloma Can be white or pink; most common on soft palate and tongue;
usually pedunculated
362
*** Inﬂ
ammatory papillary
hyperplasia
Usually involves midportion of hard palate beneath denture 512
** Verruca vulgaris Common wart; especially in younger patients; most common on
labial mucosa
364
** Leukoplakia (some
variants)
Examples: proliferative verrucous leukoplakia, granular or
nodular leukoplakia
391
** Squamous cell carcinoma Examples with papillary surface changes 409
* Hairy leukoplakia Usually lateral border of tongue; rough surface with vertical
ﬁ
ssures; usually associated with HIV infection
268
* Giant cell ﬁ
broma Usually in children and young adults; most common on gingiva 509
* Verruciform xanthoma Most common on gingiva and hard palate 372
* Verrucous carcinoma Especially in older patients with long history of snuff or chewing
tobacco use; especially in mandibular vestibule

and buccal
mucosa; may be white or red
422
* Condyloma acuminatum Venereal wart; broad-based lesions with blunted projections;
frequently multiple
366
* Multifocal epithelial
hyperplasia
Usually multiple, ﬂ
at-topped papular lesions; usually in children;
most common in Native

Americans and Inuit; color may

vary
from normal to white
367
* Darier’s disease Most commonly appears as pebbly appearance of hard palate;
associated crusty, greasy skin

lesions; hereditary
751
* Acanthosis nigricans
(malignant type)
Most commonly appears as generalized pebbly alteration of
upper lip; pigmented, pebbly skin

changes in ﬂ
exural areas;
associated gastrointestinal malignancy
803http://dentalebooks.com

PART 3: MUCOSAL AND SOFT TISSUE PATHOLOGY: MASSES OR ENLARGEMENTS
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
A. SOFT TISSUE MASSES (LUMPS AND BUMPS): LOWER LIP
*** Mucocele Typically pale blue; often exhibits cyclic swelling and rupturing;
labial mucosa only
454
*** Fibroma Usually normal in color 507
** Squamous cell carcinoma Tumor with rough, granular, irregular surface; usually on
vermilion border
409
* Other mesenchymal
tumors
Examples: hemangioma, neuroﬁ
broma, lipoma Chapter 12
* Salivary duct cyst May be bluish; labial mucosa only 457
* Salivary gland tumor Usually mucoepidermoid carcinoma Chapter 11
* Keratoacanthoma Volcano-shaped mass with central keratin plug; rapid
development; vermilion border only
406
B. SOFT TISSUE MASSES (LUMPS AND BUMPS): UPPER LIP
** Fibroma Usually normal in color 507
** Salivary gland tumor Usually canalicular adenoma (older than age 40) or
pleomorphic adenoma (younger than age 40)
Chapter 11
** Salivary duct cyst May be bluish 457
* Minor gland sialolith Small, hard submucosal mass; may be tender 459
* Other mesenchymal
tumors
Examples: hemangioma, neuroﬁ
broma, neurilemoma Chapter 12
* Nasolabial cyst Fluctuant swelling of lateral labial vestibule 27
C. SOFT TISSUE MASSES (LUMPS AND BUMPS): BUCCAL MUCOSA
*** Fibroma Usually normal in color; along occlusal plane 507
** Lipoma May be yellow; soft to palpation 523
** Mucocele Typically pale blue; often exhibits cyclic swelling and rupturing 454
* Hyperplastic lymph node Usually buccinator node; movable submucosal mass 571
* Other mesenchymal
tumors
Examples: hemangioma, neuroﬁ
broma Chapter 12
* Squamous cell carcinoma Tumor with rough, granular, irregular surface 409
* Salivary gland tumor Pleomorphic adenoma and mucoepidermoid carcinoma most
common
Chapter 11
D. SOFT TISSUE MASSES (LUMPS AND BUMPS): GINGIVA/ALVEOLAR MUCOSA
*** Parulis Fistula from nonvital tooth 136
*** Epulis ﬁ
ssuratum Ill-ﬁ
tting denture 510
*** Pyogenic granuloma Usually red, ulcerated, easily bleeding; increased frequency in
pregnant women
517
*** Peripheral ossifying ﬁ
broma May be red or normal in color; may be ulcerated 521
** Peripheral giant cell
granuloma
Reddish purple; frequently ulcerated 520
** Fibroma Usually normal in color 507
* Squamous cell carcinoma Tumor with rough, granular, irregular surface 409
* Metastatic tumors May be painful and destroy bone 563
* Gingival cyst of the adult Most common in mandibular bicuspid-cuspid region; may be
blue
692
* Traumatic neuroma Edentulous mandible in mental foramen area; often painful to
palpation
524
* Kaposi’s sarcoma Especially in AIDS patients; usually purple 270
* Peripheral odontogenic
tumors
Example: peripheral ameloblastoma 710
* Congenital epulis Usually in females; especially anterior maxilla 537
926http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

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RAL

AND
M
AXILLOFACIAL
D
ISEASES

927
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
D. SOFT TISSUE MASSES (LUMPS AND BUMPS): GINGIVA/ALVEOLAR MUCOSA—cont’d
* Melanotic
neuroectodermal tumor
of infancy
Anterior maxilla; destroys underlying bone; may be pigmented 533
* Other mesenchymal
tumors
Examples: hemangioma, neuroﬁ
broma Chapter 12
E. SOFT TISSUE MASSES (LUMPS AND BUMPS): FLOOR OF MOUTH
** Ranula/mucocele Typically a pale blue, ﬂ
uctuant swelling 456
** Sialolith Usually hard mass in submandibular duct; may be associated
with tender swelling of affected gland; radiopaque mass
459
** Squamous cell carcinoma Tumor with rough, granular, irregular surface 409
** Lymphoepithelial cyst Small, yellow-white submucosal lesion 37
* Epidermoid or dermoid
cyst
Midline yellow-white submucosal lesion 33
* Salivary gland tumors Especially mucoepidermoid carcinoma Chapter 11
* Mesenchymal tumors Examples: lipoma, neuroﬁ
broma, hemangioma Chapter 12
F. SOFT TISSUE MASSES (LUMPS AND BUMPS): TONGUE
*** Fibroma Usually normal in color; most common on margins of tongue 507
** Squamous cell carcinoma Tumor with rough, granular, irregular surface 409
** Mucocele Usually anterior ventral surface; usually bluish or clear color 454
* Granular cell tumor Dome-shaped; usually on dorsum of tongue 536
* Other mesenchymal
tumors
Examples: lymphangioma, hemangioma, neuroﬁ
broma, osseous
choristoma
Chapter 12
* Pyogenic granuloma Usually red, ulcerated, easily bleeding 517
* Salivary gland tumors Especially mucoepidermoid carcinoma and adenoid cystic
carcinoma
Chapter 11
* Lingual thyroid Usually posterior midline of dorsal surface; usually in women 12
G. SOFT TISSUE MASSES (LUMPS AND BUMPS): HARD OR SOFT PALATE
*** Palatal abscess Associated with nonvital tooth 136
*** Leaf-like denture ﬁ
broma Pedunculated hyperplastic growth beneath ill-ﬁ
tting denture 511
** Salivary gland tumors Especially pleomorphic adenoma, mucoepidermoid carcinoma,
adenoid cystic carcinoma, polymorphous low-grade
adenocarcinoma; may have bluish hue
Chapter 11
** Kaposi’s sarcoma Usually purple; may be multiple; usually associated with AIDS 270
** Nasopalatine duct cyst Fluctuant swelling of anterior midline palate 28
* Other mesenchymal
tumors
Examples: ﬁ
broma, hemangioma, neuroﬁ
broma Chapter 12
* Squamous cell carcinoma Tumor with rough, granular, irregular surface; occasionally
arises from maxillary sinus
409
* Mucocele/salivary duct
cyst
Usually has bluish hue 454
* Lymphoma Often boggy and edematous; may have bluish hue; may be
bilateral
595
* Melanocytic nevus/
melanoma
Usually pigmented 382, 433
* Necrotizing
sialometaplasia
Early stage lesion; often associated with pain or paresthesia 471
* Adenomatoid hyperplasia
of minor salivary glands
Asymptomatic, painless mass 471

Continuedhttp://dentalebooks.com

928
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Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
H. SOFT TISSUE MASSES (LUMPS AND BUMPS): MULTIPLE LESIONS
** Kaposi’s sarcoma Usually purple lesions of palate and maxillary gingiva; usually
associated with AIDS
270
** Neuroﬁ
bromatosis type I
Oral and skin neuroﬁ
bromas;
café au lait
skin pigmentation
529
* Multifocal epithelial
hyperplasia
Usually ﬂ
at-topped papular lesions; usually in children; most
common in Native Americans and Inuit; color may vary from
normal to white
367
* Amyloidosis Pale, ﬁ
rm deposits, especially in tongue; periocular cutaneous
lesions frequently present; most often associated with
multiple myeloma
822
* Granulomatous diseases Examples: sarcoidosis, Crohn’s disease, leprosy 338
* Multiple endocrine
neoplasia type 2B
Mucosal neuromas of lips and tongue; adrenal
pheochromocytomas; medullary thyroid carcinoma;
marfanoid body build
532
* Tuberous sclerosis Small ﬁ
broma-like growths on gingiva; angioﬁ
bromas of face;
epilepsy; mental retardation
757
* Multiple hamartoma
syndrome
Cowden syndrome; small ﬁ
broma-like growths on gingiva;
multiple hamartomas of various tissues; breast cancer in
affected women
760
I. SOFT TISSUE MASSES (LUMPS AND BUMPS): MIDLINE NECK LESIONS
** Thyroid gland
enlargement
Examples: goiter, thyroid tumor —
* Thyroglossal duct cyst May move up and down with tongue motion 35
* Dermoid cyst Soft and ﬂ
uctuant 33
* Plunging ranula Soft and compressible 457
J. SOFT TISSUE MASSES (LUMPS AND BUMPS): LATERAL NECK LESIONS
*** Reactive
lymphadenopathy
Secondary to oral and maxillofacial infection; often tender to
palpation
571
** Epidermoid cyst Soft and movable 32
** Lipoma Soft mass 523
** Infectious mononucleosis Fatigue; sore throat; tender lymph nodes 253
** Metastatic carcinoma Deposits from oral and pharyngeal carcinomas; usually
indurated and painless; may be ﬁ
xed
417
** Lymphoma May be unilateral or bilateral; usually painless; Hodgkin’s and
non-Hodgkin’s types
592
* Salivary gland tumors Arising from submandibular gland or tail of parotid gland Chapter 11
* Submandibular sialadenitis Example: secondary to sialolithiasis 461
* Cervical lymphoepithelial
cyst
Soft and ﬂ
uctuant; most common in young adults 36
* Granulomatous diseases Examples: tuberculosis, sarcoidosis 197, 338
* Cat-scratch disease History of exposure to cat 205
* Cystic hygroma Infants; soft and ﬂ
uctuant 547
* Plunging ranula Soft and compressible 457
* Other mesenchymal
tumors
Examples: neuroﬁ
broma, carotid body tumor Chapter 12
K. GENERALIZED GINGIVAL ENLARGEMENT
*** Hyperplastic gingivitis Examples: associated with puberty, pregnancy, diabetes 156
** Drug-related gingival
hyperplasia
Examples: phenytoin, calcium-channel blockers, cyclosporine;
may be ﬁ
brotic
163
* Gingival ﬁ
bromatosis May be hereditary; onset in childhood 166
* Leukemic inﬁ
ltrate Usually boggy and hemorrhagic 587
* Wegener’s granulomatosis “Strawberry” gingivitis; may have palatal ulceration and
destruction; lung and kidney involvement
345
* Scurvy Vitamin C deﬁ
ciency 826http://dentalebooks.com

PART 4: RADIOGRAPHIC PATHOLOGY
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
A. UNILOCULAR RADIOLUCENCIES: PERICORONAL LOCATION
*** Hyperplastic dental
follicle
<
5 mm in thickness 680
*** Dentigerous cyst
>
5 mm in thickness 679
** Eruption cyst Bluish swelling overlying erupting tooth 682
** Odontogenic keratocyst — 683
* Orthokeratinized
odontogenic cyst
— 687
* Ameloblastoma Especially unicystic type 702
* Ameloblastic ﬁ
broma Usually in younger patients 719
* Adenomatoid
odontogenic tumor
Usually in anterior region of jaws; most often with maxillary
canine; usually in teenagers
713
* Calcifying odontogenic
cyst
Gorlin cyst 695
* Carcinoma arising in
dentigerous cyst
Mostly in older adults 700
* Intraosseous muco-
epidermoid carcinoma
Mostly in posterior mandible 490
* Other odontogenic
lesions
Examples: calcifying epithelial odontogenic tumor, odontogenic
myxoma, central odontogenic ﬁ
broma
Chapter 15
B. UNILOCULAR RADIOLUCENCIES: PERIAPICAL LOCATION
*** Periapical granuloma Nonvital tooth 127
*** Periapical cyst Nonvital tooth 130
** Periapical cemento-
osseous dysplasia (early)
Especially in black females; usually apical to mandibular
anteriors; teeth are vital
641
* Periapical scar Usually endodontically treated tooth with destruction of
cortical plate
130
* Dentin dysplasia type I Multiple periapical granulomas or cysts; shortened, malformed
roots
108
C. UNILOCULAR RADIOLUCENCIES: OTHER LOCATIONS
*** Developing tooth bud Within alveolar bone —
** Lateral radicular cyst Nonvital tooth; lateral canal 132
** Nasopalatine duct cyst Between and apical to maxillary central incisors; palatal
swelling may occur
28
** Lateral periodontal cyst Especially in mandibular bicuspid-cuspid region 692
** Residual (periapical) cyst Edentulous area 132
** Odontogenic keratocyst — 683
** Central giant cell
granuloma
Especially in anterior mandible 626
** Stafne bone defect Angle of mandible below mandibular canal 24
* Cemento-osseous
dysplasia
Early stage; usually in young adult and middle-aged black
women; usually in mandible
640
* Central ossifying ﬁ
broma Early-stage lesion 646
* Ameloblastoma Especially unicystic type 702
* Other odontogenic cysts
and tumors
Examples: ameloblastic ﬁ
broma, central odontogenic ﬁ
broma,
calcifying odontogenic cyst
Chapter 15
* Langerhans cell
histiocytosis
“Histiocytosis X”; usually in children or young adults 590

Continued
929http://dentalebooks.com

930
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Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
C. UNILOCULAR RADIOLUCENCIES: OTHER LOCATIONS—cont’d
* Melanotic
neuroectodermal tumor
of infancy
Anterior maxilla; may be pigmented 533
* Median palatal cyst Clinical midline swelling of hard palate 31
* Neurilemoma/neuroﬁ
broma
Usually associated with mandibular nerve 528
D. MULTILOCULAR RADIOLUCENCIES
*** Odontogenic keratocyst — 683
*** Ameloblastoma Especially in posterior mandible; often associated with
impacted tooth
702
** Central giant cell
granuloma
Especially in anterior mandible 626
* Ameloblastic ﬁ
broma Especially in younger patients 719
* Odontogenic myxoma “Cobweb” trabeculation 729
* Central odontogenic
ﬁ
broma
— 726
* Calcifying epithelial
odontogenic tumor
Often associated with impacted tooth 716
* Orthokeratinized
odontogenic cyst
Often associated with impacted tooth 687
* Lateral periodontal cyst
(botryoid type)
Especially in mandibular bicuspid-cuspid region 692
* Calcifying odontogenic
cyst
Especially in cases with minimal or no calciﬁ
cations; often
associated with impacted tooth
695
* Central hemangioma/
arteriovenous
malformation
Especially in younger patients; may have honeycombed
radiographic appearance; may pulsate
540
* Aneurysmal bone cyst Especially in younger patients 634
* Cherubism Hereditary; onset in childhood; multiple quadrants involved 629
* Hyperparathyroidism
(brown tumor)
Usually elevated serum calcium levels 838
* Intraosseous muco-
epidermoid carcinoma
Usually in posterior mandible 490
* Fibrous dysplasia Very rarely on panoramic ﬁ
lms of mandibular lesions 635
E. RADIOLUCENCIES: POORLY DEFINED OR RAGGED BORDERS
*** Periapical granuloma or
cyst
Nonvital tooth 127
*** Focal osteoporotic
marrow defect
Especially edentulous areas in posterior mandible; more
common in females
619
** Osteomyelitis Usually painful or tender 141
** Bisphosphonate-
associated
osteonecrosis
Exposed necrotic bone 299
* Simple bone cyst Mandibular lesion that scallops up between roots of teeth;
usually in younger patients
631
* Metastatic tumors Painful; paresthesia; usually in older adults 669
* Osteoradionecrosis History of radiation therapy; painful 296
* Multiple myeloma May be painful; in older adults 604
* Primary intraosseous
carcinomas
Odontogenic or salivary origin 711
* Osteosarcoma Often painful; usually in young adults 660
* Chondrosarcoma — 664
* Ewing’s sarcoma Almost always in children 667
* Other primary bone
malignancies
Examples: ﬁ
brosarcoma, lymphoma —http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

OF
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AND
M
AXILLOFACIAL
D
ISEASES

931
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
E. RADIOLUCENCIES: POORLY DEFINED OR RAGGED BORDERS—cont’d
* Desmoplastic ﬁ
broma of
bone
Especially in younger patients 658
* Massive osteolysis Phantom (vanishing) bone disease 622
* NICO (neuralgia-inducing
cavitational
osteonecrosis)
Local or referred pain 866
F. RADIOLUCENCIES: MULTIFOCAL OR GENERALIZED
*** Cemento-osseous
dysplasia
Early stage lesions; usually in black females; usually in mandible 640
** Nevoid basal cell
carcinoma syndrome
Odontogenic keratocysts 688
** Multiple myeloma Painful; in older adults; “punched-out” lesions 604
* Cherubism Usually multilocular; onset in childhood; hereditary 629
* Hyperparathyroidism Multiple brown tumors 838
* Langerhans cell
histiocytosis
“Histiocytosis X”; in children and young adults; teeth “ﬂ
oating
in air”
590
G. RADIOPACITIES: WELL-DEMARCATED BORDERS
*** Torus or exostosis Associated with bony surface mass 19
*** Retained root tip Remnants of periodontal ligament usually seen —
*** Condensing osteitis Usually at apex of nonvital tooth 147
*** Idiopathic osteosclerosis Most commonly associated with roots of posterior teeth; no
apparent inﬂ
ammatory etiology
620
** Pseudocyst of the
maxillary sinus
Homogeneous, dome-shaped relative opacity rising above bony
ﬂ
oor of maxillary sinus
320
** Odontoma, compound Toothlike structures with thin, radiolucent rim at junction with
surrounding bone; may prevent eruption of teeth; more
common in anterior segments of jaws
724
** Odontoma, complex Amorphous mass with thin, radiolucent rim at junction with
surrounding bone; may prevent eruption of teeth; more
common in posterior segments of jaws
724
** Cemento-osseous
dysplasia
Late-stage lesions; especially in middle-aged and older black
women; usually in mandible
640
** Soft tissue radiopacity
superimposed on bone
Examples: sialoliths, calciﬁ
ed nodes, phleboliths, bullet
fragments, shotgun pellets, amalgam tattoos (See also
Appendix List, Part 4, Q, page 933)
—
* Intraosseous foreign body — —
* Osteoma Associated with bony surface mass 650
* Enamel pearl Furcation area of molar tooth 93
* Osteoblastoma/osteoid
osteoma/cementoblastoma
Late-stage lesions 653
H. RADIOPACITIES: POORLY DEMARCATED BORDERS
** Cemento-osseous
dysplasia
Late stage lesions; especially in middle-aged and older black
women; usually in mandible
640
** Condensing osteitis Usually at apex of nonvital tooth 147
** Bisphosphonate-
associated
osteonecrosis
Sclerosis of alveolar crestal bone; exposed necrotic bone 299
** Sclerosing osteomyelitis May be painful 144
** Fibrous dysplasia “Ground glass” appearance; onset usually in younger patients 635
* Paget’s disease of bone “Cotton wool” appearance; late-stage lesions; in older patients 623
* Proliferative periostitis “Onion-skin” cortical change; in younger patients; often
associated with nonvital tooth
148

Continuedhttp://dentalebooks.com

932
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Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
H. RADIOPACITIES: POORLY DEMARCATED BORDERS—cont’d
* Osteosarcoma May have “sunburst” cortical change; frequently painful; usually
in young adults
660
* Chondrosarcoma — 664
I. RADIOPACITIES: MULTIFOCAL OR GENERALIZED
** Florid cemento-osseous
dysplasia
Late-stage lesions; especially in middle-aged and older black
women; usually in mandible
641
** Idiopathic osteosclerosis — 620
** Bisphosphonate-
associated
osteonecrosis
Multifocal sites of involvement; sclerosis of alveolar crestal
bone; exposed necrotic bone
299
* Paget’s disease of bone “Cotton wool” appearance; late-stage lesions; in older patients;
more common in maxilla
623
* Gardner syndrome Multiple osteomas; epidermoid cysts; gastrointestinal polyps
with high tendency toward malignant transformation;
hereditary
651
* Polyostotic ﬁ
brous
dysplasia
“Ground glass” appearance; onset usually in younger patients;
may be associated with
café au lait
skin pigmentation and
endocrine abnormalities (McCune-Albright syndrome)
635
* Osteopetrosis Hereditary; recessive form may be associated with secondary
osteomyelitis, visual and hearing impairment
615
J. MIXED RADIOLUCENT/RADIOPAQUE LESIONS: WELL-DEMARCATED BORDERS
*** Developing tooth — —
** Cemento-osseous
dysplasia
Intermediate-stage lesions; especially in middle-aged black
women; usually in mandible
640
** Odontoma Compound or complex type; in younger patients; may prevent
eruption of teeth
724
* Central ossifying ﬁ
broma — 646
* Ameloblastic
ﬁ
bro-odontoma
Usually in children 721
* Adenomatoid
odontogenic tumor
Usually in anterior region of jaws; most often with maxillary
canine; usually in teenagers
713
* Calcifying epithelial
odontogenic tumor
Pindborg tumor; often associated with impacted tooth; may
show “driven snow” opacities
716
* Calcifying odontogenic
cyst
Gorlin cyst; may be associated with odontoma 695
* Osteoblastoma/osteoid
osteoma
Intermediate-stage lesion; usually in younger patients; often
painful
653
* Cementoblastoma Intermediate-stage lesion; attached to tooth root 655
K. MIXED RADIOLUCENT/RADIOPAQUE LESIONS: POORLY DEMARCATED BORDERS
** Osteomyelitis With sequestrum formation or with sclerosing type; often
painful
141
** Bisphosphonate-associated
osteonecrosis
Exposed necrotic bone 299
* Metastatic carcinoma Especially prostate and breast carcinomas; may be painful 669
* Osteosarcoma/
chondrosarcoma
May be painful 660http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

OF
O
RAL

AND
M
AXILLOFACIAL
D
ISEASES

933
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
L. MIXED RADIOLUCENT/RADIOPAQUE LESIONS: MULTIFOCAL OR GENERALIZED
** Florid cemento-osseous
dysplasia
Intermediate-stage lesions; especially in middle-aged black
women; usually in mandible
641
** Bisphosphonate-associated
osteonecrosis
Exposed necrotic bone 299
* Paget’s disease of bone In older patients; more common in maxilla 623
M. UNIQUE RADIOGRAPHIC APPEARANCES: “GROUND GLASS” (FROSTED GLASS) RADIOPACITIES
* Fibrous dysplasia Onset usually in younger patients 635
* Hyperparathyroidism May cause loss of lamina dura 838
N. UNIQUE RADIOGRAPHIC APPEARANCES: “COTTON WOOL” RADIOPACITIES
** Cemento-osseous
dysplasia
Especially in middle-aged black women; usually in mandible 640
* Paget’s disease of bone In older patients; more common in maxilla 623
* Gardner syndrome Multiple osteomas; epidermoid cysts; gastrointestinal polyps
with high tendency toward malignant transformation;
hereditary
651
* Gigantiform cementoma Hereditary; facial enlargement may be present 645
O. UNIQUE RADIOGRAPHIC APPEARANCES: “SUNBURST” RADIOPACITIES
* Osteosarcoma Often painful; usually in young adults 660
* Intraosseous hemangioma Especially in younger patients 540
P. UNIQUE RADIOGRAPHIC APPEARANCES: “ONION-SKIN” RADIOPACITIES
* Proliferative periostitis In younger patients; often associated with nonvital tooth; best
seen with occlusal radiograph
148
* Ewing sarcoma In young children 667
* Langerhans cell
histiocytosis
“Histiocytosis X”; usually in children or young adults 590
Q. SOFT TISSUE RADIOPACITIES
*** Amalgam tattoo Markedly radiopaque; associated with surface discoloration 308
** Other foreign bodies Examples: bullet fragments, shotgun pellets —
** Sialolith Glandular pain may be present while patient is eating 459
** Calciﬁ
ed lymph nodes Example: tuberculosis 197
** Phlebolith May occur in varicosities or hemangiomas 16
* Tonsillolith — 185
* Osseous and cartilaginous
choristomas
Most common on tongue 552
* Calcinosis cutis May be seen with systemic sclerosis (especially CREST
syndrome)
801
* Myositis ossiﬁ
cans Reactive calciﬁ
cation in muscle —http://dentalebooks.com

PART 5: PATHOLOGY OF TEETH
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
A. HYPERDONTIA (EXTRA TEETH)
*** Idiopathic supernumerary
teeth
Mesiodens, paramolar, distomolar 77
** Cleft lip and palate Extra lateral incisor or canine 1
* Gardner syndrome Osteomas and gastrointestinal polyps 651
* Cleidocranial dysplasia Hypoplastic or missing clavicles; failure of tooth eruption 618
B. HYPODONTIA (MISSING TEETH)
*** Idiopathic hypodontia Missing third molars, lateral incisors 77
** Cleft lip and palate Missing lateral incisor or canine 1
* Hereditary hypohidrotic
ectodermal dysplasia
Cone-shaped teeth 741
* Incontinentia pigmenti Cone-shaped teeth 750
* Radiotherapy during
childhood
Stunted tooth development 58
C. MACRODONTIA (LARGER THAN NORMAL TEETH)
** Fusion Joining of two tooth germs 84
** Gemination Incomplete splitting of a tooth germ 84
* Idiopathic macrodontia — 83
* Facial hemihyperplasia Affected side only; nondental tissues also enlarged 38
* Gigantism Abnormally tall stature 831
D. MICRODONTIA (SMALLER THAN NORMAL TEETH)
*** Supernumerary teeth Mesiodens; fourth molars 77
*** Peg-shaped lateral incisors Cone-shaped teeth 83
** Dens invaginatus Cone-shaped teeth; tendency for pulpal death and periapical
pathosis
90
** Cleft lip and palate Lateral incisor or canine 1
* Idiopathic microdontia Usually generalized 83
* Hereditary hypohidrotic
ectodermal dysplasia
Cone-shaped teeth; sparse, blond hair; diminished sweating 741
* Radiotherapy during
childhood
Stunted tooth development 58
* Congenital syphilis Hutchinson’s incisors 190
* Hypopituitarism Associated dwarﬁ
sm 831
E. MALFORMED CROWN
*** Mesiodens and other
supernumeraries
Cone-shaped teeth or microdont 77
** Environmental enamel
hypoplasia
Example: high fever during tooth development 55
** Peg-shaped lateral incisors Cone-shaped teeth 83
** Dens invaginatus Cone-shaped teeth; tendency toward pulpal death and
periapical pathosis
90
** Turner’s tooth Infection or trauma to associated primary tooth 56
** Fusion or gemination “Double” tooth 84
* Talon cusp Extra cusp on lingual of anterior tooth 87
* Dens evaginatus Extra cusp on occlusal of premolar tooth 88
* Amelogenesis imperfecta Hereditary defect in enamel formation 99
* Dentinogenesis imperfecta Fracturing away of enamel due to hereditary defect in dentin
formation; gray-yellow opalescent teeth; calciﬁ
ed pulp
chambers
106
934http://dentalebooks.com

Appendix
D
IFFERENTIAL
D
IAGNOSIS

OF
O
RAL

AND
M
AXILLOFACIAL
D
ISEASES

935
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
E. MALFORMED CROWN—cont’d
* Regional odontodysplasia Poor tooth formation in a focal area; “ghost teeth” 112
* Congenital syphilis Hutchinson’s incisors; mulberry molars 190
* Vitamin D–resistant rickets Hereditary condition; high pulp horns 847
* Renal osteodystrophy Abnormal calcium and phosphate metabolism 839
* Hypoparathyroidism Possible associated endocrine-candidiasis syndrome 837
* Pseudohypoparathyroidism — 837
* Epidermolysis bullosa Hereditary blistering skin disease 761
* Radiotherapy during
childhood
Stunted tooth development 58
F. ENAMEL LOSS AFTER TOOTH FORMATION
*** Caries — —
*** Trauma Fractured tooth —
*** Attrition Physiologic loss of tooth structure 60
*** Abrasion Pathologic loss of tooth structure 60
** Erosion Chemical loss of tooth structure 60
* Dentinogenesis imperfecta Hereditary defect in dentin formation; poor junction between
enamel and dentin
106
* Amelogenesis imperfecta Hereditary defect in enamel formation; especially hypocalciﬁ
ed
types
99
G. EXTRINSIC STAINING OF TEETH
*** Tobacco Black or brown 70
*** Coffee, tea, and cola drinks Brown or black 70
** Chromogenic bacteria Brown, black, green, or orange 70
** Chlorhexidine Yellow-brown 70
H. INTRINSIC DISCOLORATION (“STAINING”) OF TEETH
*** Aging Yellow-brown; less translucency —
*** Death of pulp Gray-black; less translucency 72
** Fluorosis White; yellow-brown; brown; mottled 58
** Tetracycline Yellow-brown; yellow ﬂ
uorescence 73
** Internal resorption “Pink tooth of Mummery” 65
* Calciﬁ
c metamorphosis Yellow 123
* Dentinogenesis imperfecta Blue-gray; translucent 106
* Amelogenesis imperfecta Yellow-brown 99
* Congenital erythropoietic
porphyria
Yellow; brown-red; red ﬂ
uorescence 71
* Erythroblastosis fetalis Yellow; green 71
I. ABNORMALLY SHAPED ROOTS
*** External root resorption Secondary to infection, cyst, tumor 65
*** Dilaceration Abnormal curvature 97
** Hypercementosis Excessive cementum production 96
** Supernumerary roots — 98
** Concrescence Joining of teeth by cementum 84
** Taurodontism Enlarged pulp chambers; shortened roots 94
** Enamel pearl Ectopic enamel in furcation 93
* Benign cementoblastoma Tumor attached to root 655
* Radiotherapy during
childhood
Stunted root development 58
* Dentinogenesis imperfecta Shortened roots; obliterated pulps 106
* Dentin dysplasia type I Shortened, pointed roots (“rootless teeth”); obliterated pulps;
periapical pathosis
108

Continuedhttp://dentalebooks.com

936
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PPENDIX
Frequency of
Occurrence Lesion or Condition Comments or Special Characteristics Page
J. ENLARGED PULP CHAMBER OR CANAL
** Internal resorption Secondary to caries or trauma 65
** Taurodontism Enlarged pulp chambers; shortened roots 94
* Dentinogenesis imperfecta “Shell teeth” 106
* Regional odontodysplasia “Ghost teeth” 112
* Vitamin D–resistant rickets High pulp horns 847
* Hypophosphatasia — 845
* Dentin dysplasia type II “Thistle-tube” pulps; pulp stone formation 108
K. PULPAL CALCIFICATION
*** Pulp stones Asymptomatic radiographic ﬁ
nding 126
*** Secondary dentin Response to caries 123
** Calciﬁ
c metamorphosis Pulpal obliteration secondary to aging or trauma 123
* Dentinogenesis imperfecta Pulpal obliteration by excess dentin 106
* Dentin dysplasia type I Pulpal obliteration by excess dentin; “chevron”-shaped pulp
chambers
108
* Dentin dysplasia type II Pulpal obliteration of primary teeth; pulp stones in permanent
teeth
108
L. THICKENED PERIODONTAL LIGAMENT
*** Periapical abscess Focal thickening at apex of nonvital tooth; painful, especially on
percussion of involved tooth
135
*** Current orthodontic
therapy
——
** Increased occlusal function — —
* Systemic sclerosis
(scleroderma)
Generalized widening 798
* Sarcoma or carcinoma
inﬁ
ltration
Especially osteosarcoma; localized to teeth in area of tumor 661, 669
M. GENERALIZED LOSS OF LAMINA DURA
* Hyperparathyroidism Calcium removed from bones; bone may have “ground glass”
appearance
838
* Osteomalacia Vitamin D deﬁ
ciency in adults 827
* Paget’s disease of bone “Cotton wool” change hides lamina dura 623
* Fibrous dysplasia “Ground glass” change hides lamina dura 635
N. PREMATURE EXFOLIATION OF TEETH
*** Trauma Avulsed tooth —
** Aggressive periodontitis Premature alveolar bone loss 173
** Immunocompromised
states
AIDS, leukemia, chemotherapy 272
** Diabetes mellitus Increased susceptibility to infection and severity of periodontitis 842
* Osteomyelitis Bone destruction loosening teeth 141
* Cyclic or chronic
neutropenia
Increased susceptibility to infection; premature alveolar bone
loss
583
* Langerhans cell
histiocytosis
“Histiocytosis X”; eosinophilic granuloma; premature alveolar
bone loss
590
* Dentin dysplasia type I “Rootless teeth” 108
* Regional odontodysplasia “Ghost teeth” 112
* Papillon-Lefèvre syndrome Palmar and plantar hyperkeratosis; premature periodontitis 176
* Down syndrome Premature periodontitis —
* Hypophosphatasia Lack of cementum production in primary teeth 845
* Scurvy Vitamin C deﬁ
ciency 826 http://dentalebooks.com

Index
Page numbers followed by
f
indicate ﬁ
gures;
t,
tables;
b,
boxes.
Acquired immunodeﬁ
ciency syndrome
(AIDS), 264-281.
See also

Human immunodeﬁ
ciency
virus (HIV) infection.
cytomegalovirus coinfection in, 245
cytomegalovirus infections in, 255
disseminated histoplasmosis in, 225
Acral keratosis, in multiple hamartoma
syndrome, 760
Acral lentiginous melanoma
clinical features of, 435, 435f, 436f
histopathologic features of, 436, 436f
Acro-osteolysis, in systemic sclerosis,
798, 798f
Acrobrachycephaly, in Apert syndrome,
43
Acrodynia, from mercury exposure in
infants and children, 315
Acrodysostosis, 837-838
Acromegaly, oral manifestations of, 832-
833, 832f, 833f
Acrosclerosis, 801-803
Actinic cheilosis, 404, 405-406, 405f,
406f
lip vermilion carcinoma associated
with, 414
Actinic elastosis, 406
Actinic keratosis, 404-405, 404f, 405f
in xeroderma pigmentosum, 747-748
Actinic lentigines, in seborrheic
keratosis, 374
Actinic lentigo, 377-378, 377f, 378f
Actinomycosis, 203-205, 203f, 204f
Acute apical periodontitis, 135
Acute atrophic candidiasis, 215
Acute chest syndrome, in sickle cell
crisis, 577
Acute herpetic gingivostomatitis
clinical features of, 242, 242f, 243f
treatment and prognosis of, 246-247
Acyclovir
for acute herpetic gingivostomatitis,
246
for herpes zoster, 252
prophylactic, for immunocompromised
patients, 247
for recurrent herpes labialis, 247
for varicella, 249-250
Adamantiades syndrome, 336-338
Addison’s disease, 841-842
disseminated histoplasmosis and, 225
paracoccidioidomycosis and, 229
937
Adenine arabinoside (vidarabine), for
herpes lesions in
immunocompromised patients,
247
Adenocarcinoma(s)
acinic cell, 491-492, 491f, 492f
basal cell, 485
colon, metastatic, 564f
low-grade, polymorphous, 497-498,
497f, 498f
salivary, 498-499, 499f
Adenoid cystic carcinoma, 495-497,
495f, 496f
Adenoid form, of seborrheic keratosis,
375
Adenolymphoma, 482
Adenoma(s)
basal cell, 484-485, 485f
canalicular, 484, 484f
carcinoma ex pleomorphic
clinical features of, 493, 493f
histopathologic features of, 494
treatment and prognosis of, 494
monomorphic, 483-484
oxyphilic, 480-481, 481f
pituitary, gigantism from, 831-832
pleomorphic, 477-480, 477f, 478f,
479f, 480f.
See also

Pleomorphic adenoma.
Adenomatoid hyperplasia of minor
salivary glands, 471
Adenomatoid odontogenic tumors,
713-715, 713f, 714f, 715f
calcifying odontogenic cysts associated
with, 695
Adenosquamous carcinoma, 425
African Burkitt’s lymphoma, 600
Age spot, 377-378
Aggressive periodontitis, 173-176.
See
also
Periodontitis, aggressive.
Aglossia, 9
Agranulocytosis, 582-583
AIDS.
See
Acquired immunodeﬁ
ciency
syndrome.
AIDS-dementia complex, 266
AIDS-related complex (ARC), 266
Air introduction
into parotid duct, 323
into tissues, cervicofacial emphysema
from, 323-324, 323f
Alarm clock headache, 869
Albers-Schönberg disease, 615-617
A
Abfraction, tooth wear by, 61-62, 64, 64f
Abrasion, tooth wear by, 61-62, 62f, 63f
Abscess(es)
gingival, 171
Munro
in erythema migrans, 781, 781f
in psoriasis, 794
periapical, 128, 135-138.
See also

Periapical abscess.
periodontal
clinical and radiographic features
of, 170-171, 170f, 171f
treatment and prognosis of, 173
Abuse
human
classiﬁ
cation of, 911-912
epidemiology of, 911-912, 912b
recognizing and reporting, dentistry
in, 913-914
signs and symptoms of, 912-913,
912f, 913f
methamphetamine, orofacial
complications of, 303, 303f
ABVD regimen, for Hodgkin’s
lymphoma, 595
Acantholysis
in Darier’s disease, 751
in pemphigus vulgaris, 768, 768f
Acantholytic dyskeratosis, focal, 752-753
Acanthomatous ameloblastoma, 705-
706, 706f
Acanthosis
in leukoplakia, 394
in nicotine stomatitis, 403, 403f
Acanthosis nigricans, 803-804, 803f,
804f
Acanthotic form, of seborrheic keratosis,
375
Accessory cusps, 87-90
clinical features of, 87-89
cusp of Carabelli as, 87, 87f
dens evaginatus as, 88-89, 89f
prognosis for, 90
radiographic features of, 87-89
talon cusp as, 87-88, 88f
treatment of, 89-90
Accidents, mass fatality identiﬁ
cation in,
dentistry’s role in, 900
Acinic cell adenocarcinoma, 491-492,
491f, 492f
Ackerman’s tumor, 422-423http://dentalebooks.com

938 Index
Albright hereditary osteodystrophy,
837-838
Alcohol
leukoplakia and, 389
squamous cell carcinoma and,
411
Alkaline phosphatase, serum levels of,
elevated, in diagnosis of Paget’s
disease of bone, 625
Alkaptonuria, tooth discoloration in, 71
Allergic contact stomatitis, 350-351
Allergic fungal sinusitis, 234
Allergic mucosal reactions to systemic
drug administration, 347-350
clinical features of, 348-349, 349f
diagnosis of, 349-350
histopathologic features of, 349
treatment and prognosis of, 350
Allergies
allergic contact stomatitis as, 350-351
allergic mucosal reactions to systemic
drug administration as,
347-350
lichenoid contact stomatitis from
dental restorative materials,
354-356
orofacial granulomatosis as, 341-345.
See also
Orofacial
granulomatosis.
ALS (amyotrophic lateral sclerosis), 873
Alternate light source photography, of
bite marks for evidence, 909
Alveolar cavitational osteopathosis,
866-868
Alveolar cyst, of newborn, 691-692,
692f
Alveolar osteitis, 150-151
Alveolar rhabdomyosarcoma, 560t, 561
Alveolar soft-part sarcoma, 562-563,
562f
Alveolitis, ﬁ
brinolytic, 150-151
Amalgam, dental
lichenoid reaction to, lichen planus
resembling, 785
mercury in, lichenoid contact
stomatitis from, 354-355
tooth discoloration from, 72-73, 73f
Amalgam tattoo, 308-311, 309f, 310f,
311f
AMBN
gene mutation, in amelogenesis
imperfecta, 100
Amelanotic melanoma, 435
Ameloblastic carcinoma, 711-712, 711f,
712f
Ameloblastic carcinosarcoma, 723
Ameloblastic dentinosarcomas, 723
Ameloblastic ﬁ
bro-odontoma, 721-722,
721f, 722f, 724
Ameloblastic ﬁ
bro-odontosarcomas, 723
Ameloblastic ﬁ
brodentinoma, 722
Ameloblastic ﬁ
broma, 719-720, 720f,
722
Ameloblastic ﬁ
brosarcoma, 722-723,
723f
Ameloblastic sarcoma, 722-723, 723f
Ameloblastin disorders, in amelogenesis
imperfecta, 100
Ameloblastoma(s)
calcifying odontogenic cysts associated
with, 695
conventional solid or multicystic
intraosseous, 702-707
acanthomatous pattern of, 705-706,
706f
basal cell pattern of, 706-707, 707f
clinical and radiographic features
of, 702-704, 703f, 704f, 705f
desmoplastic pattern of, 706, 706f
follicular pattern of, 705, 705f
granular cell pattern of, 706, 706f
histopathologic features of, 705-
707, 705f, 706f, 707f
plexiform pattern of, 705, 706f
treatment and prognosis of, 707,
707f
dentigerous cysts evolving into, 682
extraosseous, 710-711
malignant, 711-712
peripheral, 710-711, 710f
pigmented, 533
unicystic, 708-710, 708f, 709f
Ameloblasts, damage to, enamel defects
from, 55
Amelogenesis imperfecta, 55, 99-106
classiﬁ
cation of, 99, 99t
modiﬁ
ed, 100t
clinical and radiographic features of,
101-105
histopathologic features of, 105
hypocalciﬁ
ed, 103-104, 104f
hypomaturation, 102-103, 104f
hypoplastic, 101-102, 101f, 102f,
103f
with taurodontism, 104-105, 105f
treatment and prognosis of, 105-106
Amelogenin, disorders of, in
amelogenesis imperfecta, 100
AMELX
gene mutation, in amelogenesis
imperfecta, 100
American Burkitt’s lymphoma, 601
Aminobisphosphonates, 299, 299b
Amitriptyline, for postherpetic neuralgia,
865
Amlexanox, for recurrent aphthous
stomatitis, 336
Amphotericin B
for blastomycosis, 228
for candidiasis, 221, 222-223t
for coccidioidomycosis, 231
for cryptococcosis, 232
for disseminated histoplasmosis,
226
for paracoccidioidomycosis, 230
for zygomycosis, 233
Amputation neuroma, 524-526, 524f,
525f
Amyloid, 822
deposition of
in amyloidosis, 824, 824f
in multiple myeloma, 604-605
Amyloidosis, 822-825
clinical features of, 823-824, 823f,
824f
diagnosis of, 825
hemodialysis-associated, 823-824
heredofamilial, 824
histopathologic features of, 824-825,
824f
macroglossia in, 11
myeloma-associated, 823
organ-limited, 823
primary, 823
secondary, 823
systemic, 823-824
treatment and prognosis of, 825
Amyotrophic lateral sclerosis (ALS), 873
Analgesics
opioid, for atypical facial pain, 866
for osteoarthritis, 878
Anaphylactic stomatitis, from systemic
drug administration, 347-348
Ancient neurilemomas, 527
Anemia, 576-578, 577b
aplastic, 580-581, 581f
Cooley’s, 579
Fanconi’s, aplastic anemia in, 580
hemolytic, autoimmune, bilirubin
excess in, 821
iron-deﬁ
ciency, oral manifestations of,
827-828
Mediterranean, 579
myelophthisic, 588
sickle cell, 576-578, 578f
bilirubin excess in, 821
Anesthesia dolorosa, after surgery for
trigeminal neuralgia, 863
Anesthetic necrosis, 303-304, 304f
Aneurysmal bone cyst, 634-635, 634f,
635f
Angina, Ludwig’s, 138-141.
See also

Ludwig’s angina.
Angina bullosa hemorrhagica, 774
Angiocentric immunoproliferative lesion,
602-604
Angiocentric T-cell lymphoma, 602-604
Angioedema, 356-358, 357f, 358f
Angioﬁ
bromas
facial, in tuberous sclerosis, 758, 758f
nasopharyngeal, 544-546, 545f, 546f
Angiogenesis, in squamous cell
carcinoma, 419
Angiolipoma, 524
Angiomatosis
bacillary, in cat-scratch disease, 206
of bone, massive osteolysis related to,
622
encephalotrigeminal, 543-5444, 543f,
544f
Sturge-Weber, 543-544, 543f, 544f
Angiomyolipoma, in tuberous sclerosis,
758
Angiomyomas, 549-550, 550f
Angioneurotic edema, 356-358, 357f,
358f
Angiosarcoma, 556-557, 556f, 557fhttp://dentalebooks.com

Index

939
Angular cheilitis, 214t, 216, 217f
infectious causes of, 304
in iron-deﬁ
ciency anemia, 828
Anidulafungin, for candidiasis, 224
Ankyloglossia, 11-12, 11f
Ankylosis, 75-77, 76f
temporomandibular joint, 882
Anodontia, 77
in ectodermal dysplasia, 742
Anthropometry, 890
Antibiotics
for actinomycosis, 204-205
for Ludwig’s angina, 140
for neuralgia-inducing cavitational
osteonecrosis, 868
for periapical abscess, 138
for periodontal abscess, 173
for periodontitis, 172
for sinusitis, 208
for suppurative osteomyelitis, 143
Antibody(ies)
cytoplasmic, basal cell, in allergic
mucosal reactions to systemic
drug administration, 349
monoclonal, in chronic lymphocytic
leukemia, 589
Anticonvulsants, for trigeminal neuralgia,
862
Antidepressants, tricyclic
for atypical facial pain, 866
for postherpetic neuralgia, 865
Antigens, bullous pemphigoid, 776
Antiinﬂ
ammatory agents, for migraine,
871
Antimalarials
discolorations of oral mucosa related
to, 317, 318
for rheumatoid arthritis, 880
Antineoplastic therapy
dental hypoplasia caused by, 58, 58f
noninfectious oral complications of,
294-299
clinical features of, 294-297, 295f,
296f, 297f
dermatitis as, 295
hemorrhage as, 294
loss of taste as
clinical features of, 296
treatment and prognosis of,
298-299
mucositis as
clinical features of, 294-295,
295f, 296f
treatment and prognosis of, 298
osteoradionecrosis as
clinical features of, 296-297, 297f
treatment and prognosis of, 299
treatment and prognosis of,
298-299
trismus as, 297
xerostomia as
clinical features of, 295-296, 296f
treatment and prognosis of, 298
Antirheumatid drugs, disease-modifying,
880
Antitoxin, for diphtheria, 187
Antivirals, early, for postherpetic
neuralgia, 864
Antoni A, in neurilemoma, 527, 527f
Antoni A tissue, in palisaded
encapsulated neuroma, 526
Antoni B, in neurilemoma, 527, 527f
Antral pseudocysts, 320, 321-323, 321f,
322f
Antrolith
in aspergillosis, 234
in chronic sinusitis, 208
Anxiety, lichen planus and, 783
APECED (autoimmune
polyendocrinopathy-
candidiasis-ectodermal
dystrophy) syndrome, 219,
220f
Apert syndrome, 43-45, 44f, 45f
Aphasia, before migraine, 871
Aphthosis
complex, 334
simple, 334
Aphthous stomatitis, recurrent, 331-336.
See also
Recurrent aphthous
stomatitis.
Aphthous ulcerations
herpetiform, 333
clinical features of, 334, 334f
HIV-associated, 278, 278f
major, 333
clinical features of, 334, 334f
minor, 333
clinical features of, 333-334, 334f
Aphthouslike lesions, nonspeciﬁ
c, drugs
associated with, 348b
Apical periodontal cyst, 130-135.
See also

Periapical cyst.
Apical periodontitis
acute, 135
chronic, 127-130.
See also
Periapical
granuloma.
Aplasia, salivary gland, 453-454, 454f
Aplastic anemia, 580-581, 581f
Appliances, for orofacial clefts, 4
ARC (AIDS-related complex), 266
Argyria, 315, 315f
Arsenic, systemic intoxication from,
314
clinical features of, 315
Arteriovenous malformations, 540
intrabony, 541f
treatment of, 543
Arteritis
cranial, 871-872
giant cell, 871-872
temporal, 871-872
Artery, caliber-persistent, 16, 16f
Arthralgia, in temporomandibular joint
dysfunction, 881
Arthritis
in Behçet’s syndrome, 338
degenerative, 877-878
psoriatic, in psoriasis, 793
reactive, 781-782
Arthroplasty, for osteoarthritis, 878
Ascher syndrome
double lip in, 6-7, 6f
eyelid edema in, 6, 7f
Ascorbic acid
deﬁ
ciency of, clinical features of, 826,
827f
functions and sources of, 825
Ash-leaf spots, in tuberous sclerosis, 758
Aspergilloma, 234
Aspergillosis, 234-235, 234f, 235f
Aspirin, mucosal necrosis from, 292,
292f
Asteroid bodies, in sarcoidosis, 340,
340f
Atrophic candidiasis, acute, 215
Atrophic glossitis, in iron-deﬁ
ciency
anemia, 828
Attrition, tooth wear by, 61, 62, 62f
Atypical Ewing sarcoma, 668
Atypical facial pain, 865-866, 865b
Atypical histiocytic granuloma, 287,
289f
Aura, before migraine, 871
Auriculotemporal syndrome, 876-877
Autoantibodies, in immune-mediated
dermatologic diseases, 764
Autoimmune hemolytic anemia,
bilirubin excess in, 821
Autoimmune multiorgan syndrome,
paraneoplastic, 769-771
Autoimmune polyendocrinopathy-
candidiasis-ectodermal
dystrophy (APECED)
syndrome, 219, 220f
hypoparathyroidism in, 837
Autopsy, 889
Autosomal dominant smooth pattern, of
hypoplastic amelogenesis
imperfecta, 101, 102f
Avulsed teeth, reimplanted, external
resorption of root in, 66-67,
68f
B
Bacillary angiomatosis, in cat-scratch
disease, 206
Bacillus Calmette-Guérin (BCG) vaccine
for tuberculosis, 198
Bacteria, pulpitis from, 121
Bacterial stains, tooth discoloration from,
70
BAL (2,3-dimercaptopropanol), for heavy
metal intoxication, 316
Balanitis circinata, in reactive arthritis,
782
Ballooning degeneration, of epithelial
cells in herpes simplex
infection, 245, 245f
Bannayan-Riley-Ruvalcaba syndrome,
multiple hamartoma syndrome
and, 760
Barbell in tongue, 311-312, 312f
Basal cell adenocarcinoma, 485
Basal cell adenoma, 484-485, 485fhttp://dentalebooks.com

940 Index
Basal cell carcinoma, 429-430
clinical features of, 430-431, 430f,
431f
developing from xeroderma
pigmentosum, 748
histopathologic features of, 431, 431f
morpheaform, 431
nevoid, 431
nodular, 430
noduloulcerative, 430, 430f
peripheral ameloblastoma
differentiated from, 710
pigmented, 430-431, 431f
sclerosing, 431
superﬁ
cial, 431
treatment and prognosis of, 431-432
Basal cell cytoplasmic antibody, in
allergic mucosal reactions to
systemic drug administration,
349
Basaloid squamous carcinoma, 425-426,
426f
Basosquamous carcinoma, 431
Bathing trunk nevus, 385
Batson’s plexus, in metastases to oral soft
tissues, 563
BCG (Bacillus Calmette-Guérin) vaccine
for tuberculosis, 198
Beck-Wiedemann syndrome,
macroglossia in, 10
Becker’s nevus, 41
Behçet’s syndrome, 336-338, 337f
Bell’s palsy, 859-861, 860f
Bence Jones proteins, in multiple
myeloma, 604
Benign acanthosis nigricans, 803
Benign ethnic neutropenia, 581
Benign juvenile melanoma, 386
Benign lymphoepithelial lesion, 465-
466, 466f
Benign mucous membrane pemphigoid,
771-775.
See also
Mucous
membrane pemphigoid.
Benign osteopetrosis, 616
Betel chewer’s mucosa, 286
Betel quid chewing
oral submucous ﬁ
brosis from, 401-
403, 402f
squamous cell carcinoma from, 411
Betel quid lichenoid lesions, 402
Biﬁ
d condyle, 19, 19f
Biﬁ
d tongue, 311, 312f
Biﬁ
d uvula, 3, 4f
Biliary atresia, tooth discoloration
associated with, 72
Biliary cirrhosis, graft-versus-host disease
mimicking, 791
Bilirubin
excess, in jaundice, 821
excess accumulation of, tooth
discoloration associated with,
71-72, 72f
Bioﬁ
lm, periodontitis and, 168
Birbeck granules, in Langerhans cell
histiocytosis, 591, 592f
Bismuth, systemic intoxication from,
314
clinical features of, 315
Bisphosphonate-associated osteonecrosis
(BON), 299-303, 299b
clinical and radiographic features of,
299-300, 300f, 301f
histopathologic features of, 301, 301f
treatment and prognosis of, 301-303
Bisphosphonate therapy
for multiple myeloma, 605
for osteogenesis imperfecta, 615
for Paget’s disease of bone, 625-626
Bite marks
analysis of, guidelines for, 906-907
characteristics of, 905-906, 905f, 906t
description of, 907
as evidence, 903-911
analysis of, 910-911, 911f
basic principles of, 903-904, 903f
collection of, 907-910
examination of suspect in, 907
examination of victim in, 907
historical and legal issues related to,
904-905
impressions of, 909-910
photography of, 907-909, 908f,
908t
saliva and, 909
study casts of, 909-910, 910f, 911f
tissue samples and, 910
Black hairy tongue, 13-15, 14f, 15f
Blast transformation, in chronic myeloid
leukemia, 590
Blastomycosis, 226-228, 227f, 228f
Bleeding disorders, inherited, 573, 573t
Blistering
in erythema multiforme, 776
in pemphigus vulgaris, 765
Block-Sulzberger syndrome, 750-751
Blood transfusions, for thalassemia
major, 580
Blood vessels
malformations of, 538-543.
See also

Vascular malformations.
“staghorn,” in hemangiopericytoma–
solitary ﬁ
brous tumor, 546,
546f
Blue nevus, 386-388, 387f
Bohn’s nodules, 26-27, 691
BON.
See
Bisphosphonate-associated
osteonecrosis.
Bone cyst, Stafne, 24-25, 26f
Bone eburnation, 620
Bone marrow edema, 866-868
Bone marrow transplantation
for aplastic anemia, 581
for Gaucher disease, 819-820
graft-versus-host disease after, 790
for infantile osteopetrosis, 617
for thalassemia major, 580
Bone scar, 620
Bone sequestration, oral ulcerations
with, 319-320, 320f
Bone whorl, 620
Botryoid odontogenic cyst, 692-695,
693f, 694f.
See also
Periodontal
cyst, lateral.
Botryoid rhabdomyosarcoma, 560t, 561
Botryomycosis, mimicking
actinomycosis, 203
Bourneville-Pringle syndrome, 757-759
Bowenoid actinic keratosis, 404
Brachycephaly, in Crouzon syndrome,
42
Bradycardia, in hypothyroidism, 834
Branchial cleft cyst, 36-37, 37f
Brandysine isolate, 106
Brown tumor, of hyperparathyroidism,
839, 839f
Bruising, in thrombocytopenia, 585,
585f
Buccal bifurcation cysts, 698-700, 699f
associated with cervical enamel
extensions, 94
Buccal exostoses, 19-20, 20f
Bulbar palsy, progressive, 873
Bulbar paralysis, 873
Bull neck, in Ludwig’s angina, 139
Bullous impetigo, 181-182
Bullous lichen planus, 785
Bullous pemphigoid, 766t, 775-776,
775f, 776f
Bullous pemphigoid antigens (BP180
and BP230), 776
Bullous skin lesions, in toxic epidermal
necrolysis, 778, 778f
Bull’s eye lesions, in neuralgia-inducing
cavitational osteonecrosis, 867
Burkitt’s lymphoma, 600-602, 601f,
602f
Burning mouth syndrome, 873-875,
874b
Burning tongue syndrome, 873-875,
874b
Burns
cotton roll, 293, 293f
electrical, 289-290, 290f
thermal, 290-291, 291f
Burton’s line, in lead intoxication, 314
C
Café au lait
pigmentation
in Jaffe-Lichtenstein syndrome, 636,
637, 638f
in McCune-Albright syndrome, 636
in neuroﬁ
bromatosis type I, 530, 530f
Calciﬁ
c metamorphosis, 123, 125f
tooth discoloration from, 72
Calciﬁ
c necrotic detritus, in neuralgia-
inducing cavitational
osteonecrosis, 868
Calciﬁ
cations
Liesegang ring, in calcifying epithelial
odontogenic tumors, 717, 717f
peripheral ﬁ
broma with, 521-523
pulpal, 126-127, 126f, 127f
subcutaneous, in
pseudohypoparathyroidism,
838http://dentalebooks.com

Index

941
Calciﬁ
cations—cont’d
tramlilne, in skull in Sturge-Weber
angiomatosis, 543, 544f
Calcifying cystic odontogenic tumor,
695-697, 695f, 696f, 697f
Calcifying epithelial odontogenic tumors,
716-718, 716f, 717f
Calcifying ﬁ
broblastic granuloma,
521-523
Calcifying ghost cell odontogenic cyst,
695-697, 695f, 696f, 697f
Calcifying odontogenic cyst, 695-697,
695f, 696f, 697f
Calcinosis cutis, in CREST syndrome,
801, 802f
Calcitonin, for giant cell granuloma, 628
Calcium, for pseudohypoparathyroidism,
838
Caliber-persistent artery, 16, 16f
Canalicular adenoma, 484, 484f
Canals of Scarpa, 29
Cancrum oris, 158, 201-203
Candidal leukoplakia, 214t, 217-218,
219f, 389-390, 389f
Candidiasis, 213-224
atrophic, acute, 215
chronic multifocal, 214t, 216, 217f
clinical features of, 213-219
diagnosis of, 221
erythematous, 214t, 215-217, 215f,
216f, 217f, 218f
histopathologic features of, 219-220,
220f, 221f
HIV-associated, 267-268, 267f, 268f
hyperplastic
chronic, 214t, 217-218, 219f
squamous cell carcinoma and, 412
mucocutaneous, 214t, 218-219,
220f
oral, complicating diabetes, 844
prognosis of, 221-224
pseudomembranous, 213-215, 214f,
214t, 215f
treatment of, 221-224, 222-223t
amphotericin B in, 221, 222-223t
clotrimazole in, 221-222, 222-223t
echinocandins in, 224
ﬂ
uconazole in, 222-223t, 223-224
imidazole agents in, 221-223,
222-223t
iodoquinol in, 224
itraconazole in, 222-223t, 224
ketoconazole in, 222-223, 222-223t
nystatin in, 221, 222-223t
polyene agents in, 221, 222-223t
posaconazole in, 224
triazoles in, 222-223t, 223-224
Candidosis, 213.
See also
Candidiasis.
Canker sores, 331-336
Cannon’s disease, 743-744
Capdepont’s teeth, 106-108
Capillary lymphangioma, 547
Capillary malformation, histopathologic
features of, 542, 542f
Capsaicin, for herpes zoster, 253
Capsaicin cream, topical, for trigeminal
neuralgia, 862
Carbamazepine, for trigeminal neuralgia,
862
Carcinoma(s)
adenoid cystic, 495-497, 495f, 496f
adenosquamous, 425
ameloblastic, 711-712, 711f, 712f
basosquamous, 431
lobular, 497-498
lung, metastatic, 564f
lymphoepithelial, 466
maxillary sinus, 426-427, 426f
Merkel cell, 432-433, 432f
mucoepidermoid, 487-491.
See also

Mucoepidermoid carcinoma.
adenosquamous carcinoma as,
425
nasopharyngeal, 428-428, 428f, 429f
nonkeratinizing, nasopharyngeal, 429
odontogenic, 700-701, 700f, 701f
clear cell, 712-713, 712f, 713f
ghost cell, 697
“self-healing,” 406-408
“snuff dipper’s,” 401
spindle cell, 423-425, 424f
squamous, basaloid, 425-426, 426f
squamous cell, 409-421.
See also

Squamous cell carcinoma.
oral, HIV-associated, 279, 279f
proliferative verrucous leukoplakia
transforming into, 392
smokeless tobacco-related, 400-401
terminal duct, 497-498
verrucous, 392, 422-423, 422f, 443f
Carcinoma ex papillary cystadenoma
lymphomatosum, 483
Carcinoma ex pleomorphic adenoma
clinical features of, 493, 493f
histopathologic features of, 494
treatment and prognosis of, 494
Carcinoma
in situ,
394-395, 395f
ex mixed tumor, 494
Carcinosarcoma
ameloblastic, 723
clinical features of, 493
histopathologic features of, 494
treatment and prognosis of, 494-495
Cardiac rhabdomyoma, in tuberous
sclerosis, 758
Carotid artery syndrome, 24
Carotid body tumor, 535-536, 536f
Cartilage-hair syndrome, neutropenia in,
582
Cartilaginous choristomas, 552, 552f
Cartilaginous rests, in soft tissues, 318
Caspofungin, for candidiasis, 224
Cat-scratch disease, 205-207, 205f,
206f
Cauterization, chemical, for odontogenic
keratocysts, 686
Cavernous lymphangioma, 547, 548f
Cavernous sinus thrombosis, 138, 139
clinical features of, 139-140, 140f
treatment and prognosis of, 141
Cavitations, in neuralgia-inducing
cavitational osteonecrosis, 868,
868f
Celiac sprue, iron-deﬁ
ciency anemia in,
828
Cellular blue nevus, 387
Cellulitis, 138-141
cavernous sinus thrombosis
complicating, 138-141.
See also

Cavernous sinus thrombosis.
complicating periapical abscess,
135-136
Ludwig’s angina complicating, 138-
141.
See also
Ludwig’s angina.
Cemental dysplasia, 641, 641f, 642f
Cementifying ﬁ
broma, 646-648.
See also

Ossifying ﬁ
broma.
Cemento-osseous dysplasias of jaws,
640-645
clinical and radiographic features of,
640-643, 641f, 642f, 643f
diagnosis of, 644
ﬂ
orid, 641-643, 642f, 643f
focal, 640, 641f
histopathologic features of, 643-644,
644f
periapical, 641, 641f, 642f
treatment and prognosis of, 644-645
Cemento-ossifying ﬁ
broma, 646-648.
See
also
Ossifying ﬁ
broma.
Cementoblastoma, 655-656, 655f, 656f,
731-732
Cementoma(s), 641, 641f, 642f
gigantiform, familial, 645-646, 646f
true, 655-656, 655f, 656f, 731-732
Cementum-like particles, in cemento-
osseous dysplasias of jaws, 644,
644f
Central giant cell granuloma, 626-629.
See also
Giant cell granuloma.
Central mucoepidermoid carcinoma,
490-491
Central nervous system, in Behçet’s
syndrome, 338
Central odontogenic ﬁ
broma, 727
Central osteoma, 650
Central papillary atrophy of tongue,
214t, 216
Cephalgia, histaminic, 868-869
Cerebral palsy, Riga-Fede disease in,
289
Cervical enamel extensions, 93, 94, 94f
Cervical lymphangiomas, 547-548
Cervical lymphoepithelial cyst, 36-37,
37f
Cervical ranula, 457, 457f
Cervical resorption, invasive, 68-69
Cervicofacial emphysema, 323-324,
323f
Chancre, in primary syphilis, 188,
189f
Charm needles/pins, implantation of,
311, 312, 313f
Cheek chewing, chronic, 285-287, 286f,
287fhttp://dentalebooks.com

942 Index
Cheilitis
actinic, 405-406
angular, 214t, 216, 217f
infectious causes of, 304
in iron-deﬁ
ciency anemia, 828
exfoliative, 304-305, 305f, 306f
lupus, in systemic lupus
erythematosus, 795
Cheilitis glandularis, 462-463, 463f
Cheilitis granulomatosa of Miescher,
342, 342f
Cheilocandidiasis, 216, 217f, 304
Cheilosis, actinic, 404, 405-406, 405f,
406f
lip vermilion carcinoma associated
with, 414
Chelating agents, for heavy metal
intoxication, 316
Chemical cauterization, for odontogenic
keratocysts, 686
Chemical injuries
anesthetic necrosis as, 303-304, 304f
from antineoplastic therapy, 294-299.
See also
Antineoplastic therapy,
noninfections oral
complications of.
bisphosphonate-associated
osteonecrosis as, 299-303.
See
also
Bisphosphonate-associated
osteonecrosis (BON).
from methamphetamine abuse, 303,
303f
myospherulosis as, 324-325, 324f
of oral mucosa, 291-294
from aspirin, 292, 292f
clinical features of, 293, 293f
from endodontic materials, 292-
293, 293f
histopathologic features of, 293,
294f
from hydrogen peroxide, 292, 292f
from phenol, 292, 292f
from silver nitrate, 292
treatment and prognosis of,
293-294
smoker’s melanosis as, 316-317, 316f
systemic metallic intoxication as, 313-
316.
See also
Metallic
intoxication, systemic.
Chemical irritation, pulpitis from, 121
Chemodectoma, 535-536
Chemotherapy
for actinic keratoses in xeroderma
pigmentosum, 748
for Burkitt’s lymphoma, 602
dental hypoplasia caused by, 58
for Ewing sarcoma, 668
for Hodgkin’s lymphoma, 594-595
for leukemia, 589
for multiple myeloma, 605
for non-Hodgkin’s lymphoma, 598
noninfectious oral complications of,
294-295, 295f
for osteosarcoma of jaw, 663
for squamous cell carcinoma, 420-421
Cherubism, 629-630, 630f, 631f, 632f
Chevrons, parakeratin, in smokeless
tobacco keratosis, 399, 400f
Chickenpox, 248-250, 248f, 249f
Childhood hypophosphatasia, 846
Children, Langerhans cell histiocytosis
in, 590
Chlorhexidine, tooth discoloration from,
71
Chlorodontia, from hyperbilirubinemia,
72
Chlorophyll-containing foods, tooth
discoloration from, 70-71
Chlorpromazine, discolorations of oral
mucosa related to, 318, 318f
Cholinesterase inhibitors, for myasthenia
gravis, 872
Chondromas, 656-657
soft tissue, 552
Chondromatosis, synovial, 657-658,
658f
Chondrometaplasia, 657-658
Chondromyxoid ﬁ
broma of jaws, 657,
657f
Chondrosarcomas of jaws, 664-667
clinical and radiographic ﬁ
ndings in,
664-665, 665f
grades of, 665f, 6665-666
histopathologic ﬁ
ndings in, 665, 665f
mesenchymal, 666-667, 667f
postirradiation, 664
treatment and prognosis of, 666
variants of, 666
Chorda tympani syndrome, 877
Choristomas, osseous and cartilaginous,
552, 552f
Christmas disease, 573, 573t
Chromosome, Philadelphia, in chronic
myeloid leukemia, 587
Chronic fatigue syndrome, in infectious
mononucleosis, 254
Chronic recurrent multifocal
osteomyelitis (CRMO), 144,
146
Chronic sclerosing sialadenitis, 462,
462f
Chrysiasis, from gold therapy, 316
Chvostek’s sign, in hypoparathyroidism,
837
Cicatricial pemphigoid, 766t, 771-775.
See also
Mucous membrane
pemphigoid.
Cidofovir, for herpes lesions in
immunocompromised patients,
247
Cinnamon ﬂ
avoring, artiﬁ
cial, contact
stomatitis from, 352-354, 353f,
354f
Cinnamon reaction, oral mucosal, lichen
planus resembling, 785
Ciproﬂ
oxacin, tooth discoloration from,
73
Cirrhosis, biliary, graft-versus-host
disease mimicking, 791
Civatte bodies, in lichen planus, 786
CL.
See
Cleft lip.
Clark’s classiﬁ
cation, of cutaneous
melanoma, 437t
Clavicles, abnormalities of, in
cleidocranial dysplasia, 618,
618f
Clear cell chondrosarcoma, 666
Clear cell odontogenic carcinoma, 712-
713, 712f, 713f
Clear cell odontogenic tumor, 712-713,
712f, 713f
Clear cells, in mucoepidermoid
carcinoma, 488, 489f
Cleft(s)
facial
lateral, 2-3
oblique, 3
orofacial, 1-5.
See also
Orofacial clefts.
of upper lip, median, 3
Cleft lip (CL)
bilateral, 3f
development of, 2
upper median, 3
Cleft palate (CP), 3f
development of, 2
submucous, 3-4, 4f
Cleft uvula, 3, 4f
Clefting, subepithelial, in epidermolysis
bullosa, 763, 763f
Cleidocranial dysplasia, 618-619, 618f,
619f
Clofazimine, for leprosy, 201
Clorhexidine, for recurrent aphthous
stomatitis, 336
Clotrimazole
for candidiasis, 221-222, 222-223t
for candidiasis in HIV infection, 268
Clotting factor replacement, for
hemophilia, 574-575
Cluster headache, 868-869
CMV (cytomegalovirus), 240, 255-256
Coated tongue, 14, -15 14f
Cobalamin deﬁ
ciency, pernicious
anemia from, 829
Coccidioidomycosis, 230-231
Coffee, tooth discoloration from, 70
Cognitive behavioral therapy, for
migraine, 871
COL1A1
gene mutation, in
dentinogenesis imperfecta,
106
COL1A2
gene mutation, in
dentinogenesis imperfecta, 106
Colchicine, for recurrent aphthous
stomatitis, 336
“Cold sore,” clinical features of, 243-
244, 243f
Cole-Engman syndrome, 746-747
Collagen, diffuse deposition of, in
systemic sclerosis, 800, 801f
Colloid, in lichen planus, 786
Coloboma, in mandibular dysostosis, 45
Colon, adenocarcinoma of, metastatic,
564f
Commissural lip pits, 5, 5fhttp://dentalebooks.com

Index

943
Complement pathway, activation of, in
angioedema, 357
Complex hemihyperplasia, 39
Complex odontomas, 724, 725f, 726f
Compound nevus
clinical features of, 383
histopathologic features of, 384, 384f
Compound odontomas, 724, 725f, 726f
Computed tomography, cone-beam, in
mass fatality incident
identiﬁ
cation, 902
Computer software technology, in mass
fatality incident identiﬁ
cation,
902-903
Concrescence
clinical features of, 85-86, 86f, 87f
deﬁ
nition of, 84
prognosis for, 87
treatment of, 87
Condensing osteitis, 147-148, 148f, 620
Condylar aplasia, 19
Condylar hyperplasia, 17-18, 18f
Condylar hypoplasia, 18-19
Condylar osteomas, 650
Condyle, biﬁ
d, 19, 19f
Condyloma acuminatum, 366-367, 366f,
367f
Condylomata lata, in secondary syphilis,
189, 190f, 192f
Cone-beam computed tomography, in
mass fatality incident
identiﬁ
cation, 902
Congenital agranulocytosis, 583
Congenital condylar hypoplasia, 18-19
Congenital epulis, 537-538, 537f, 538f,
539f
Congenital erythropoietic porphyria,
tooth discoloration in, 71, 71f
Congenital ﬁ
stulas, of lower lip, 5-6, 6f
Congenital granular cell lesion, 537-538,
537f, 538f, 539f
Congenital melanocytic nevus, 385-386,
385f
Congenital rubella syndrome (CRS), 261
Congenital syphilis, clinical features of,
190-191, 191f
Congenital toxoplasmosis, 236
Conical supernumerary teeth, 81
Conjunctival musoca, in paraneoplastic
pemphigus, 770, 770f
Consumption, 196
Contact stomatitis
allergic, 350-351
from artiﬁ
cial cinnamon ﬂ
avoring,
352-354, 353f, 354f
lichenoid, from dental restorative
materials, 354-356, 355f, 356f
Cooley’s anemia, 579
Cornea, in hereditary benign
intraepithelial dyskeratosis,
744
Coronal dens invaginatus, 90-91, 90f,
91f
Coronal dentin dysplasia, 110, 111f
Coronoid hyperplasia, 17
Corps ronds, in Darier’s disease, 751
Corticosteroids
for Behçet’s syndrome, 338
for chronic ulcerative colitis, 789
for giant cell granuloma, 628
for infectious mononucleosis, 254-255
for paraneoplastic pemphigus, 771
for pemphigus, 769
for recurrent aphthous stomatitis, 335,
335f
replacement, for Addison’s disease,
842
systemic
for Bell’s palsy, 861
for mucous membrane pemphigoid,
775
for pyostomatitis vegetans, 850
for temporal arteritis, 872
topical
for erosive lichen planus, 787,
788f
for graft-versus-host disease lesions,
792
for mucous membrane pemphigoid,
774-775
for psoriasis, 794
Cotton roll burn, 293, 293f
Cowden syndrome, 760-761
Coxsackieviruses, 256-259
CP.
See
Cleft palate.
Cranial arteritis, 871-872
Craniectomy, in Apert syndrome, 44
Craniofacial dysostosis, 42-43, 43f
Craniofacial ﬁ
brous dysplasia, 636
CREST syndrome, 801-803
Cretinism, oral manifestations of,
834-835
Cribriform pattern in adenoid cystic
carcinoma, 496, 496f
Criminal disasters, mass fatality
identiﬁ
cation in, dentistry’s role
in, 900-901
“Crocodile tears,” 877
Crohn’s disease, oral manifestations of,
848-849, 848f, 849f
Crouzon syndrome, 42-43, 43f
Crowe’s sign, in neuroﬁ
bromatosis type
I, 530
CRS (congenital rubella syndrome), 261
Cryosurgery, for hereditary hemorrhagic
telangiectasia lesions, 755
Cryotherapy, liquid nitrogen, for verruca
vulgaris, 366
Cryptococcosis, 231-232, 232f
Cunnilingus, oral lesions from, 308,
308f
Cushing’s syndrome, oral manifestations
of, 840-841
Cusp(s)
accessory, 87-90.
See also
Accessory
cusps.
of Carabelli
clinical and radiographic features
of, 87, 87f
treatment and prognosis of, 89-90
Cusp(s)—cont’d
talon
clinical and radiographic features
of, 87-88, 88f
treatment and prognosis of, 90
Cutaneous horns
in actinic keratosis, 404
in verruca vulgaris, 364
Cutaneous sinus, from dental abscesses,
136, 137f
Cutaneous T-cell lymphoma, 598-600,
599f, 600f
Cutright lesion, 318-319
Cyclic neutropenia, 583-584, 584f
Cylindrical cell papilloma, 370-371
Cyst(s)
apical periodontal, 130-135.
See also

Periapical cyst.
bone
aneurysmal, 634-635, 634f, 635f
simple, 631-634.
See also
Simple
bone cyst.
Stafne, 24-25, 26f
buccal bifurcation, 698-700, 699f
deﬁ
nition of, 25
developmental, 25-38
Bohn’s nodules as, 26-27
branchial cleft cyst as, 36 to 37, 37f
dermoid cyst as, 33-35, 34f, 35f
Epstein’s pearls as, 26-27, 27f
follicular cysts of skin as, 32-33, 32f,
33f, 34f
“globulomaxillary cyst” as, 28
Klestadt cyst as, 27-28
“median mandibular cyst” as, 32
median palatal cyst as, 31-32, 31f
nasoalveolar cyst as, 27-28
nasolabial cyst as, 27-28, 27f, 28f
nasopalatine duct cyst as, 28-31,
29f, 30f, 31f
nasopalatine duct cysts as.
See also

nasopalatine duct cysts.
oral lymphoepithelial cyst as, 37-38,
38f, 39f
palatal cysts of newborn as, 26-27,
27f
thyroglossal duct cyst as, 35-36, 36f
epidermoid, of skin in Gardner
syndrome, 652, 653f
eruption, 682, 682f, 683f
gingival
of adult, 692, 692f, 693f
of newborn, 691-692, 692f
of incisive papilla, 30, 30f
maxillary, postoperative, 320, 321
mucus duct, 457-459, 458f
mucus retention, 457-459, 458f
odontogenic, 678-701.
See also

Odontogenic cysts.
periapical, 128, 130-135.
See also

Periapical cyst.
primordial, 683, 683f
radicular, 130-135.
See also
Periapical
cyst.
retention, 321http://dentalebooks.com

944 Index
Cyst(s)—cont’d
salivary duct, 457-459, 458f
subchondral, in osteoarthritis, 878
surgical ciliated, 320, 322f
traumatic ciliated, 320
Cystadenoma lymphomatosum,
papillary, 482-483, 482f, 483f
Cystic hygroma, 547, 548
Cystic lymphangioma, 547
Cytoid, in lichen planus, 786
Cytomegalovirus (CMV, HHV-5), 240,
255-256, 256f
Cytoplasmic vacuoles, in hereditary
mucoepithelial dysplasia, 749,
749f
D
D-penicillamine, for rheumatoid
arthritis, 880
Dapsone
for leprosy, 201
for recurrent aphthous stomatitis, 336
Darier’s disease, 751-752, 751f, 752f
isolated, 752-753
Darrier-White disease, 751-752
Daubert v. Merrell Dow Pharmaceuticals

ruling, 904
Death
cause of, determining, 889
mechanism of, determining, 889
mode or manner of, determining, 889
undetermined, 889
Dedifferentiated chondrosarcoma, 666
Dedifferentiated liposarcomas, 554
Dedifferentiation, in spindle cell
carcinoma, 424
Deferoxamine, in thalassemia major
management, 580
Degenerative arthritis, 877-878
Degenerative joint disease, 877-878
Demastication, 61
Denigerous cyst, carcinoma arising in,
700, 700f
Denileukin diftitox, for mycosis
fungoides, 600
Dens evaginatus
clinical and radiographic features of,
88-89, 89f
treatment and prognosis of, 90
Dens in dente, 90-93
Dens invaginatus, 90-93
clinical and radiographic features of,
90-92, 90f, 91f, 92f
treatment and prognosis of, 92-93
Dense bone island, 620
Dental evaluation, in identiﬁ
cation,
894-903
Dental ﬂ
uorosis, 58-60, 59f
Dental plaque, periodontitis and, 168
Dental restorative materials.
See also

Amalgam, dental.
lichenoid contact stomatitis from,
354-356, 355f, 356f
tooth discoloration from, 72-73, 73f
Dental transposition, 81
Denti, primary, 123
Denticles, 126, 127
Dentigerous cysts, 679-682
central, 680, 680f
circumferential, 680, 680f
clinical and radiographic features of,
679-680, 679f, 680f, 681f
deﬁ
nition of, 679
histopathologic features of, 681-682,
681f
inﬂ
amed, 681, 681f
lateral, 680, 680f
noninﬂ
amed, 681
treatment and prognosis of, 682
Dentin
ﬁ
brous dysplasia of, 110
interface, 124
opalescent, hereditary, 106-108
secondary, 123-124
clinical and radiographic features
of, 124-125, 124f, 125f
histopathologic features of, 125,
125f
physiologic, 123-124, 124f, 125f
reparative, 125f
treatment and prognosis of,
125-126
tertiary, 124
clinical and radiographic features
of, 124-125
histopathologic features of, 125
treatment and prognosis of,
125-126
Dentin dysplasia, 108-112
clinical and radiographic features of,
109-110, 109f, 110f, 111f
histopathologic features of, 110-111,
111f
systemic diseases correlated with,
109b
treatment and prognosis of, 111-112
Dentinogenesis imperfecta, 106-108,
106t, 107f, 107t, 108f
Dentinogenic ghost cell tumor, 695-697.
695f, 696f, 697f
Dentinomas, ﬁ
broameloblastic,
peripheral, 727
Dentinosarcomas, ameloblastic, 723
Dentistry, forensic, 887-916.
See also

Forensic dentistry.
Dentists, as expert witnesses, 914
Denture epulis, 510-512
Denture ﬁ
broma, leaﬂ
ike, 511
Denture injury tumor, 510-512
Denture papillomatosis, 512-514, 513f
Denture stomatitis, 214t, 216-217,
218f
Dermal analogue tumors, 485
Dermal cylindromas, 485
Dermal melanocytoma, 386-388
Dermatitis
from antineoplastic therapy, 295
impetiginized, 181
lichenoid, 782
perioral, 352, 352f
Dermatoﬁ
broma, 514
Dermatosis, bullous, linear IgA, 774
Dermatosis papulosa nigra, in seborrheic
keratosis, 374, 374f
Dermoid cyst, 33-35, 34f, 35f
Desferrioxamine, in thalassemia major
management, 580
Desmoids, extraabdominal, 515
Desmoplasia, in squamous cell
carcinoma, 419
Desmoplastic ameloblastoma, 704,
705f
histopathologic features of, 706, 706f
Desmoplastic ﬁ
bromas, 515
of jaws, 658-660, 659f
Desmopressin, for factor VIII deﬁ
ciency,
574
Desmosomes, immunologic attack on,
in pemphigus vulgaris,
765-766
Desquamative gingivitis, 162-163
in chronic ulcerative colitis, 789
in erosive lichen planus, 785, 785f
in mucous membrane pemphigoid,
771, 772f
Developmental abnormalities, from
radiation therapy, 298
Diabetes mellitus
clinical features of, 843-844
complications of, 844
oral manifestations of, 842-845
treatment and prognosis of, 844-845
Differentiated nonkeratinizing
carcinoma, nasopharyngeal,
429
Diffuse hyperplastic oncocytosis, 481
Diffuse inﬁ
ltrative lymphocytosis
syndrome (DILS), HIV-
associated, 275
Diffuse linear pulp calciﬁ
cations, 126,
127, 127f
Diffuse sclerosing osteomyelitis,
144-147
DiGeorge syndrome,
hypoparathyroidism in, 837
Digital photography, in mass fatality
incident identiﬁ
cation, 902
Digital radiography, for dental record,
888
Dilaceration, 97-98, 97f, 98f
Dilated odontome, 91
DILS (diffuse inﬁ
ltrative lymphocytosis
syndrome), HIV-associated,
275
2,3-Dimercaptopropane-1 sulfonate
(DMPS), for heavy metal
intoxication, 316
2,3-Dimercaptopropanol (BAL), for
heavy metal intoxication, 316
2,3-Dimercaptosuccinic acid (DMSA),
for heavy metal intoxication,
316
Dimorphism, in
Candida albicans,
213
Diphtheria, 186-188
Discoid lupus erythematosus, 795http://dentalebooks.com

Index

945
Discoloration of teeth, environmental,
70-74, 70b
extrinsic
from bacterial stains, 70
from chlorophyll-containing foods,
70-71
clinical features of, 70-71, 70b, 71f
from medications, 71
from tea/coffee use, 70
from tobacco use, 70, 71f
intrinsic, 71-73, 72f, 73f
prognosis for, 74
treatment of, 73-74
Disseminated aspergillosis, 234
Disseminated coccidioidomycosis, 230
Disseminated histoplasmosis, 225
Distodens, 81
Distomolar, 81
Distraction osteogenesis, for orofacial
clefts, 5
DLX3
gene mutation, in amelogenesis
imperfecta, 100
DMPS (2,3-dimercaptopropane-1
sulfonate), for heavy metal
intoxication, 316
DMSA (2,3-dimercaptosuccinic acid), for
heavy metal intoxication, 316
DNA, in identiﬁ
cation, 893-894
Dopamine antagonists, for migraine, 871
Down syndrome, macroglossia in, 10f,
11
Drainage
of periapical abscess, 138
for suppurative osteomyelitis, 143
Drug(s)
administration of, systemic, allergic
mucosal reactions to, 347-350.
See also
Allergic mucosal
reactions to systemic drug
administration.
associated with altered taste, 876t
causing agranulocytosis, 582-583
causing neutropenia, 582
discolorations of oral mucosa related
to, 317-318, 317f, 318f
erythema multiforme major from, 777
lichenoid reactions to, 782
lichen planus resembling, 785
pemphigus-like eruptions from, 766
producing xerostomia, 465t
for temporomandibular joint
dysfunction, 881b
tooth discoloration from
extrinsic, 71
intrinsic, 73, 73f
toxic epidermal necrolysis triggered
by, 777-778
Drug-related gingival hyperplasia, 163-
166, 163b, 163f, 164f, 165f
clinical features of, 164-165, 164f,
165f
histopathologic features of, 165
medications associated with, 163b
treatment and prognosis of, 165-166
Dry socket, 150-151
DSPP gene mutation, in dentinogenesis
imperfecta, 106
Ductal papillomas, 485-487, 486f, 487f
Duct(s)
nasopalatine, 28
development of, 28
thyroglossal, cysts of, 35-36, 36f
Dwarﬁ
sm, pituitary, oral manifestations
of, 831
Dysgeusia and hypogeusia, 875-876,
875b, 876t
Dyskeratoma
follicular, 752-753
warty, 752-753, 752f
Dyskeratosis
acantholytic, focal, 752-753
intraepithelial, hereditary benign,
744-745, 744f, 745f
Dyskeratosis congenita, 746-747, 747f
aplastic anemia in, 580
neutropenia in, 582
Dyskeratosis follicularis, 751-752
isolated, 752-753
Dyspareunia, in mucous membrane
pemphigoid, 772
Dysphagia
in basaloid squamous carcinoma, 425
in Plummer-Vinson syndrome,
828-829
in progressive bulbar palsy, 873
sideropenic, oral manifestations of,
828-829
Dystrophic types, of epidermolysis
bullosa, 761-763, 762f, 762t,
763f
E
Eagle syndrome, 23-24, 24f
Early-onset periodontitis, 173
EBV.
See
Epstein-Barr virus.
Ecchymosis
in submucosal hemorrhage, 305
in thrombocytopenia, 585, 585f
Ecchymotic type, of Ehler-Danlos
syndrome, 757
Echinocandins, for candidiasis, 224
Echoviruses, 256-259
Ectodermal dysplasia, 741-743
Ectomesenchyme, odontogenic, tumors
of, 726-732
cementoblastoma as, 731-732
odontogenic ﬁ
broma as, 726-729.
See
also
Odontogenic ﬁ
bromas.
odontogenic myxoma as, 729-731,
730f, 731f
Ectopic enamel, 93-94
Eczema herpeticum, 244
Eczematous stage, of mycosis fungoides,
599
Edema
angioneurotic, 356-358, 357f, 358f
bone marrow, 866-868
EDTA (ethylenediaminetetraacetic acid),
for heavy metal intoxication,
316
Ehlers-Danlos syndromes, 755-757,
756f, 756t, 757f
Elastosis
actinic, 406
solar, 404, 406
basal cell carcinoma and, 431
Electrical burns, 289-290, 290f
Electrocautery, for hereditary
hemorrhagic telangiectasia
lesions, 755
Elephant man, 531
Elephantiasis gingivae, 166-168, 166f,
167f, 168f
Elephantiasis neuromatosa, in
neuroﬁ
bromatosis type I, 529,
530f
Embryonal rhabdomyosarcoma,
560-561, 560f, 560t, 561f
Emphysema, cervicofacial, 323-324,
323f
ENAM gene mutation, in amelogenesis
imperfecta, 100
Enamel
defects in, factors associated with, 55b
demarcated opacities of, 56
development of, stages of, 55
diffuse opacities of, 56
ectopic, 93-94
environmental abnormalities of,
55-56, 56f
hypoplasia of, 56, 56f
syphilitic, 60
mottled, 59
pitting of, in tuberous sclerosis,
758-759
Enamel agenesis, 102
Enamel pearls, 93, 93f, 94
radicular, 92
Enameled conglomerates, in regional
odontodysplasia, 113, 113f
Enamelin disorders, in amelogenesis
imperfecta, 100
Enamelysin disorders, in amelogenesis
imperfecta, 100
Encephalotrigeminal angiomatosis, 543-
544, 543f, 544f
Endemic Burkitt’s lymphoma, 601
Endocrine-candidiasis syndrome, 214t,
219
hypoparathyroidism in, 837
Endodontic materials, mucosal necrosis
from, 292-293, 293f
Endodontic therapy
for condensing osteitis, 148
for internal resorption, 70
for periapical cysts, 135
for periapical granuloma, 129-130
for periapical pathosis, 125-126
for proliferative periostitis, 150
for regional odontodysplasia, 113
Endosteal osteoma, 650
Endothelial cells, vascular, in juvenile
hemangiomas, 541-542, 541f,
542f
Enostosis, 620http://dentalebooks.com

946 Index
Enteric duplication cysts, 34
Enterocystomas, 34
Enteroviruses, 256-259
clinical features of, 257-259, 258f,
259f
diagnosis of, 259
histopathologic features of, 259
treatment and prognosis of, 259
Entropion, in mucous membrane
pemphigoid, 772, 773f
Environmental factors, in orofacial cleft
development, 2, 2b
Enzyme replacement therapy, for
Gaucher disease, 819
Eosinophilic granuloma, 590-592, 591f,
592f
of tongue, 287, 290f
Eosinophilic ulceration, of oral mucosa,
287
Ephelis, 376-377, 376f
Epidemic parotitis, 263-264, 264f
Epidermal implantation cysts, 32
Epidermal inclusion cysts, 32
Epidermoid cells, in mucoepidermoid
carcinoma, 488, 488f
Epidermoid cysts, 32-33, 32f, 33f, 34
of skin in Gardner syndrome, 652,
653f
Epidermolysis bullosa
clinical features of, 761-763, 762f,
762t, 763f
histopathologic features of, 763, 763f
treatment and prognosis of, 763-764
Epidermolysis bullosa acquisita, 761,
774
Epidermotropism, in mycosis fungoides,
599
Epididymoorchitis, in mumps, 263-264
Epiloia, 757-759
Epimyoepithelial islands, in benign
lymphoepithelial lesion, 466,
466f
Epistaxis, frequent, in hereditary
hemorrhagic telangiectasia,
754
Epithelial cells
spindle-shaped
in adenomatoid odontogenic
tumors, 714-715, 715f
in neuroﬁ
broma, 528, 529f
in synovial sarcoma, 562, 562f
Epithelial dysplasia
in leukoplakia, 394-395, 395f, 396
in lichen planus, 786
Epithelial hyperplasia, multifocal,
367-368, 367f, 368f
Epithelial rests
clear cell, in lateral periodontal cysts,
694
hyperchromatic, in clear cell
odontogenic carcinoma, 712-
713, 712f
odontogenic, in nevoid basal cell
carcinoma syndrome, 690,
691f
Epithelioid leiomyomas, 549
Epstein-Barr virus (EBV, HHV-4), 240
Burkitt‘s lymphoma and, 595-596
infectious mononucleosis from, 253
Epstein’s pearls, 26-27, 27f, 691
Epulis
congenital, 537-538, 537f, 538f,
539f
denture, 510-512
ossifying ﬁ
broid, 521-523
Epulis ﬁ
ssuratum, 510-512, 511f, 512f
Epulis granulomatosa, 518, 519f
Erlenmeyer ﬂ
ask deformities of long
bones in Gaucher disease, 819
Erosion, tooth wear by, 61, 63-64, 63f,
64f
Erosive lichen planus
clinical features of, 785, 785f
desquamative gingivigis in, 771
diagnosis of, 787
treatment and prognosis of, 787-788
Eruption, disturbances of, localized,
74-77
ankylosis as, 75-77, 76f
impaction as, 74-75, 74f, 75f
Eruption cyst, 682, 682f, 683f
Eruption sequestrum, 74, 75f
Eruptive Grzybowski type of
keratoacanthoma, 407
Erysipelas, 182-183
Erythema, gingival, linear, HIV-
associated, 272-273, 273f
Erythema areata migrans, 779-781
Erythema migrans, 779-781, 780f,
781f
psoriasis and, 793
Erythema multiforme, 766t, 776-779
in allergic mucosal reactions to
systemic drug administration,
347
clinical features of, 776-778, 777f,
778f
histopathologic features of, 778, 779f
HSV triggering, 241-242
treatment and prognosis of, 779
Erythema multiforme major, 777, 778f
Erythema nodosum, in sarcoidosis, 339
Erythematous cutaneous papules, in
Darier’s disease, 751, 751f
Erythematous stage, of mycosis
fungoides, 599
Erythroblastosis, tooth discoloration
associated with, 72
Erythrocytes.
See
Red blood cells.
Erythrocytosis, primary acquired,
586-587
Erythroleukoplakia, 388-397, 392, 393f,
397.
See also
Leukoplakia.
Erythromelelgia, 586
Erythroplakia, 392, 393f, 397-398, 397f,
398f
Erythroplasia, 397-398
of Queyrat, 397-398
Erythropoietic porphyria, congenital,
tooth discoloration in, 71, 71f
Esophageal webs
in Plummer-Vinson syndrome, 829
squamous cell carcinoma and, 411
Esthesioneuroblastoma, 555-556
Ethambutol, for tuberculosis, 198
Ethnicity, AIDS cases and, 265t, 266
Ethylenediaminetetraacetic acid (EDTA),
for heavy metal intoxication,
316
Ewing sarcoma, 667-669, 668f
Exanthema subitum, 240
Exfoliative cheilitis, 304-305, 305f, 306f
Exophthalmos, in Graves’ disease, 836,
836f
Exophytic osteoma, 650
Exophytic papilloma, 369
Exostoses, 19-23, 20f
buccal, 19-20, 20f
in osteoarthritis, 878
Expert witnesses, dentists as, 914
Extraabdominal desmoids, 515
Extraction, surgical, for
cementoblastoma, 655-656
Extramedullary plasmacytoma, 606
Extranodal NK/T-cell lymphoma,
nasal-type, 602-604, 603f
Extraosseous ameloblastoma, 710-711
Extraosseous form of calcifying
odontogenic cysts, 697
Eye(s)
in Behçet’s syndrome, 338
in Graves’ disease, 836, 836f
in hereditary benign intraepithelial
dyskeratosis, 744, 745f
in hereditary mucoepithelial dysplasia,
749
in mucous membrane pemphigoid,
772, 772f
yellow color of, in jaundice, 822, 822f
F
Facial angioﬁ
bromas, in tuberous
sclerosis, 758, 758f
Facial cleft
lateral, 2-3
oblique, 3
Facial dysesthesia, after surgery for
trigeminal neuralgia, 863
Facial hemiatrophy, progressive, 40-41,
41f
Facial pain
atypical, 861, 865-866, 865b
in Bell’s palsy, 859-861
in burning mouth syndrome, 873-875,
874b
in cluster headache, 868-869
in glossopharyngeal neuralgia,
863-864
in migraine, 870-871
in motor neuron disease, 873
in myasthenia gravis, 872-873, 872b
in neuralgia-inducing cavitational
osteonecrosis, 866-868, 867b,
867f, 868f
in osteoarthritis, 877-878http://dentalebooks.com

Index

947
Facial pain—cont’d
in paroxysmal hemicrania, 869-870
in postherpetic neuralgia, 864-865
in temporal arteritis, 871-872
in trigeminal neuralgia, 861-863
Facies, masklike, in systemic sclerosis,
799, 799f
Facies leprosa, 200
Factor IX deﬁ
ciency, 573, 573t, 574f,
575
Factor VIII deﬁ
ciency, 573-575, 573t,
574f
Famciclovir
prophylactic, for
immunocompromised patients,
247
for recurrent herpes labialis, 247
Familial dysautonomia, Riga-Fede
disease in, 289
Familial gigantiform cementoma,
645-646, 646f
Familial white folded dysplasia, 743-744
Fanconi’s anemia, aplastic anemia in,
580
Fasciculation, in amyotrophic lateral
sclerosis, 873
Federation Dentaire International Two-
Digit System for dental
numbering, 896, 896t
Fellatio, submucosal palatal hemorrhage
from, 307, 308f
Ferguson Smith type of
keratoacanthoma, 407
Fetal rhabdomyomas, 551-552
“Fever blister,” clinical features of,
243-244, 243f
Fever(s)
glandular, 253-255, 254f
San Joaquin Valley, 230-231
uveoparotid, associated with
sarcoidosis, 339
Fibrinolytic alveolitis, 150-151
Fibro-odontoma, ameloblastic, 721-722,
721f, 722f, 724
Fibro-odontosarcomas, ameloblastic,
723
Fibro-osseous lesions of jaws, 635-670
cemento-osseous dysplasias as, 640-
645.
See also
Cemento-osseous
dysplasias of jaws.
cementoblastoma as, 655-656
familial gigantiform cementoma as,
645-646
ﬁ
brous dysplasia as, 635-640.
See also

Fibrous dysplasia, of jaws.
osseous dysplasia as, 640-645.
See also

Cemento-osseous dysplasias of
jaws.
ossifying ﬁ
broma as, 646-648, 647f,
648f.
See also
Ossifying ﬁ
broma.
true cementoma as, 655-656
Fibroameloblastic dentinoma,
peripheral, 727
Fibroblastic granuloma, calcifying,
521-523
Fibroblasts, cellular proliferation of, in
desmoplastic ﬁ
broma, 659,
659f
Fibrodentin, 124
Fibrodentinoma, ameloblastic, 722
Fibroepithelial polyp, 511, 512f
Fibrolipoma, 523-524
Fibroma(s), 507-510, 508f, 509f
ameloblastic, 719-720, 720f, 722
cementifying, 646-648.
See also

Ossifying ﬁ
broma.
cemento-ossifying, 646-648.
See also

Ossifying ﬁ
broma.
chondromyxoid, of jaws, 657, 657f
denture, leaﬂ
ike, 511
desmoplastic, 515
of jaws, 658-660, 659f
giant cell, 509-510, 509f, 510f
odontogenic, 726-729.
See also

Odontogenic ﬁ
broma(s).
ossifying, 646-648, 647f, 648f.
See also

Ossifying ﬁ
broma.
peripheral, 521-523, 521f, 522f
peripheral, with calciﬁ
cation, 521-523
Fibromatosis, 515, 515f
gingival, 166-168, 166f, 167f, 168f
Fibromatosis gingivae, 166-168, 166f,
167f, 168f
Fibromyxomas, 731
Fibrosarcoma(s), 553, 553f
ameloblastic, 722-723, 723f
postirradiation, 664
Fibrosis
nodular subepidermal, 514
submucous, oral, 401-403, 402f
Fibrous dysplasia
of dentin, 110
of jaws, 635-640
clinical and radiographic features
of, 636-639, 636f, 637f, 638f
histopathologic features of, 639,
639f
monostotic, 636, 636f, 637f, 638f
polyostotic, 636-637, 638f, 639
treatment and prognosis of,
639-640
Fibrous histiocytoma, 514-515, 514f
malignant, 553-554, 554f
Fibrous hyperplasia, from cunnilingus,
308, 308f
Fibrous nodule, 507-509
Fibrous periapical scars, 130, 130f
Fibroxanthoma, 514
Fingerprinting, identiﬁ
cation by,
890-891
Fissured tongue, 13, 13f, 780, 780f
Fistula(s)
congenital, of lower lip, 5-6, 6f
soft palate, lateral, 16-17, 17f
Fixed drug eruptions, medications
implicated in, 348b
Flat torus, 21
Fluconazole
for candidiasis, 222-223t, 223-224
for cryptococcosis, 232
Fluorescence, x-ray, of dental remains,
888, 888f
Fluorescent photography, of bite marks
for evidence, 909
Fluorescent treponemal antibody
absorption (FTA-ABS) test for
syphilis, 193
Fluoride, dental ﬂ
uorosis from, 58-60,
59f
Fluoroquinolones, for gonorrhea, 195
Fluorosis, dental, 58-60, 59f
Flushing, gustatory, 876-877
Focal acantholytic dyskeratosis, 752-753
Focal cemento-osseous dysplasia, 148
Focal epithelial hyperplasia, 367-368,
367f, 368f
Focal ﬁ
brous hyperplasia, 507-509
Focal melanosis, 379-380, 380f
Focal osteoporotic marrow defect, 619-
620, 620f
Focal periapical osteopetrosis, 620
Focal sclerosing osteomyelitis, 147-148
Folic acid, for gingival hyperplasia, 166
Follicular ameloblastoma, 705, 705f
Follicular cysts, 679-682.
See also

Dentigerous cysts.
of skin, 32-33, 32f, 33f, 34f
Follicular dyskeratoma, 752-753
Forchheimer’s sign, in rubella, 262
Fordyce granules, 7-8, 7f, 8f
Foreign body gingivitis, 160-161, 161f,
162f
lichenoid, 782
Forensic dentistry, 887-916
autopsy in, 889
bite pattern evidence in, 903-911.
See
also
Bite marks.
human abuse and, 911-914
identiﬁ
cation in, 889-903.
See also

Identiﬁ
cation, in forensic
dentistry.
record management for, 887-889
Forked tongue, 311, 312f
Formication, from methamphetamine
abuse, 303
Foscarnet (trisodium phosphonoformate
hexahydrate), for herpes lesions
in immunocompromised
patients, 247
Fournier’s molars, in congenital syphilis,
191
Franceschetti-Zwahlen-Klin syndrome,
45-46, 45f
Freckle(s), 376-377, 376f
Hutchinson’s, 435
Freckle-like lesions, in Peutz-Jegher’s
syndrome, 753, 753f
Frenal tag, 508, 508f
Frey syndrome, 876-877, 877f
Frictional keratosis, 390, 390f
Frye
test of admissibility, 904
FTA-ABS (ﬂ
uorescent treponemal
antibody absorption) test for
syphilis, 192
Fungiform papilloma, 369, 369fhttp://dentalebooks.com

948 Index
Fusion
clinical features of, 84-85, 85f, 86f
deﬁ
nition of, 84
prognosis for, 86-87
treatment of, 86-87
G
Galvanic lesions, 354-355
Ganciclovir, for cytomegalovirus
infections, 256
Gangrene, orofacial, 201-203
Gangrenous stomatitis, 201-203
Gardner syndrome, 32, 651-653, 652f,
653f
Garment nevus, 385
Gaucher disease, 819-820
Riga-Fede disease in, 289
Gemination
bilateral, 84f
clinical features of, 84-85, 84f, 85f
deﬁ
nition of, 84
prognosis for, 86-87
treatment of, 86-87
Generalized pattern, of hypoplastic
amelogenesis imperfecta, 101,
101f
Generalized thin hypoplastic
amelogenesis imperfecta, 102
Generalized Wegener’s granulomatosis,
345
Genetic comparison, in identiﬁ
cation,
893-894
Genetic factors, in orofacial cleft
development, 2, 2b
Genital lesions, in Behçet’s syndrome,
337
Geographic tongue, 779-781
German measles, 261-263
Germinal centers, in lymphoid
hyperplasia, 572
Ghost cell tumors
dentinogenic, 695-697, 695f, 696f,
697f
epithelial odontogenic, 695
Ghost cells, eosinophilic, in calcifying
odontogenic cyst, 696-6976f,
697f
Ghost teeth, 112, 113f
Giant cell arteritis, 871-872
Giant cell ﬁ
broma, 509-510, 509f, 510f
Giant cell granuloma
central odontogenic ﬁ
broma
associated with, 727, 728f
clinical and radiographic features of,
626-628, 627f
histopathologic features of, 628,
628f
of jaws in hyperparathyroidism, 839-
840, 840f
peripheral, 520-521, 520f, 521f
treatment and prognosis of, 628-629
Giant-cell hyaline angiopathy, in
periapical cyst, 133
Giant cell lesion, 626-629
Giant cell tumors, 626-629
Giant cells
in cementoblastoma, 655, 656f
in cherubism, 630, 632f
in giant cell granuloma, 628, 628f
multinucleated, in aneurysmal bone
cyst, 635, 635f
Warthin-Finkedey, in rubeola, 261,
261f
Giant hairy nevus, 385
Gigantiform cementoma, familial,
645-646, 646f
Gigantism, oral manifestations of,
831-832
Gilbert syndrome, jaundice in, 822
Gingival cyst
of adult, 692, 692f, 693f
of newborn, 691-692, 692f
Gingival erythema, linear, HIV-
associated, 272-273, 273f
Gingival ﬁ
bromatosis, 166-168, 166f,
167f, 168f
Gingival granular cell tumor of newborn,
537
Gingival hemorrhage, green tooth
staining secondary to, 71
Gingivectomy, for gingival ﬁ
bromatosis,
168
Gingivitis, 154-163
chronic hyperplastic, 156, 156f
clinical features of, 154-156, 155f,
156f
desquamative, 162-163
in chronic ulcerative colitis, 789
in erosive lichen planus, 785, 785f
in mucous membrane pemphigoid,
771, 772f
foreign body, 160-161, 161f, 162f
lichenoid, 782
granulomatous, 160-162, 161f, 162f
histopathologic features of, 157, 157f
local factors associated with, 155,
155b
marginal, 156, 156f
necrotizing ulcerative.
See
Necrotizing
ulcerative gingivitis (NUG).
papillary, 156
plasma cell, 159-160, 159f, 160g
puberty, 154, 155f
scorbutic, 826, 827f
strawberry, 345, 345f
systemic factors associated with, 155,
155b
treatment and prognosis of, 157
types of, 155b
Gingivostomatitis
atypical, 159-160
herpetic, acute, clinical features of,
242, 242f, 243f
herpetic acute, treatment and
prognosis of, 246-247
necrotizing, 158
Glands, salivary.
See
Salivary glands.
Glandular epithelium, in pleomorphic
adenomas, 479
Glandular fever, 253-255, 254f
Glandular odontogenic cysts, 697-698,
698f
“Globulomaxillary cyst,” 28
Glomus jugulare tumor, 535-536
Glomus tympanicum tumor, 535-536
Glossitis
atrophic, in iron-deﬁ
ciency anemia,
828
interstitial, in tertiary syphilis, 190
luetic, in tertiary syphilis, 190, 191f
median rhomboid, 214t, 216
migratory, benign, 779-781
in diabetes, 844
in Plummer-Vinson syndrome, 828,
829f
Glossodynia, 873-875, 874b
Glossopharyngeal neuralgia, 863-864
Glossopyrosis, 873-875, 874b
Glucocorticoids, for rheumatoid arthritis,
880
Glycosaminoglycans, inability to process,
in mucopolysaccharidoses, 816
Gold
for rheumatoid arthritis, 880
systemic intoxication from, 314
clinical features of, 315-316
Goldenhar syndrome, 19
Gonococcal ophthalmia neonatorum,
194
Gonorrhea, 193-195, 194f
Gorlin cyst, 695-697, 695f, 696f, 697f
Gorlin sign, in Ehlers-Danlos syndrome,
757
Gorlin syndrome, 688-691.
See also

Nevoid basal cell carcinoma
syndrome.
multiple odontogenic keratocysts in,
684
Grading, of lesions in squamous cell
carcinoma, 419, 420f
Graft-versus-host disease (GVHD),
790-793
acute, 791
chronic, 791
clinical features of, 791-792, 791f,
792f
oral, lichen planus resembling, 785
oral manifestations of, 791-792
Grains, in Darier’s disease, 751
Granular cell ameloblastoma, 706, 706f
Granular cell lesion, congenital, 537-
538, 537f, 538f, 539f
Granular cell odontogenic ﬁ
broma, 729,
729f
Granular cell odontogenic tumor, 729,
729f
Granular cell schwannoma, 536
Granular cell tumor, 536-537, 536f,
537f
Granular leukoplakia, 391, 391f, 392f,
393f
Granulocytic sarcoma, in leukemia, 588
Granuloma(s)
eosinophilic, 590-592, 591f, 592f
of tongue, 287http://dentalebooks.com

Index

949
Granuloma(s)—cont’d
ﬁ
broblastic, calcifyiing, 521-523
giant cell, 626-629.
See also
Giant cell
granuloma.
central odontogenic ﬁ
broma
associated with, 727, 728f
peripheral, 520-521, 520f, 521f
histiocytic, atypical, 287, 289f
Langerhans cell, 590-592, 591f, 592f
lethal, midline, 602-604
periapical, 127-130.
See also
Periapical
granuloma.
pulse, in periapical cyst, 133
pyogenic, 517-519, 518f, 519f
gingivitis with, 156, 156f
traumatic, 287, 288f
Granulomatosis
Langerhans cell, 590-592, 591f, 592f
lymphomatoid, 602-603
orofacial, 341-345.
See also
Orofacial
granulomatosis.
in Crohn’s disease, 848-849
Wegener’s, 345-347, 345f, 346f
Granulomatous gingivitis, 160-162,
161f, 162f
Graves’ disease, 835-836
Growth hormone
production of
diminished, in pituitary dwarﬁ
sm,
831
increased
in acromegaly, 832
in gigantism, 831-832
replacement therapy with, for pituitary
dwarﬁ
sm, 831
Guillain-Barre syndrome, facial
weakness in, 860
Gum boil, complicating periapical
abscess, 136
Gumma, in tertiary syphilis, 190
Gustatory lacrimation syndrome, 877
Gustatory sweating and ﬂ
ushing,
876-877
H
HAART (highly active antiretroviral
therapy)
for cytomegalovirus infections in AIDS
patients, 256
for HIV infection, 280, 281b
for Kaposi’s sarcoma in HIV infection,
271
Hailey-Hailey disease, 766
Haim-Munk syndrome, 176
Hairy leukoplakia, oral, 14
Epstein-Barr virus causing, 253
in HIV infection, 268-270, 269f
Hairy tongue, 13-15, 14f, 15f
Halo nevus, 386, 386f
Hamartoma(s)
epithelial, odontogenic, 727
multiple, gingival ﬁ
bromatosis in, 166
odontomas as, 724
Hamazaki-Wesenberg bodies, in
sarcoidosis, 340
Hamman’s crunch, in
pneumomediastinum, 324
Hand-foot-and-mouth disease, clinical
features of, 257-258, 258f
Hand-Schüller-Christian disease,
histiocytosis in, 590
Hansen disease, 198-201.
See also

Leprosy.
Hashimoto’s thyroiditis, 834
Headache
alarm clock, 869
cluster, 868-869
migraine, 870-871, 870t
Heck’s disease, 367-368, 367f, 368f
Heerfordt’s syndrome, associated with
sarcoidosis, 339
Hemangioendothelioma, 556
kaposiform, 540
Hemangioma(s)
histopathologic features of, 541-542,
541f, 542f
of infancy, clinical and radiographic
features of, 539-540, 540f
lobular capillary, 518
in multiple hamartoma syndrome,
760
sclerosing, 514
strawberry, 539-540, 540f
treatment and prognosis of, 542-543
tufted, 540
Hemangiopericytoma-like tumor,
546-547
Hemangiopericytoma–solitary ﬁ
brous
tumor (HPC-SFT), 546-547,
546f
Hematoma(s)
eruption, 682, 682f
in submucosal hemorrhage, 305, 307f
in thrombocytopenia, 585, 585f
Hematopoiesis, cyclic, 583-584, 584f
Hemiageusia, 875
Hemicrania, paroxysmal, 869-870
Hemicrania continua, 869
Hemidesmosomal type, of epidermolysis
bullosa, 761
Hemidesmosomes, antibodies binding to,
in bullous pemphigoid, 776
Hemifacial atrophy, progressive, 40-41,
41f
Hemifacial hyperplasia, 18, 39
macroglossia in, 11
Hemifacial microsomia, 19
in temporomandibular joint ankylosis,
882
Hemihypertrophy, 38-40, 39b, 40f
Hemiphyperplasia, 38-40, 39b, 40f
Hemochromatosis, from blood
transfusions for thalassemia
major, 580
Hemodialysis, amyloidosis associated
with, 823-824
Hemoglobin H (HbH) disease, 580
Hemoglobinopathies, 576
Hemolytic anemia, autoimmune,
bilirubin excess in, 821
Hemophilia, 573-575, 573t, 574f
Hemorrhage
from antineoplastic therapy, 294
gingival, green tooth staining
secondary to, 71
palatal, submucosal, from fellatio, 307,
308f
submucosal, 305-307, 306f, 307f
Hemorrhagic bone cyst, 631-634.
See
also
Simple bone cyst.
Henderson-Paterson bodies, in
molluscum contagiosum,
371-372
Hepatitis C, lichen planus and,
782-783
Hereditary benign intraepithelial
dyskeratosis (HBID), 744-745,
744f, 745f
white sponge nevus similarities with,
743
Hereditary hemorrhagic telangiectasia
(HHT), 754-755, 754f, 755f
Hereditary mucoepithelial dysplasia,
748-750, 749f
Hereditary opalescent dentin, 106-108
Herpangina, clinical features of, 257,
258f
Herpes, 240
Herpes barbae, 244
Herpes gladiatorum, 244
Herpes labialis, clinical features of,
243-244, 243f
Herpes simplex, preceding erythema
multiforme, 776
Herpes simplex virus 1 (HSV-1),
241-245
acute herpetic gingivostomatitis from,
242, 242f, 243f
antibodies to, decreased risk of HSV-2
infection and, 241
herpes labialis from, 243-244,
243f
herpetic whitlow from, 244, 244f
pharyngotonsillitis from, 243
primary infection with, 241
recrudescent infection with, 241
recurrent infection with, 241
secondary infection with, 241
Herpes simplex virus 2 (HSV-2),
241-245
exposure to, sexual activity and, 241
infections with, increase in, reasons
for, 241
pharyngotonsillitis from, 243
Herpes simplex virus (HSV), 240,
241-248
HIV-associated, 275, 275f
incubation period for, 241
Herpes simplex virus (HSV) infection(s)
clinical features of, 242-245, 242f,
243f, 244f, 245f
diagnosis of, 246
histopathologic features of, 245-246,
245f, 246f
treatment and prognosis of, 246-248http://dentalebooks.com

950 Index
Herpes zoster, 250-253
clinical features of, 250-252, 251f
diagnosis of, 252
facial pain in, 864
histopathologic features of, 252
HIV-associated, 276
treatment and prognosis of, 252-253
Herpes zoster ophthalmicus, 864
Herpetic gingivostomatitis, acute
clinical features of, 242, 242f, 243f
treatment and prognosis of, 246-247
Herpetic paronychia, 244, 244f
Herpetic whitlow, 244, 244f
Herpetiform aphthous ulcerations, 333
clinical features of, 334, 334f
Herpetoviridae, 240
Heterotopic oral gastrointestinal cysts,
34
HHT (hereditary hemorrhagic
telangiectasia, 754-755, 754f,
755f
HHV-5 (cytomegalovirus), 240, 255-
256, 256f
HHV-4 (Epstein-Barr virus), 240
HHV-6 (human herpesvirus 6), 240
HHV-7 (human herpesvirus 7), 240
HHV-8 (human herpesvirus 8), 240-241
HHV-3 (varicella-zoster virus), 248-250
HHV (varicella-zoster virus), 240
Hide-bound disease, 798-801
Highly active antiretroviral therapy
(HAART).
See
HAART (highly
active antiretroviral therapy).
Histamine, for Bell’s palsy, 860
Histaminic cephalgia, 868-869
Histiocytic granuloma, atypical, 287,
289f
Histiocytoma, ﬁ
brous, 514-515, 514f
malignant, 553-554, 554f
Histiocytosis, Langerhans cell, 590-592,
591f, 592f
Histiocytosis X, 590-592, 591f, 592f
Histoplasmosis, 224-226, 225f, 226f
HIV-associated, 277-278, 277f, 278f
HIV.
See
Human immunodeﬁ
ciency
virus.
Hodgkin’s lymphoma, 592-595
Ann Arbor classiﬁ
cation system for,
594t
clinical features of, 593, 593f
histopathologic features of, 593-594,
594f
lymphocyte depletion subtype of, 594
lymphocyte-rich, 594
mixed cellularity form of, 594
nodular lymphocyte-predominant,
594
nodular sclerosis subtype of, 594
staging of, 593
treatment and prognosis of, 594-595
Horn cysts, in seborrheic keratosis, 374,
375f
Horton’s syndrome, 868-869
HPC-SFT (hemangiopericytoma-solitary
ﬁ
brous tumor), 546-547, 546f
HPV.
See
Human papillomavirus.
HSV-1 (herpes simplex virus 1), 241-
245.
See also
Herpes simplex
virus 1.
HSV-2 (herpes simplex virus 2),
241-245
HSV (herpes simplex virus), 240
5-HT
1
agonists, for migraine, 871
Human herpes viruses, 240-241
Human herpesvirus 6 (HHV-6), 240
Human herpesvirus 7 (HHV-7)
Human herpesvirus 8 (HHV-8),
240-241
Human immunodeﬁ
ciency virus (HIV),
264-281
epidemiology of, 264-265, 265t
risk factors for, 265-266
transmission of, 265
Human immunodeﬁ
ciency virus (HIV)
infection
clinical features of, 266-267
diagnosis of, 280, 280b
oral and maxillofacial manifestations
of
aphthous ulcerations as, 278, 278f
candidiasis as, 267-268, 267f, 268f
classiﬁ
cation of, 266, 267b
herpes simplex virus as, 275, 275f
histoplasmosis as, 277-278, 277f,
278f
human papillomavirus as, 276-277,
276f, 277f
hyperpigmentation as, 274
Kaposi’s sarcoma as, 270-271, 270f,
271f
molluscum contagiosum as, 278-
279, 279f
mycobacterial infection as, 274
non-Hodgkin’s lymphoma as, 272,
272f
oral hairy leukoplakia as, 268-270,
269f
oral squamous cell carcinoma as,
279, 279f
periodontal disease as, 272-274,
273f, 274f
persistent generalized
lymphadenopathy as, 271-272,
272f
salivary gland disease as, 275
thrombocytopenia as, 275
varicella-zoster virus as, 276
treatment and prognosis of, 280-281,
281b
Human papillomavirus (HPV)
condyloma acuminatum from,
366-367
focal epithelial hyperplasia from,
367-368
HIV-associated, 276-277, 276f, 277f
squamous papilloma from, 362-364
verruca vulgaris from, 364-366
Hunter syndrome, features of, 817t
Hurler syndrome, features of, 817t
Hutchinson’s freckle, 435
Hutchinson’s incisors, 60
in congenital syphilis, 191, 191f
Hutchinson’s triad, in congenital syphilis,
190
Hyaline, in lichen planus, 786
Hyaline bodies, in periapical cyst, 133,
134f
Hyalinosis cutis et mucosae, oral
manifestations of, 820-821
Hydrocortisone cream, for exfoliative
cheilitis, 305, 306f
Hydrogen peroxide, mucosal burns from,
292, 292f
Hydrop fetalis, 580
Hydropic degeneration, of epithelium, in
lichen planus, 786, 786f
Hydroxychloroquine therapy, for chronic
ulcerative colitis, 789-790
Hyperbaric oxygen therapy, for Bell’s
palsy, 861
Hyperbilirubinemia, tooth discoloration
associated with, 71-72, 72f
Hypercarotenemia, jaundice confused
with, 822
Hypercementosis, 96-97, 96b, 96f, 97f
Hyperchromatic nuclei, in squamous cell
carcinoma, 419
Hypercortisolism, oral manifestations of,
840-841
Hyperdontia, 77
clinical features of, 80-81, 80f, 81f
syndromes associated with, 78b
Hyperelasticity of skin, in Ehlers-Danlos
syndromes, 756, 756f
Hyperglycemia, in diabetes mellitus,
842
Hyperkeratosis
in leukoplakia, 394
in nicotine stomatitis, 403, 403f
Hyperkeratotic form, of seborrheic
keratosis, 375
Hypermobility type, of Ehlers-Danlos
syndrome, 756t, 757
Hyperorthokeratosis, in leukoplakia,
394, 394f
Hyperparakeratosis, in leukoplakia, 394
Hyperparathyroidism, 838-840
Hyperpigmentation
in Addison’s disease, 842, 842f
HIV-associated, 274
Hyperplastic candidiasis, chronic, 214t,
217-218, 219f
Hyperplastic gingivitis, chronic, 156,
156f
Hypersensitivity, to dental resins, 355
Hypertaurodontism, 95, 95f
Hyperthyroidism, oral manifestations of,
835-836
Hypertrichosis, in congenital
melanocytic nevus, 385, 385f
Hypoadrenocorticism, 841-842
Hypocalciﬁ
ed amelogenesis imperfecta,
103-104, 104f
Hypodactylia, in oromandibular-limb
hypergenesis syndromes, 9http://dentalebooks.com

Index

951
Hypodontia, 77
clinical features of, 79-80, 79f
in ectodermal dysplasia, 742
in incontinentia pigmenti, 750, 750f
prognosis for, 82
syndromes associated with, 78b
treatment of, 82
Hypoglossia, 9
Hypohidrotic ectodermal dysplasia,
741-742
Hypomaturation amelogenesis
imperfecta, 102-103, 104f
Hypomaturation/hypoplastic
amelogenesis imperfecta, 104-
105, 105f
Hypomelia, in oromandibular-limb
hypergenesis syndromes, 9
Hypoparathyroidism, oral manifestations
of, 837, 837f
Hypophosphatasia, oral manifestations
of, 845-847, 846f
Hypoplastic amelogenesis imperfecta,
101-102, 101f, 102f, 103f
Hypotaurodontism, 95, 95f
Hypothermia, in hypothyroidism, 834
Hypothyroidism
macroglossia in, 11
oral manifestations of, 834-835, 834f,
835f
I
Icterus, oral manifestations of, 821-822
Identiﬁ
cation, forensic
dental, 894-903, 895f, 896t
antemortem record examination in,
898-899
comparison of antemortem and
postmortem records and
written conclusions in, 899,
899f
guidelines for, 897-899
postmortem examination in, 897-
898, 898f
exclusion of evidence for, 890
by ﬁ
ngerprinting, 890-891
in forensic dentistry, 889-903
instrument kit for, 897b
insufﬁ
cient evidence for, 890
in mass fatality incident
dentistry’s role in, 899-903
technologic aides in, 90-1-903
by personal recognition, 890, 890f
by physical anthropologic examination
of bones and teeth, 891-893,
891t, 892f
positive, criteria for, 889
presumptive, criteria for, 889-890
by serologic and genetic comparison,
893-894
Idiopathic bone cavity, 631-634.
See also

Simple bone cyst.
Idiopathic facial pain, 865-866
Idiopathic midline destructive disease,
602-604
Idiopathic osteosclerosis, 620-622, 621f
Idiopathic thrombocytopenic purpura
(ITP), 585-586
Imidazole agents, for candidiasis, 221-
223, 222-223t
Immune-mediated dermatologic
diseases, 764-804.
See also

Dermatologic diseases ,
immune-mediated.
Immune thrombocytopenic purpura
(ITP), 585-586
Immunobullous diseases, 764
Immunocompromised hosts
cytomegalovirus infections in, 255
HSV infections in
recurrent, clinical features of, 244-
245, 245f
treatment of, 247
Immunodeﬁ
ciency-associated Burkitt’s
lymphoma, 601
Immunoﬂ
uorescence
direct, 764, 764f
indirect, 764f, 765
Immunologic disease
Behçet’s syndrome as, 336-338, 337f
orofacial granulomatosis as, 341-345.
See also
Orofacial
granulomatosis.
recurrent aphthous stomatitis as.
See
also
Recurrent aphthous
stomatitis.
recurrent aphthous stomatitis as,
331-336
sarcoidosis as, 338-341.
See also

Sarcoidosis.
Wegener’s granulomatosis as,
345-347
Immunoprecipitation studies, in
paraneoplastic pemphigus
diagnosis, 770
Immunoproliferative lesion,
angiocentric, 602-604
Immunosuppression
Kaposi’s sarcoma associated with,
558
squamous cell carcinoma and, 412
Immunosuppressive therapy
for mucous membrane pemphigoid,
775
for paraneoplastic pemphigus, 771
Impaction, 74-75, 74f, 75f
Impetiginized dermatitis, 181
Impetigo, 181-182, 182f
staphylococcal, 181-182
Impetigo contagiosa, 181
Incisive canal cyst, 28-31.
See also

Nasopalatine duct cyst.
Incisive canals, 28
Incisive papilla, cysts of, 30, 30f
Incisor(s)
Hutchinson’s, 60
in congenital syphilis, 191, 191f
shovel-shaped
clinical and radiographic features
of, 89, 89f
treatment and prognosis of, 90
Incontinentia pigmenti, 750-751, 751f
Indomethacin
for paroxysmal hemicrania, 870
in paroxysmal hemicrania diagnosis,
869
Induction chemotherapy, for leukemia,
589
Infancy, melanotic neuroectodermal
tumor of, 533-535, 534f
Infantile hypophosphatasia, 845
Infantile osteopetrosis, 616, 616f
Infection(s)
bacterial, 181-212.
See also
Bacterial
infections.
Vincent’s, 157-159
viral, 240-284.
See also
Viral
infections.
Infectious mononucleosis, 253-255,
254f
Inﬁ
ltrating lipomas, 524
Inﬂ
ammatory ﬁ
brous hyperplasia,
510-512
Inﬂ
ammatory papillary hyperplasia,
512-514, 513f
Inﬂ
iximab, for Crohn’s disease, 849
Infraocclusion, 75
Infrared photography, of bite marks for
evidence, 908-909
Infundibular cyst, 32-33, 32f, 33f
Insulin, for diabetes, 845
Insulin shock, 845
Interface dentin, 124
Interferon alfa-2a, for giant cell
granuloma, 628
Intermediate osteopetrosis, 616
Interstitial glossitis, in tertiary syphilis,
190
Intestinal polyps, in Peutz-Jegher’s
syndrome, 753
Intoxication, metallic, systemic, 313-316.
See also
Metallic intoxication,
systemic.
Intradermal nevus
clinical features of, 383, 383f
histopathologic features of, 384,
384f
Intraductal papilloma, 485-487
Intraluminal unicystic ameloblastoma,
708, 708f, 709f
Intramedullary ﬁ
bous scar, in bone
marrow edema, 868
Intramucosal nevus
clinical features of, 383, 383f
histopathologic features of, 384, 384f
Intramuscular lipomas, 524
Intraosseous mucoepidermoid
carcinoma, 490-491, 490f
evolving from dentigerous cysts, 682
Intraosseous variant of calcifying
odontogenic cysts, 697
Invasive cervical resorption, 68-69
Inverted ductal papilloma, 486-487,
487f
Inverted follicular keratosis of Helwig,
375http://dentalebooks.com

952 Index
Inverted papilloma, 369-370, 370f
Iodine, radioactive, for Graves’ disease,
836
Iodoquinol, for candidiasis, 224
Iodoquinol cream, for exfoliative
cheilitis, 305, 306f
Iron, supplemental, for iron-deﬁ
ciency
anemia, 828
Iron deﬁ
ciency, squamous cell
carcinoma and, 411
Iron-deﬁ
ciency anemia, oral
manifestations of, 827-828
Irregular dentin, 124
Irritation dentin, 124
Irritation ﬁ
broma, 507-509
Ischemic myeloﬁ
brosis, in bone marrow
edema, 868
Ischemic osteonecrosis, 866-868
Isoniazid, for tuberculosis, 198
Isthmus-catagen cyst, 32
ITP (idiopathic thrombocytopenic
purpura), 585-586
Itraconazole
for aspergillosis, 235
for candidiasis, 222-223t, 224
J
Jackson-Lawler type of pachyonychia
congenita, 745-746
Jadassohn-Tièche nevus, 386-388
Jaffe-Lichtenstein syndrome, 636, 637,
638f
Jarisch-Herxheimer reaction, in syphilis,
193
Jasassohn-Lewandowsky type of
pachyonychia congenita,
745-746
Jaundice
oral manifestations of, 821-822
tooth discoloration associated with,
71-72, 72f
Jaw claudication, in temporal arteritis,
871
Joint disease, degenerative, 877-878
Joint replacement, for osteoarthritis,
878
Jugulotympanic paragangliomas, 535
Junctional epidermolysis bullosa, 761,
762t
Junctional nevus
clinical features of, 383
histopathologic features of, 384, 384f
Juvenile aggressive ﬁ
bromatoses, 515
Juvenile hemangioendothelioma,
541-542
Juvenile hemangiomas, 541-542, 541f,
542f
Juvenile melanoma, benign, 386
Juvenile nasopharyngeal angioﬁ
broma,
545
Juvenile ossifying ﬁ
broma, 648-650,
649f, 650f
Juvenile periodontitis, 173
Juxtacortical osteosarcoma of jaws,
663-664, 663f
K
Kabuki syndrome, 6
Kallikrein-4, disorders of, in
amelogenesis imperfecta, 100
Kaposiform hemangioendothelioma, 540
Kaposi’s sarcoma herpesvirus (KSHV),
240-241
Kaposi’s sarcoma (KS), 240-241, 557-
559, 557f, 558f
in HIV infection, 270-271, 270f, 271f
Kaposi’s varicelliform eruption, 244
Kasabach-Merritt phenomenon,
hemangiomas associated with,
540
Keratin horn
in actinic keratosis, 404
in verruca vulgaris, 364
Keratin pearls, in squamous cell
carcinoma, 419
Keratinizing squamous cell carcinoma,
nasopharyngeal, 429
Keratinocytes, eosinophilic, necrotic, in
erythema multiforme, 778,
779f
Keratoacanthoma, 406-408, 407f, 408f
Keratocarcinoma, 406-408
Keratoconjunctivitis sicca, in Sjögren
syndrome, 467, 468
Keratocyst, odontogenic, 683-687.
See
also
Odontogenic keratocyst.
Keratocystic odontogenic tumor, 683
Keratoderma palmoplantar of Unna-
Thost syndrome, 176
Keratohyaline granules, in
orthokeratinized odontogenic
cyst, 687, 688f
Keratosis follicularis, 751-752
Keratosis(es)
acral, in multiple hamartoma
syndrome, 760
actinic, 404-405, 404f, 405f
arsenical, 315
frictional, 390, 390f
sanguinaria-associated, 389, 389f
seborrheic, 374-375, 374f, 375f
smokeless tobacco, 398-401.
See also

Smokeless tobacco keratosis.
spit tobacco, 398-401.
See also

Smokeless tobacco keratosis.
tobacco pouch, 398-401.
See also

Smokeless tobacco keratosis.
with verrucous carcinoma, 422
Kerotosis follicularis, similarity of warty
dyskeratoma to, 752
Ketoconazole, for candidiasis, 222-223,
222-223t
Kidney
carcinoma of, metastatic to tongue,
563f
failure of, uremic stomatitis in, 851,
851f
stones in, in hyperparathyroidism, 838
“Kissing disease,” 253-255, 254f
Kleeblattschädel
deformity, in Crouzon
syndrome, 43
Klestadt cyst, 27-28
KLK4
gene mutation, in amelogenesis
imperfecta, 100
Koilocytes
in condyloma acuminatum, 366-367,
367f
in squamous papilloma, 364
in verruca vulgaris, 365, 365f
Koilonychia, in Plummer-Vinson
syndrome, 829
Koplik’s spots, in rubeola, 260, 260f
Kostmann syndrome, agranulocytosis in,
583
KS.
See
Kaposi’s sarcoma.
KSHV (Kaposi’s sarcoma herpesvirus),
240-241
Kveim test, for sarcoidosis, 341
L
Labial melanotic macule, 379
Labret, 311-312, 312f
Lacrimo-auriculo-dento-digital (LADD)
syndrome, salivary gland
aplasia in, 453, 454
Lactic acid, topical, for verruca vulgaris,
366
LADD (lacrimo-auriculo-dento-digital)
syndrome, salivary gland
aplasia in, 453, 454
Langerhans cell histiocytosis, 590-592,
591f, 592f
Langerhans cells, in Langerhans
cell histiocytosis, 591-592,
592f
Large cell Ewing sarcoma, 668
Laryngeal papillomatosis, 363-364
Larynx
lesions of, in mucous membrane
pemphigoid, 772-773
mucosa of
in lipoid proteinosis, 820
precancerous lesions of, 410t
Lasers, ﬂ
ashlamp pulsed dye, for port
wine stains, 543, 544
Latent bone cyst, 24-25
Lateral periodontal cysts, 28, 131, 692-
695, 693f, 694f.
See also

Periodontal cyst, lateral.
Lateral radicular cysts, 131
clinical and radiographic features of,
132, 133f
Lateral soft palate ﬁ
stulas, 16-17, 17f
LE.
See
Lupus erythematosus.
Lead, systemic intoxication from, 313
clinical features of, 314
Leaﬂ
ike denture ﬁ
broma, 511
Leiomyoblastomas, 549
Leiomyosarcoma, 559, 559f
Lentigo
actinic, 377-378, 377f, 378f
senile, 377-378
Lentigo maligna melanoma, clinical
features of, 435, 435f
Lentigo simplex, 378, 378f
Lentigo solaris, 377-378http://dentalebooks.com

Index

953
Leonine facies, in multibacillary leprosy,
199
Leontiasis ossea, in Paget’s disease of
bone, 624
Lepromatous leprosy, 199, 199f, 200f,
201f
tooth discoloration in, 72
Leprosy, 198-201
clinical features of, 199-200, 199f
diagnosis of, 201
histopathologic features of, 200-201,
200f, 201f
lepromatous, 199, 199f, 200f, 201f
tooth discoloration in, 72
multibacillary, 199, 199f, 200f,
201f
paucibacillary, 199, 200f
treatment and prognosis of, 201
tuberculoid, 199
Lesch-Nyhan syndrome
Riga-Fede disease in, 289
self-inﬂ
icted bites in, 903
Leser-Trélat sign, in seborrheic keratosis,
375
Letterer-Siwe disease, histiocytosis in,
590
Leukemia, 587-590
acute lymphoblastic
in children, prognosis of, 589
clinical features of, 588
acute myeloid, 587
clinical features of, 587-588
treatment and prognosis of, 590
chronic lymphocytic
clinical features of, 588
paraneoplastic pemphigus
associated with, 769
prognosis of, 590
treatment of, 589
chronic myeloid, 587
clinical features of, 587-588
treatment and prognosis of, 590
diagnosis of, 589
genetic disorders associated with,
587
histopathologic features of, 588
treatment and prognosis of, 589-590
Leukoedema, 8-9, 8f, 9f
Leukokeratosis, 388-397.
See also

Leukoplakia.
Leukoplakia, 388-397
alcohol and, 389
candidal, 214t, 217-218, 219f, 389-
390, 389f
causes of, 388-390
clinical features of, 390-393, 390f,
391f, 392f, 393f
granular, 391, 391f, 392f, 393f
histopathologic features of, 394-396,
394f, 395f
homogeneous, 391, 391f
incidence of, 388
malignant transformation in, 394-396
risk of, 396-397
microorganisms and, 389-390, 389f
Leukoplakia—cont’d
oral hairy, 14
Epstein-Barr virus causing, 253
in HIV infection, 268-270, 269f
in oral submucous ﬁ
brosis, 402
prevalence of, 388
proliferative verrucous, 391-392, 392f
sanguinaria and, 389, 389f
speckled, 392, 393f
squamous cell carcinoma and, 410
thick, 391, 391f, 393f
thin, 391, 391f, 393f
tobacco and, 388-389
trauma and, 390, 390f
treatment and prognosis of, 396-397
ultraviolet radiation and, 389
verrucous, 391, 392f, 393f
in verrucous carcinoma, 422
Lhermitte-Duclos disease, multiple
hamartoma syndrome and,
760
Libman-Sachs endocarditis, in systemic
lupus erythematosus, 795
Lichen planus, 766t, 782-788
bullous, 785
clinical features of, 783-785, 783f,
784f, 785f
diagnosis of, 787
erosive
clinical features of, 785, 785f
desquamative gingivitis in, 771
diagnosis of, 787
treatment and prognosis of,
787-788
histopathologic features of, 785-787,
786f
malignant transformation of, 788
reticular
clinical features of, 783, 784f, 785
diagnosis of, 787, 787f
treatment and prognosis of, 787
treatment and prognosis of, 787-788
Lichenoid amalgam reaction, lichen
planus resembling, 785
Lichenoid contact stomatitis, from dental
restorative materials, 354-356,
355f, 356f
Lichenoid dermatitis, 782
Lichenoid drug reaction, lichen planus
resembling, 785
Lichenoid eruptions, medications
implicated in, 348b
Lichenoid foreign body gingivitis, 782
Lichenoid lesions, betel quid, 402
Lichenoid mucositis, 782
Lie bumps, 330-331
Liesegang ring calciﬁ
cations, in
calcifying epithelial
odontogenic tumors, 717,
717f
Limited Wegener’s granulomatosis, 345
Linea alba, 285
Linear gingival erythema, HIV-
associated, 272-273, 273f
Linear IgA bullous dermatosis, 774
Lingual cortical mandibular defect,
24-25
Lingual mandibular salivary gland
depression, 24-25
Lingual papillitis, transient, 330-331,
331f
Lingual thyroid, 12-13, 12f
Lip(s)
cleft
development of, 2
upper median, 3
double, 6-7, 6f
lower, congenital ﬁ
stulas of, 5-6, 6f
in paraneoplastic pemphigus, 769,
770f
piercings of, 311-312, 312f
salivary gland tumors affecting, 475,
477f
Lip pits
commissural, 5, 5f
paramedian, 5-6, 6f
Lip shave.
See
Vermilionectomy.
Lip vermilion, carcinoma of, 414-415,
415f, 4141f
Lipid reticuloendothelioses, oral
manifestations of, 818-820
Lipoid proteinosis, oral manifestations of,
820-821, 820f, 821f
Lipomas, 523-524, 523f, 524f
in multiple hamartoma syndrome,
760
Liposarcoma, 554-555, 554f
Lisch nodules, in neuroﬁ
bromatosis type
I, 530
Lithotripsy, shock wave, for sialolithiasis,
461
Liver spot, 377-378
Lobectomy, for acinic cell
adenocarcinomas, 492
Lobular capillary hemangioma, 518
Lobular carcinoma, 497-498
Lobular torus, 21
Localized pattern, of hypoplastic
amelogenesis imperfecta, 101
Löfgren’s syndrome, associated with
sarcoidosis, 339
Lou Gehrig disease, 873
Ludwig’s angina, 138-139
clinical features of, 139, 139f
prognosis for, 140-141
treatment of, 140
Lues, 188-193.
See also
Syphilis.
Lues maligna, 190
Luetic glossitis, in tertiary syphilis, 190,
191f
Luminal unicystic ameloblastoma, 708,
709f
Lung cancer, metastatic, 564f
Lupus band test, in lupus erythematosus
diagnosis, 797
Lupus cheilitis, in systemic lupus
erythematosus, 795
Lupus erythematosus (LE), 794-798
abnormal immunologic ﬁ
ndings in,
798thttp://dentalebooks.com

954 Index
Lupus erythematosus (LE)—cont’d
cutaneous
chronic, 794
clinical features of, 795-796, 796f
subacute, 794
clinical features of, 796
diagnosis of, 797, 798t
discoid, 795
histopathologic features of, 796-797,
797f
lichen planus resembling, 785
systemic, 794
clinical features of, 794-795, 795f,
795t
treatment and prognosis of, 797-798
Lupus erythematosus-like eruptions,
medications implicated in,
348b
Lupus pernio, in sarcoidosis, 339
Lupus vulgaris, in tuberculosis, 196
Lyell’s disease, 777
Lymph node dissection, for melanoma,
439
Lymphadenopathy, generalized,
persistent, in HIV infection,
271-272, 272f
Lymphangiomas, 547-549, 547f, 548f
macroglossia in, 11
Lymphocyte depletion subtype of
Hodgkin’s lymphoma, 594
Lymphocytosis, diffuse inﬁ
ltrative, HIV-
associated, 275
Lymphoepithelial carcinoma, 466
Lymphoepithelial cyst, oral, 37-38, 38f,
39f
Lymphoepithelial lesion, benign,
465-466, 466f
Lymphoepithelioma, in nasopharyngeal
carcinoma, 429
Lymphoid hyperplasia, 571-572, 572f
Lymphoid stroma, in Warthin tumor,
483, 483f
Lymphoma(s)
Burkitt’s, 600-602, 601f, 602f
extranodal NK/T-cell, nasal-type,
602-604, 603f
Hodgkin’s, 592-595.
See also
Hodgkin’s
lymphoma.
MALT, epimyoepithelial islands in,
466
marginal zone B-cell, epimyoepithelial
islands in, 466
non-Hodgkin’s, 595-598.
See also
Non-
Hodgkin’s lymphoma.
in HIV infection, 272, 272f
paraneoplastic pemphigus associated
with, 769
risk of, in Sjögren syndrome, 470
T-cell
angiocentric, 602-604
cutaneous, 598-600, 599f, 600f
Lymphomatoid granulomatosis, 602-603
Lymphonodular pharyngitis, acute,
clinical features of, 258-259,
259f
Lymphoproliferative disorder,
posttransplant, 596
Lyon hypothesis, 742
M
Macrodontia, 83-84
Macroglossia, 9, 9f
causes of, 10b
in hemihyperplasia, 39, 40f
Macule, oral melanotic, 379-380, 380f
Maffucci syndrome, 656
Magrognathia, 83
Major aphthous ulcerations, 333
clinical features of, 334, 334f
Malformation syndromes, associated
with hemihyperplasia, 39b
Malignant acanthosis nigricans, 803
Malignant ameloblastomas, 711-712
Malignant ﬁ
brous histiocytoma, 553-
554, 554f
Malignant lymphoepithelial lesion, 466
Malignant melanoma, 433-439.
See also

Melanoma.
Malignant mixed tumors, 491-495
carcinoma ex pleomorphic adenoma
as
clinical features of, 493, 493f
histopathologic features of, 494,
494f
treatment and prognosis of, 494
carcinosarcoma as
clinical features of, 493
histopathologic features of, 494
treatment and prognosis of,
494-495
metastasizing
clinical features of, 493-494
histopathologic features of, 494
treatment and prognosis of, 495
Malignant osteopetrosis, 616
Malignant peripheral nerve sheath
tumor, 555
complicating neuroﬁ
bromatosis type I,
531, 531f
Malignant schwannoma, 555
complicating neuroﬁ
bromatosis type I,
531, 531f
Malignant transformation
of keratoacanthoma, 408
of leukoplakia, 394-396
risk of, 396-397
of lichen planus, 788
of oral submucous ﬁ
brosis, 402-403
Malignant transformation potential,
deﬁ
nition of, 388b
Malignant Triton tumor, 555
Malignant Warthin tumor, 483
MALT lymphomas, epimyoepithelial
islands in, 466
Mandible
in cherubism, 629, 630f, 631f
enlarged, in acromegaly, 832, 833f
“Mandibular cyst, median,” 32
Mandibular dysostosis, 45-46, 45f
Mandibulofacial dysostosis, 19
Marble bone disease, 615-617
Marginal gingivitis, 156, 156f
Marginal zone B-cell lymphomas,
epimyoepithelial islands in,
466
Maroteaux-Lamy syndrome, features of,
817t
Mask of pregnancy, 378-379, 379f
Massive osteolysis, 622-623, 622f, 623f
Mast cell degranulation, in angioedema,
356
Matrix formation, in enamel
development, 55
Maturation, in enamel development, 55
Maxilla, melanotic neuroectodermal
tumor of infancy in, 533, 534f
Maxillary sinus, carcinoma of, 426-427,
426f
Mazabraud syndrome, 637
McCune-Albright syndrome, 636, 637,
639
gigantism in, 832
Measles, 259-261, 260f, 261f
German, 261-263
Mechanical damage, pulpitis from, 120
“Median mandibular cyst, 32
Median palatal cyst, 31-32, 31f
Median rhomboid glossitis, 214t, 216
Medication-associated gingival
enlargement, 63b, 163-166,
163f, 164f, 165f.
See also

Drug-related gingival
hyperplasia.
Medications.
See
Drug(s).
Mediterranean anemia, 579
Megadontia, 83
Megalodontia, 83
Melanin pigmentation of oral mucosa,
associations with, 381b
Melanoacanthoma, oral, 380-382, 381f,
382f
Melanoacanthosis, 380-382, 381f, 382f
Melanocarcinoma, 433-439.
See also

Melanoma.
Melanocytic nevus
acquired, 382-385, 383f, 384f
clinical features of, 382-383, 383f
histopathologic features of, 383-
384, 384f
treatment and prognosis of,
384-385
congenital, 385-386, 385f
variants of, 385-388
Melanocytoma, dermal, 386-388
Melanoma, 385, 433-439
acral lentiginous
clinical features of, 435, 435f, 436f
histopathologic features of, 436,
436f
amelanotic, 435
clinical features of, 434-435, 434b
cutaneous, classiﬁ
cation of
Clark’s, 437t
TNM, 438t
deaths from, 433http://dentalebooks.com

Index

955
Melanoma—cont’d
histopathologic features of, 436-437,
436f, 437f
incidence of, 433
juvenile, benign, 386
lentigo maligna, clinical features of,
435, 435f
metastatic to gingiva, 563f
nodular
clinical features of, 435
histopathologic features of, 436-
437, 437f
oral, 435, 435f, 436f
radial growth phase of, 434
risk factors for, 433
sites of, 433-434
staging of, 437, 438t
superﬁ
cial spreading
clinical features of, 434-435, 434f
histopathologic features of, 436,
436f
treatment and prognosis of, 437-439
vertical growth phase of, 434
Melanosis
focal, 379-380, 380f
smoker’s, 316-317, 316f
Melanotic neuroectodermal tumor of
infancy, 533-535, 534f
Melanotic progonoma, 533
Melasma, 378-379, 379f
Meleda disease, 176
Melkersson-Rosenthal syndrome, 342,
342f, 343f
tongue in, 13
Membranous basal cell adenoma, 485
MEN (multiple endocrine neoplasia)
type 2A, 532
MEN (multiple endocrine neoplasia)
type 2B, 532-533, 532f, 533f
Meningoencephalitis, in mumps, 264
Meniscectomy, for synovial
chondromatosis, 658
Menorrhagia, iron deﬁ
ciency from, 827
Mental retardation, in Apert syndrome,
44
Mercury
in dental amalagam, lichenoid contact
stomatitis from, 354-355
systemic intoxication from, 313-314
clinical features of, 314-315
Merkel cell carcinoma, 432-433, 432f
Mesenchymal chondrosarcomas, 666
of jaw, 666-667, 667f
Mesiodens, 80f, 81
Mesotaurodontism, 95, 95f
Metallic intoxication, systemic, 313-316
arsenic, 314
clinical features of, 315
bismuth, 314
clinical features of, 315
clinical features of, 314-316
gold, 314
clinical features of, 315-316
lead, 313
clinical features of, 314
Metallic intoxication, systemic—cont’d
mercury, 313-314
clinical features of, 314-315
silver, 314
clinical features of, 315, 315f
treatment and prognosis of, 316
Metamorphosis, calciﬁ
c, 123, 125f
Metastases
to jaws, 669-670, 669f, 670f
to oral soft tissues, 563-564, 563f,
564f
Metastasizing mixed tumor
clinical features of, 493-494
histopathologic features of, 494
treatment and prognosis of, 495
Methamphetamine abuse, orofacial
complications of, 303, 303f
Methotrexate, for rheumatoid arthritis,
880
8-Methoxypsoralen, for mycosis
fungoides, 600
Metronidazole, for noma, 202-203
MHA-TP (microhemabblutination assay
for antibody to
T. pallidum
) for
syphilis, 192
Micafungin, for candidiasis, 224
Microangiopathy, complicating diabetes
mellitus, 844
Microdontia, 83, 83f
Microglossia, 9, 9f
Microhemagglutination assay for
antibody to
T. pallidum
(MHA-
TP) for syphilis, 192
Microinfarction, in neuralgia-inducing
cavitational osteonecrosis,
868
Microorganisms, leukoplakia and,
389-390, 389f
Microsomia, hemifacial, in
temporomandibular joint
ankylosis, 882
Microstomia, in systemic sclerosis, 799,
799f
Midline lethal granuloma, 602-604
Midline malignant reticulosis, 602-604
Migraine, 870-871, 870t
Migrainous neuralgia, 868-869
Migratory glossitis, benign, 779-781
in diabetes, 844
Mikulicz disease, 465
Mikulicz syndrome, 465
Mikulicz’s aphthae, 333
Miliary tuberculosis, 196
Mineralization, in enamel development,
55
Minocycline
discolorations of oral mucosa related
to, 317-318, 317f, 318f
for mucous membrane pemphigoid,
775
tooth discoloration from, 73
Minor aphthous ulcerations, 333
clinical features of, 333-334, 333f
MMP-20 gene mutation, in amelogenesis
imperfecta, 100
Mohs micrographic surgery
for basal cell carcinoma, 432
for Merkel cell carcinoma, 433
Molar(s)
Fournier’s, in congenital syphilis,
191
Moon’s, in congenital syphilis, 191
mulberry, 60
in congenital syphilis, 191, 191f
Molar incisor hypomineralization, 58
Molariform supernumerary teeth, 81
Mole, 382-385, 383f, 384f.
See also

Melanocytic nevus, acquired.
Molluscum bodies, in molluscum
contagiosum, 279, 279f,
371-3722f
Molluscum contagiosum, 371-372, 371f,
372f
HIV-associated, 278-279, 279f
Mono, 253-255, 254f
Monoclonal antibodies, for chronic
lymphocytic leukemia, 589
Monoclonal gammopathy, in multiple
myeloma, 605
Monomorphic adenoma, 483-484
Monostotic ﬁ
brous dysplasia of jaws,
636, 636f, 637f, 638f
Moon facies, in Cushing’s syndrome,
840, 841f
Moon’s molars, in congenital syphilis,
191
MOPP regimen, for Hodgkin’s
lymphoma, 595
Morpheaform basal cell carcinoma,
431
Morquio-A syndrome, features of, 817t
Morquio-B syndrome, features of, 817t
Morsicatio buccarum, 285-287, 286f,
287f
Morsicatio labiorum, 286
Morsicatio linguarum, 286, 286f
Motor neuron disease, 873
Mouth
dry, 464-465, 464t, 465t.
See also

Xerostomia.
trench, 157-159
Mucinosis, oral focal, 516-517, 517f
Mucocele, 454-456, 454f, 455f, 455t,
456f
Mucocutaneous candidiasis, 214t,
218-219, 220f
Mucoepidermoid carcinoma, 487-491
adenosquamous carcinoma as, 425
central, 490-491
clinical features of, 487, 488f
grading systems for, 489, 489t
high-grade, 489
histopathologic features of, 488-489,
488f, 489f
intermediate-grade, 489
intraosseous, 490-491, 490f
low-grade, 489
treatment and prognosis of, 490
Mucoepithelial dysplasia, hereditary,
748-750, 749fhttp://dentalebooks.com

956 Index
Mucopolysaccharidosis, oral
manifestations of, 816-818,
817t, 818f
Mucosa-associated lymphoid tissue,
lymphomas of, epimyoepithelial
islands in, 466
Mucosal lentiginous melanoma, clinical
features of, 435
Mucositis
from antineoplastic therapy
clinical features of, 294-295, 295f,
296f
treatment and prognosis of, 298
lichenoid, 782
necrotizing ulcerative, 158, 158f
in noma, 202, 202f
psoriasiform, in erythema migrans,
781
Mucous cells, in mucoepidermoid
carcinoma, 488, 488f, 489f
Mucous membrane pemphigoid, 766t,
771-775
bullous pemphigoid resembling, 775
clinical features of, 771-773, 771f,
772f, 773f
conditions mimicking, 774
histopathologic features of, 773-774,
773f
systemic agents for, 775
topical agents for, 774-775
treatment and prognosis of, 774-775
Mucous patches, in secondary syphilis,
189, 189f
Mucus duct cyst, 457-459, 458f
Mucus escape reaction, 454-456, 454f,
455f, 455t, 456f
Mucus extravasation phenomenon,
454-456, 454f, 455f, 455t,
456f
Mucus retention cyst, 457-459, 458f
Muir-Torre syndrome, keratoacanthomas
in, 407
Mulberry molars, 60
in congenital syphilis, 191, 191f
Multibacillary leprosy, 199, 199f, 200f,
201f
Multicystic intraosseous ameloblastoma,
702-707.
See also

Ameloblastoma(s), conventional
solid or multicystic
intraosseous.
Multifocal epithelial hyperplasia, 367-
368, 367f, 368f
Multifocal papilloma virus epithelial
hyperplasia, 367-368, 367f,
368f
Multinodular oncocytic hyperplasia, 481
Multiple endocrine neoplasia (MEN)
type 2A, 532
type 2B, 532-533, 532f, 533f
macrogloassia in, 11
Multiple hamartoma, gingival
ﬁ
bromatosis in, 166
Multiple hamartoma syndrome, 760-
761, 760f, 761f
Multiple idiopathic root resorption, 69,
69f
Multiple myeloma, 604-606, 604f,
605f
plasmacytoma and, 606
Multiple sclerosis, trigeminal neuralgia
in, 861
Mumps, 263-264, 264f
Munro abscesses
in erythema migrans, 781, 781f
in psoriasis, 794
Mural unicystic ameloblastoma, 709,
709f
Murray-Puretic-Drescher syndrome,
gingival ﬁ
bromatosis in, 166
Muscular atrophy, progressive, 873
Mycobacterial infection, HIV-associated,
274
Mycoplasma pneumoniae
infection,
preceding erythema
multiforme, 776
Mycosis cells, in mycosis fungoides,
600
Mycosis fungoides, 598-600, 599f,
600f
Myelodysplasia syndromes, 587, 588f
Myeloﬁ
brosis, ischemic, in bone marrow
edema, 868
Myeloid tumor, extramedullary, in
leukemia, 588
Myeloma, amyloidosis associated with,
823
Myelophthisic anemia, 588
Myoblastoma, granular cell, 536
Myoepithelial cells, in pleomorphic
adenomas, 479, 479f, 480f
Myoepithelial sialadenitis, 465-466,
466f
Myoepitheliomas, 479
Myoﬁ
broma, 515-516, 516f
Myoﬁ
bromatosis, 515-516, 516f
Myositis, in temporomandibular joint
dysfunction, 881
Myospasm, in temporomandibular joint
dysfunction, 881
Myospherulosis, 324-325, 324f
Myxedema, oral manifestations of,
834-835
Myxoﬁ
bromas, 727, 731
Myxoid chondrosarcoma, 666
Myxoid liposarcomas, 554
Myxoma, odontogenic, 729-731, 730f,
731f
N
Nails
in dyskeratosis congenita, 747, 747f
in lichen planus, 783, 783f
in pachyonychia congenita, 745-746,
745f
in Plummer-Vinson syndrome, 829
Nasoalveolar cyst, 27-28
Nasolabial cyst, 27-28, 27f, 28f
Nasopalatine duct(s), 28
development of, 28
Nasopalatine duct cyst, 28-31
clinical features of, 29-30, 29f
histopathologic features of, 30-31, 30f,
31f
prognosis of, 31
radiographic features of, 29-30, 29f,
30f
treatment of, 31
Nasopharyngeal angioﬁ
broma, 544-546,
545f, 546f
Nasopharyngeal carcinoma, 428-429,
428f, 429f
Natal teeth, 81, 82f
treatment of, 82
Natural disasters, mass fatality
identiﬁ
cation in, dentistry’s role
in, 900
Natural killer T-cell lymphoma,
extranodal, nasal-type, 602-
604, 603f
Neck
bull, in Ludwig’s angina, 139
dissection of
for lymph node metastasis from
squamous cell carcinoma, 421
radical
for mucoepidermoid carcinoma,
490
for spindle cell carcinoma, 424
Necrosis, anesthetic, 303-304, 304f
Necrotizing gingivostomatitis, 158
Necrotizing sialometaplasia, 471-473,
472f
Necrotizing stomatitis, 158, 201-203
HIV-associated, 273-274, 274f
Necrotizing ulcerative gingivitis (NUG),
157-159, 158f
gonorrhea lesions simulating, 194
HIV-associated, 273, 273f
in infectious mononucleosis, 254
Necrotizing ulcerative mucositis, 158,
158f
in noma, 202, 202f
Necrotizing ulcerative periodontitis
(NUP), 158, 169
clinical and radiographic features of,
170
HIV-associated, 273, 273f, 274f
treatment and prognosis of, 173
Needles, charm, implantation of, 311,
312, 313f
Neonatal teeth, 81
Neoplasia-induced pemphigus, 769-771
Nephrolithiasis, in hyperparathyroidism,
838
Nerve sheath tumor, peripheral,
malignant, 555
complicating neuroﬁ
bromatosis type I,
531, 531f
Neuralgia
facial, atypical, 865-866, 865b
glossopharyngeal, 863-864
migranous, 868-869
postherpetic, 252, 864-865
sphenopalatine, 868-869http://dentalebooks.com

Index

957
Neuralgia—cont’d
trigeminal, 861-863, 861b, 863b
tympanic plexus, 863
vagoglossopharyngeal, 863-864
Neuralgia-inducing cavitational
osteonecrosis (NICO), 866-868,
867b, 867f, 868f
Neurilemoma, 526-528, 527f
Neuroblastoma, olfactory, 555-556, 556f
Neuroendocrine carcinoma of skin,
432-433
Neuroﬁ
broma, 528-529, 528f, 529f
Neuroﬁ
bromatosis, 528-529
macroglossia in, 11
Neuroﬁ
bromatosis type I (NF1),
529-531, 529b, 529f, 530f,
531f
Neuroﬁ
bromatosis type II (NF2), 526,
527
Neuroﬁ
brosarcoma, 555
complicating neuroﬁ
bromatosis type I,
531, 531f
Neurogenic sarcoma, 555
Neuroma(s)
in multiple hamartoma syndrome,
760
palisaded encapsulated, 525-526,
526f
solitary circumscribed, 525-526,
526f
traumatic, 524-526, 524f, 525f
Neuronopathic features, of Niemann-
Pick disease, 819
Neurosurgical procedures, for trigeminal
neuralgia, 862-863
Neutropenia, 581-582
cyclic, 583-584, 584f
Nevoid basal cell carcinoma syndrome,
431
clinical features of, 688-690, 688b,
689f
histopathologic features of, 690, 691f
multiple odontogenic keratocysts in,
684, 688, 690
radiographic features of, 689, 689f,
690, 690f
treatment and prognosis of, 691
Nevus ﬂ
ammeus, in Sturge-Weber
angiomatosis, 543, 544f
Nevus(i)
bathing trunk, 385
Becker’s, 41
blue, 386-388, 387f
compound
clinical features of, 383
histopathologic features of, 384,
384f
developmental, types of, 382b
garment, 385
giant hairy, 385
halo, 386, 386f
intradermal
clinical features of, 383, 383f
histopathologic features of, 384,
384f
Nevus(i)—cont’d
intramucosal
clinical features of, 383, 383f
histopathologic features of, 384,
384f
Jadassohn-Tièche, 386-388
junctional
clinical features of, 383
histopathologic features of, 384,
384f
melanocytic
acquired, 382-385, 383f, 384f.
See
also
Melanocytic nevus,
acquired.
congenital, 385-386, 385f
variants of, 385-388
spindle and epithelioid cell, 386
Spitz, 386
white sponge, 743-744, 743f, 744f
NF1 (neuroﬁ
bromatosis type I), 529-
531, 529b, 529f, 530f, 531f
NF2 (neuroﬁ
bromatosis type II, 526,
527
NHL (non-Hodgkin’s lymphoma), in HIV
infection, 272, 272f
Niacin
deﬁ
ciency of, clinical features of, 826,
826f
functions and sources of, 825
Niacinamide, for mucous membrane
pemphigoid, 775
NICO (neuralgia-inducing cavitational
osteonecrosis), 866-868, 867b,
867f, 868f
Nicotine palatinus, 403-404
Nicotine stomatitis, 403-404, 403f
Niemann-Pick disease, 819, 820
Nikolsky sign, positive, in pemphigus
vulgaris, 768
Nitrosamines, in candidiasis, squamous
cell carcinoma and, 412
Nodular basal cell carcinoma, 430
Nodular leukoplakia, 391
Nodular lymphocyte-predominant
Hodgkin’s lymphoma, 594
Nodular melanoma
clinical features of, 435
histopathologic features of, 436-437,
437f
Nodular oncocytic hyperplasia, 481-482,
482f
Nodular sclerosis subtype of Hodgkin’s
lymphoma, 594
Nodular stage, of Kaposi’s sarcoma,
558
Nodular subepidermal ﬁ
brosis, 514
Nodular torus, 21
Nodule(s)
Bohn’s, 691
ﬁ
brous, 507-509
Lisch, in neuroﬁ
bromatosis type I, 530
rheumatoid, 879
Noduloulcerative basal cell carcinoma,
430, 430f
Noma, 158, 201-203, 202f
Non-Hodgkin’s lymphoma (NHL),
595-598
classiﬁ
cation of, 595, 596b
clinical and radiographic features of,
596-597, 597f
high-grade, treatment of, 598
histopathologic features of, 597-598,
598f
in HIV infection, 272, 272f
incidence of, 595
intermediate-grade, treatment of, 598
low-grade, treatment of, 598
pathogenesis of, 595-596
treatment and prognosis of, 598
Nonbullous impetigo, 181-182
Noncarious cervical lesions, 63-64
Noninvasive carcinoma ex mixed tumor,
494
Nonkeratinizing carcinoma
differentiated, nasopharyngeal, 429
undifferentiated, nasopharyngeal, 429
Nonsteroidal antiinﬂ
ammatory drugs
(NSAIDs)
for osteoarthritis, 878
for rheumatoid arthritis, 880
NUG.
See
Necrotizing ulcerative
gingivitis.
Numb-chin syndrome, 669
NUP.
See
Necrotizing ulcerative
periodontitis.
Nystatin, for candidiasis, 221, 222-223t
O
Ochronosis, 71
Oculoauriculovertebral syndrome, 19
Oculoglandular syndrome of Parinaud,
in cat-scratch disease, 205-206
Odontoameloblastoma, 723-724
Odontodysplasia, regional, 112-113,
112b, 113f
Odontogenic carcinomas, 700-701,
700f, 701f
Odontogenic cysts, 678-701
buccal bifurcation cyst as, 698-700
calcifying, 695-697
carcinoma arising in, 700-701
classiﬁ
cation of, 679b
dentigerous cysts as, 679-682.
See also

Dentigerous cysts.
developmental, 679, 679b
eruption cyst as, 682
follicular cysts as, 679-682.
See also

Dentigerous cysts.
gingival cyst of adult as, 692
gingival cyst of newborn as, 691-692
glandular, 697-698
inﬂ
ammatory, 679, 679b
lateral periodontal cyst as, 692-695.
See also
Periodontal cyst, lateral.
in nevoid basal cell carcinoma
syndrome, 688-691.
See also

Nevoid basal cell carcinoma
syndrome.
odontogenic keratocyst as, 683-687.
See also
Odontogenic keratocyst. http://dentalebooks.com

958 Index
Odontogenic cysts—cont’d
orthokeratinized, 687-688
primordial cyst as, 683
sialo-odontogenic cysts as, 697-698,
698f
Odontogenic epithelial hamartoma, 727
Odontogenic ﬁ
broma(s), 726-729
central, 726-727, 726f, 727f
granular cell, 729, 729f
peripheral, 727-729, 728f
peripheral ameloblastoma
differentiated from, 710
Odontogenic ghost cell carcinoma, 697
Odontogenic keratocyst, 28
carcinoma arising in, 700, 701f
clinical and radiographic features of,
684-685, 684f, 685f
histopathologic features of, 685-686,
685f, 686f
treatment and prognosis of, 686-687,
686f
Odontogenic myxoma, 720f, 729-731,
731f
Odontogenic tumors, 701-732
classiﬁ
cation of, 702b
ectomesenchymal, 726-732
cementoblastoma as, 731-732
odontogenic ﬁ
bromas as, 726-729.
See also
Odontogenic ﬁ
bromas.
odontogenic myxoma as, 729-731,
730f, 731f
epithelial, 702-719
adenomatoid, 713-715, 713f, 714f,
715f
ameloblastoma as, 702-712.
See also

Ameloblastoma(s).
calcifying, 716-718, 716f, 717f
clear cell, 712-713, 712f, 713f
clear cell odontogenic carcinoma as,
712-713, 712f, 713f
granular cell, 729, 729f
mixed, 719-726
ameloblastic ﬁ
bro-odontoma as,
721-722, 721f, 722f
ameloblastic ﬁ
broma as, 719-720,
720f, 722
ameloblastic ﬁ
brosarcoma as, 722-
723, 723f
ameloblastic sarcoma as, 722-723,
723f
odontoameloblastoma as, 723-724
squamous, 718-719, 718f
Odontology, forensic, 887.
See also

Forensic dentistry.
Odontoma(s), calcifying odontogenic cyst
associated with, 695
Odontomaxillary dysplasia, segmental,
41-42, 42f
Odontome, dilated, 91
OHL.
See
Oral hairy leukoplakia.
Olfactory neuroblastoma, 555-556, 556f
Oligodontia, 77
in ectodermal dysplasia, 742, 742f
in incontinentia pigmenti, 750
Ollier disease, 656
Oncocytes, in oncocytoma, 480, 481,
481f
Oncocytic Schneiderian papilloma,
370-371
Oncocytoma, 480-481, 481f
Oncocytosis, 481-482, 482f
Oncogenes, squamous cell carcinoma
and, 412
Oncogenic viruses, squamous cell
carcinoma and, 412
Opalescent dentin, hereditary, 106-108
Ophthalmia neonatorum, gonococcal,
194
Oral ﬂ
orid papillomatosis, 423
Oral focal mucinosis, 516-517, 517f
Oral hairy leukoplakia (OHL), 14
Epstein-Barr virus causing, 253
in HIV infection, 268-270, 269f
morsicatio buccarum differentiated
from, 286
Oral lymphoepithelial cyst, 37-38, 38f,
39f
Oral melanoacanthoma, 380-382, 381f,
382f
Oral melanotic macule, 379-380, 380f
Oral piercings, 311-313, 312f, 313f
Oral squamous papilloma, HIV-
associated, 276
Oral submucous ﬁ
brosis, 401-403, 402f
Organ of Jacobson, 29
Orofacial clefts, 1-5
clinical features of, 3-4, 3-5f
development of, 1-2
nonsyndromic, causes of, 2, 2b
prognosis of, 4-5
radiographic features of, 3-4
treatment of, 4-5
Orofacial gangrene, 201-203
Orofacial granulomatosis, 341-345
clinical features of, 342-343, 342f,
343f
in Crohn’s disease, 848-849
diagnosis of, 343
histopathologic features of, 343, 343f
local causes of, interventions to rule
out, 342t
systemic evaluation of patients with,
341t
treatment and prognosis of, 343-345,
344f
Oromandibular-limb hypergenesis
syndromes, 9
Oropharyngeal carcinoma, clinical and
radiographic features of, 416-
417, 417f
Orthodontics, external resorption during,
67-69, 68f
Orthokeratinized odontogenic cysts,
687-688, 687f, 688f
carcinoma arising in, 700
Orthokeratosis, in lichen planus, 786
Osler-Weber-Rendu syndrome, 754-755
Osseous and chondromatous metaplasia,
318-319, 319f
Osseous choristomas, 552, 552f
Osseous dysplasia, 640-645.
See also

Cemento-osseous dysplasias of
jaws.
Osseous proliferation/hyperplasia,
subpontic, 20
Ossicles, in osteoarthritis, 878
Ossifying ﬁ
broid epulis, 521-523
Ossifying ﬁ
broma
clinical and radiographic features of,
647, 647f
histopathologic features of, 647-648,
648f
juvenile, 648-650, 649f, 650f
peripheral, 521-523, 521f, 522f
treatment and prognosis of, 648
Osteitis
alveolar, 150-151
condensing, 147-148, 148f, 620
Osteitis ﬁ
brosa cystica, in
hyperparathyroidism, 839
Osteoarthritis, 877-878
Osteoblastoma, 653-655, 653f, 654f
Osteodystrophy, Albright hereditary,
837-838
Osteogenesis imperfecta, 613-615, 614f,
615f
with opalescent teeth, 106
Osteoid, production of, by malignant
cells in osteosarcoma, 662,
662f
Osteoid osteoma, 654, 654f, 655
Osteolysis, massive, 622-623, 622f, 623f
Osteoma(s)
of jaws, 650-651, 651f
osteoid, 654, 654f, 655
soft tissue, 552
Osteoma cutis, in
pseudohypoparathyroidism,
838
Osteomalacia, 827
Osteomyelitis, 141-151
bacterial, 141
chronic recurrent multifocal, 144
clinical and radiographic featurres of,
141-143, 142f
complicating periapical abscess, 135
diffuse sclerosing, 141, 144-147
clinical and radiographic features
of, 145, 145f
histopathologic features of, 146
treatment and prognosis of, 147
focal sclerosing, 147-148
chronic, 620
histopathologic features of, 143, 143f
primary chronic, 141, 144
clinical and radiographic features
of, 145-146
histopathologic features of, 146
treatment and prognosis of, 147
with proliferative periostitis, 148-150
clinical and radiographic features
of, 148-149, 149f
histopathologic features of, 150,
150f
treatment and prognosis of, 150http://dentalebooks.com

Index

959
Osteomyelitis—cont’d
secondary, 141
suppurative, 141
acute
clinical and radiographic features
of, 141-142, 142f
histopathologic features of, 143,
143f
treatment and prognosis of, 143
chronic
clinical and radiographic features
of, 142-143, 142f7
histopathologic features of, 143,
143f
treatment and prognosis of,
143-144
treatment and prognosis of, 143-144
Osteonecrosis
bisphosphonate-associated, 299-303.
See also
Bisphosphonate-
associated osteonecrosis
(BON).
cavitational, neuralgia-inducing,
866-868, 867b, 867f, 868f
Osteopetrosis, 615-617, 616f, 617f
focal periapical, 620
Osteophytes
in osteoarthritis, 878
in temporomandibular joint
dysfunction, 881
Osteoporosis circumscripta, in Paget’s
disease of bone, 624
Osteoporotic marrow defect, focal,
619-620, 620f
Osteoradionecrosis, from antineoplastic
therapy
clinical features of, 296-297, 297f
treatment and prognosis of, 299
Osteosarcoma(s)
complicating Paget’s disease of bone,
626
of jaws, 660-664
clinical and radiographic features
of, 660-661, 660f, 661f,
662f
histopathologic features of, 662,
662f
peripheral, 663-664, 663f
treatment and prognosis of,
662-663
postirradiation, 664
Osteosclerosis, idiopathic, 148, 620-622,
621f
Ostia, 207
Otalgia, in temporomandibular joint
dysfunction, 881
Oxyphilic adenoma, 480-481, 481f
P
Pachyonychia congenita, 745-746, 745f,
746f
Paget’s disease of bone, 623-626
hypercementosis with, 96
monostotic, 624
polyostotic, 624
Pain
congenital indifference to, Riga-Fede
disease in, 289
facial, 859-886.
See also
Facial pain.
in temporomandibular joint
dysfunction, 880-881
in trigeminal neuralgia, 862
Palatal cysts of newborn, 26-27, 27f
Palatal exostoses, 20, 20f
Palatal tubercles, 20
Palatine cyst, 31-32
Palatinus, nicotine, 403-404
Palisaded encapsulated neuroma, 525-
526, 526f
Palmar surfaces, in pachyonychia
congenita, 746
Palmoplantar keratosis, in multiple
hamartoma syndrome, 760
Palsy, Bell’s, 859-861, 860f
Pannus, in rheumatoid arthritis, 879
Papilla
incisive, cysts of, 30, 30f
retrocuspid, 510, 510f
Papillary cystadenoma lymphomatosum,
482-483, 482f, 483f
Papillary gingivitis, 156
Papillary hyperplasia, inﬂ
ammatory,
512-514, 513f
Papillitis, lingual, transient, 330-331,
331f
Papilloma(s)
cylindrical cell, 370-371
ductal, 485-487, 486f, 487f
exophytic, 369
fungiform, 369, 369f
intraductal, 485-487
inverted, 369-370, 370f
inverted ductal, 486-487, 487f
septal, 369
sinonasal, 368-369
squamous, 362-364, 363f, 364f, 368,
369
Papillomatosis
denture, 512-514, 513f
laryngeal, 363-364
oral ﬂ
orid, 423
squamous papilloma differentiated
from, 363
Papillomavirus, human.
See
Human
papillomavirus (HPV).
Papillon-Lefèvre syndrome, 176-178,
176f, 177f
Papyraceous scarring of skin, in Ehlers-
Danlos syndrome, 757, 757f
Paracoccidioidomycosis, 229-230, 229f
Paradental cyst, 679, 699
Paragangliomas, 535-536, 536f
Parakeratin plugs, in verrucous
carcinoma, 423
Parakeratosis, in lichen planus, 786
Paralysis
bulbar, 873
facial
in Bell’s palsy, 859-861, 860f
in herpes zoster, 252
Paramedian lip pits, 5-6, 6f
Paramolar, 81, 81f
Paranasal sinus osteomas, 650-651
Paranasal sinuses, 207f
Paraneoplastic autoimmune multiorgan
syndrome, 769-771
Paraneoplastic pemphigus, 766, 766t,
769-771, 769f
Parasitosis, from methamphetamine
abuse, 303
Parathyroid hormone deﬁ
ciency, 837
Paronychia, herpetic, 244, 244f
Parosmia, taste alterations associated
with, 876
Parosteal type of osteosarcoma of jaw,
663-664, 663f
Parotid duct, air introduction into, 323
Parotid glands
acinic cell adenocarcinoma of, 491,
491f, 492f
in mumps, 263, 264f
tumors of, 473, 474t
Parotidectomy
subtotal, for mucoepidermoid
carcinoma, 490
total, for acinic cell adenocarcinomas,
492
Parotitis, epidemic, 263-264, 264f
Paroxysmal hemicrania, 869-870
Paroxysmal sialorrhea, idiopathic,
463-464
Parry-Romberg syndrome, 40-41, 41f
Parulus, complicating periapical abscess,
136
Pastia’s lines, in scarlet fever, 185
Patch stage, of Kaposi’s sarcoma, 558
Paterson-Kelly syndrome
oral manifestations of, 828-829
squamous cell carcinoma in, 411
Paucibacillary leprosy, 199, 200f
Paul-Bunnell heterophil antibodies, in
infectious mononucleosis, 254
Pautrier’s microabscesses, in mycosis
fungoides, 600, 601f
Pediatric rhabdomyosarcomas, 560t
Pegvisomant, for acromegaly, 833
Pellegra, 826, 826f
Pelvic inﬂ
ammatory disease (PID),
complicating gonorrhea, 194
Pemphigoid
bullous, 766t, 775-776, 775f, 776f
cicatricial, 766t, 771-775.
See also

Mucous membrane
pemphigoid.
mucous membrane, 766t, 771-775.
See also
Mucous membrane
pemphigoid.
Pemphigus
chronic benign familial, 766
neoplasia-induced, 769-771
paraneoplastic, 766, 766t, 769-771,
769f
Pemphigus-like eruptions, medications
implicated in, 348b
Pemphigus vegetans, 765http://dentalebooks.com

960 Index
Pemphigus vulgaris, 765-769, 766t
clinical features of, 766-768, 767f
desquamative gingivitis in, 771
histopathologic features of, 768, 768f
treatment and prognosis of, 768-769
Penicillin
for erysipelas, 183
for noma, 202-203
for scarlet fever, 185
for streptococcal pharyngitis, 184
for syphilis, 193
Periadenitis mucosa necrotica recurrens
(PMNR), 333
Periapical abscess, 128, 135-138
clinical and radiographic features of,
135-137, 136f, 137f, 138f
histopathologic features of, 137-138,
138f
treatment and prognosis of, 138
Periapical cysts, 28, 128, 130-135
clinical and radiographic features of,
131-132, 131f, 132f
histopathologic features of, 132-135,
134f
pocket, 130-131
residual, 700
treatment and prognosis of, 135
true, 131
Periapical ﬁ
brous scars, 130, 130f
Periapical granuloma, 127-130
clinical and radiographic features of,
128-129, 128f, 129f
formation of, 127-128
histopathologic features of, 129, 129f
treatment and prognosis of, 139-140
Periapical osteopetrosis, focal, 620
Pericoronitis, clinical and radiographic
features of, 171-172, 172f
Perimolysis, 61
Perinatal hypophosphatasia, 845
Perineural invasion
by adenoid cystic carcinoma, 496,
496f
by polymorphous low-grade
adenocarcinoma, 497-498f
Periodontal abscess
clinical and radiographic features of,
170-171, 170f, 171f
treatment and prognosis of, 173
Periodontal cyst
apical, 130-135.
See also
Periapical
cysts.
lateral, 28, 692-69
clinical and radiographic features
of, 693-694, 693f, 694f
histopathologic features of, 694,
694f
treatment and prognosis of, 695
Periodontal disease, 154-180
gingivitis as, 154-163
HIV-associated, 272-274, 273f, 274f
Periodontitis, 168-176
aggressive, 169, 173-176
generalized, clinical and
radiographic features of, 175
Periodontitis—cont’d
aggressive—cont’d
histopathologic features of, 175
localized, clinical and radiographic
features of, 174-175, 174f
treatment and prognosis of,
175-176
apical
acute, 135
chronic, 127-130.
See also
Periapical
granuloma.
associated with systemic disease, 169
chronic, clinical and radiographic
features of, 169-170, 170f
classiﬁ
cation of, 168-169, 169b
early-onset, 173
generalized juvenile, 173
histopathologic features of, 172
localized juvenile, 173
necrotizing ulcerative, 169.
See also

Necrotizing ulcerative
periodontitis (NUP).
prepubertal, 173
rapidly progressing, 173
systemic disorders with, 169b
treatment and prognosis of, 172-173
Perioral dermatitis, 352, 352f
Periosteal form of osteosarcoma of jaw,
663f, 664
Periosteal osteoma, 650
Periostitis, proliferative, osteomyelitis
with, 148-150.
See also

Osteomyelitis, with proliferative
periostitis.
Periostitis ossiﬁ
cans, 148-150
Peripheral ameloblastoma, 710f,
719-711
Peripheral ﬁ
broma with calciﬁ
cation,
521-523
Peripheral giant cell granuloma, 520-
521, 520f, 521f
Peripheral odontogenic ﬁ
broma, 727-
729, 728f
peripheral ameloblastoma
differentiated from, 710
Peripheral ossifying ﬁ
broma, 521-523,
521f, 522f
Peripheral osteoma, 650
Peripheral vascular disease, in diabetes
mellitus, 843
Peritonitis, necrotizing ulcerative.
See

Necrotizing ulcerative
periodontitis (NUP).
Perlèche, 216
Pernicious anemia, oral manifestations
of, 829-831, 830f
Perocoronitis, treatment and prognosis
of, 173
Persistent generalized lymphadenopathy
(PGL), in HIV infection, 271-
272, 272f
Petechiae
in submucosal hemorrhage, 305, 306f
in thrombocytopenia, 585
Peutz-Jegher’s syndrome, 753-754, 753f
PGL (persistent generalized
lymphadenopathy), in HIV
infection, 271-272, 272f
PHACE(S) syndrome, hemangiomas in,
540
Phalanges, terminal, resorption of, in
systemic sclerosis, 798, 798f
Phantom taste, 875-876
Pharyngeal mucosa, precancerous
lesions of, 410t
Pharyngitis
lymphonodular, acute, clinical features
of, 258-259, 259f
streptococcal, 183-184
Pharyngotonsillitis, 243
Phenol, mucosal burns from, 292, 292f
Phenolic agents, squamous cell
carcinoma and, 411
Phenophthalein, discolorations of oral
mucosa related to, 317
Philadelphia chromosome, in chronic
myeloid leukemia, 587
Phlebotomy, for polycythemia vera, 586
PHN (postherpetic neuralgia), 864-865
Photochemotherapy, for mycosis
fungoides, 600
Photography
of bite marks for evidence, 907-909,
908f, 908t
digital, in mass fatality incident
identiﬁ
cation, 902
Piercings, oral, 311-313, 312f, 313f
Pierre Robin sequence, clinical features
of, 4, 4f
Pigmentations, localized exogenous,
308-311
Pigmented, pattern, of hypomaturation
amelogenesis imperfecta, 103
Pigmented ameloblastoma, 533
Pigmented basal cell carcinoma, 430-
431, 431f
Pilar cyst, 32-33, 33f, 34f
Pilocarpine, systemic, for xerostomia,
465
Pindborg tumor, 716-718, 716f, 717f
Pink disease, from mercury exposure in
infants and children, 315
Pink tooth of Mummery, 66, 67f
Pins, charm, implantation of, 311, 312,
313f
Pituitary adenoma, gigantism from,
831-832
Pituitary dwarﬁ
sm, oral manifestations
of, 831
Plantar pits, in nevoid basal cell
carcinoma syndrome, 689,
689f
Plantar surfaces, in pachyonychia
congenita, 746, 746f
Plaque, dental, periodontitis and, 168
Plaque stage
of Kaposi’s sarcoma, 558
of mycosis fungoides, 599-600, 600f
Plasma cell gingivitis, 159-160, 159f,
160fhttp://dentalebooks.com

Index

961
Plasmacytoma, 606-607, 606f
Plasminogen deﬁ
ciency, 575-576, 575f,
576f
Plasmostasis, in bone marrow edema,
868
Platelets
decrease in, in thrombocytopenia,
584-585
destruction of, increased,
thrombocytopenia from, 584
production of, reduced,
thrombocytopenia from, 584
transfusion of, for thrombocytopenia,
585-586
Pleomorphic adenoma, 477-480, 477f,
478f, 479f, 480f
clinical and radiographic features of,
477-478, 477f, 478f, 479f
histopathologic features of, 478-479,
479f, 480f
treatment and prognosis of, 480
Pleomorphic lipomas, 524
Pleomorphic liposarcomas, 554
Plexiform ameloblastoma, 705, 706f
Plexiform unicystic ameloblastomas,
708f, 709, 709f
Plummer-Vinson syndrome
oral manifestations of, 828-829
squamous cell carcinoma in, 411
Plunging ranula, 457, 457f
PMNR (periadenitis mucosa necrotica
recurrens), 333
Pneumomediastinum, 324
Pneumoparotid, 323
Polyarthralgia, in rheumatoid arthritis,
879
Polycythemia rubra vera, 586-587
Polycythemia vera, 586-587
Polydipsia, in diabetes mellitus, 843
Polyene agents, for candidiasis, 221,
222-223t
Polymerase chain reaction (PCR)
analysis, in forensic
identiﬁ
cation, 893, 894
Polymorphic reticulosis, 602-604
Polymorphous low-grade
adenocarcinoma, 497-498,
497f, 498f
Polymyalgia rheumatica, in temporal
arteritis, 871
Polyostotic ﬁ
brous dysplasia of jaws,
636-637, 638f, 639
Polyp(s)
ﬁ
broepithelial, 511, 512f
intestinal, in Peutz-Jegher’s syndrome,
753
pulp, 121-122
Polyphagia, in diabetes mellitus, 843
Polypoid squamous cell carcinoma, 423-
425, 424f
Polyuria, in diabetes mellitus, 843
Popliteal pterygium syndrome, 6
Porphyria, erythropoietic, congenital,
tooth discoloration in, 71, 71f
Port wine stain, 543-544
Posaconazole, for candidiasis, 224
Postherpetic neuralgia (PHN), 252,
864-865
Postoperative maxillary cyst, 320, 321
Posttransplant lymphoproliferative
disorder, 596
PPD (puriﬁ
ed protein derivative) skin
test for tuberculosis, 198
Precancer terminology, 388b
Precancerous condition, deﬁ
nition of,
388b
Precancerous lesion
deﬁ
nition of, 388b
of oral, pharyngeal, and laryngeal
mucosa, 410t
Pregnancy
mask of, 378-379, 379f
pyogenic granuloma in, 518, 518f
Premalignancy, deﬁ
nition of, 388b
Prepubertal periodontitis, 173
Primordial cysts, 583f, 683
Progeria, secondary dentin formation
and, 123
Progonoma, melanotic, 533
Progressive facial hemiatrophy, 40-41,
41f
Progressive hemifacial atrophy, 40-41,
41f
Progressive muscular atrophy, 873
Progressive systemic sclerosis, 798-801
Proliferative verrucous leukoplakia
(PVL), 391-392, 392f
Proptosis, in Graves’ disease, 836, 836f
Protein, Bence Jones, in multiple
myeloma, 604
Proteinosis, lipoid, oral manifestations of,
820-821, 820f, 821f
Proteus-like syndrome, multiple
hamartoma syndrome and, 760
Proteus syndrome, 531
Protooncogenes, squamous cell
carcinoma and, 412
Protozoal diseases, toxoplasmosis as,
235-237, 236f, 237f
Prune belly syndrome, gingival
ﬁ
bromatosis in, 166
Psammomatoid juvenile ossifying
ﬁ
broma, 648-649
Pseudo-horn cysts, in seborrheic
keratosis, 374, 375f
Pseudoacanthosis nigricans, 803
Pseudocarcinoma, 406-408
Pseudocarcinomatous hyperplasia, in
blastomycosis, 228
Pseudocysts, antral, 320-323, 321f, 322f
Pseudoepitheliomatous hyperplasia, in
blastomycosis, 228
Pseudohypoparathyroidism, 837-838
Psoralen, for graft-versus-host disease
lesions, 792
Psoriasiform mucositis, in erythema
migrans, 781
Psoriasis, 793-794, 793f, 794f
in reactive arthritis, 782
Psoriatic arthritis, in psoriasis, 793
PTEN
hamartoma-tumor syndrome,
760-761
Pterygia, in Kabuki syndrome, 6
Puberty gingivitis, 154, 155f
Pulp
calciﬁ
cations of, 126-127, 126f, 127f
inﬂ
ammation of, 120-123.
See also

Pulpitis.
Pulp polyp, 121-122
Pulp stones, 126-127, 126f, 127f
Pulpal dysplasia, 110
Pulpalgia, 121
Pulpitis, 120-123, 122f, 123f
chronic hyperplastic, 121-122, 122f
clinical features of, 121-122, 122f
histopathologic features of, 122-123
irreversible, 121, 123f
reversible, 121, 122f
treatment and prognosis of, 123
Pulse granuloma, in periapical cyst,
133
Pulsed dye lasers, ﬂ
ashlamp, for port
wine stains, 543, 544
Puriﬁ
ed protein derivative (PPD) skin
test for tuberculosis, 198
Purpura
in submucosal hemorrhage, 305, 306f
thrombocic thrombocytopenic,
584-586
in thrombocytopenia, 585, 585f
PUVA therapy
for graft-versus-host disease lesions,
792
for mycosis fungoides, 600
for psoriasis, 794
PVL (proliferative verrucous
leukoplakia), 391-392, 392f
Pyogenic granuloma, 517-519, 518f,
519f
gingivitis with, 156, 156f
Pyostomatitis vegetans, oral
manifestations of, 850, 850f,
851f
Pyridoxine
deﬁ
ciency of, clinical features of, 826
functions and sources of, 825
Pyronine bodies, in periapical
granuloma, 129
Q
Quincke’s disease, 356-358, 357f, 358f
R
Rabies, complicating animal bites, 904
Radiation, squamous cell carcinoma and,
411
Radiation therapy
for acromegaly, 833
bone sarcomas after, 664
dental hypoplasia caused by, 58, 58f
for Ewing sarcoma, 668
for extranodal NK/T-cell lymphoma,
nasal-type, 604
for Hodgkin’s lymphoma, 594-595
for Kaposi’s sarcoma, 558http://dentalebooks.com

962 Index
Radiation therapy—cont’d
for Langerhans cell histiocytosis, 592
for leukemia, 589
for massive osteolysis, 623
for melanoma, 439
for nasopharyngeal carcinoma, 429
for non-Hodgkin’s lymphoma, 598
noninfectious oral complications of,
294, 295-298, 296f, 297f
for plasmacytoma, 606
postoperative, for mucoepidermoid
carcinoma, 490
for squamous cell carcinoma, 420,
421
for verrucous carcinoma, 423
Radicular cyst, 130-135.
See also

Periapical cyst.
Radicular dens invaginatus, 91-92, 92f
Radicular dentin dysplasia, 109-110,
109f, 110b, 110f
Radioactive iodine, for Graves’ disease,
836
Radiography, digital, for dental record,
888
Ramsay-Hunt syndrome, 252, 864
Ranula, 456-457, 456f, 457f
Rapidly progressing periodontitis, 173
Raynaud’s phenomenon
in CREST syndrome, 802
in systemic sclerosis, 798
Reactionary dentin, 124
Reactive arthritis, 781-782
Reactive osseous and chondromatous
metaplasia, 318-319, 319f
Reactive subpontine exostosis, 20, 20f
Recrudescent HSV-1 infection, 241
clinical features of, 243-244, 243f,
244f
Recurrent aphthous stomatitis, 331-336
clinical features of, 333-334, 333f,
334f
diagnosis of, 335
histopathologic features of, 334-335
systemic disorders associated with,
332b
treatment and prognosis of, 335-336,
335f
Recurrent HSV-1 infection, 241
clinical features of, 243-244, 243f,
244f
Red blood cells
destruction of, localized, tooth
discoloration from, 72
in sickle cell anemia, 577
Red strawberry tongue, in scarlet fever,
185
Reed-Sternberg cells, in Hodgkin’s
lymphoma, 592, 593, 594f
Reﬂ
ective ultraviolet photography, of
bite marks for evidence, 908
Regional enteritis, 848-849
Regional ileitis, 848-849
Regional odontodysplasia, 112-113,
112b, 113f
Reimpaction, 75
Reimplanted avulsed teeth, external
resorption of root in, 66-67, 68f
Reinclusion, 75
Reiter’s syndrome, 781-782
Relative macrodontia, 83
Relative microdontia, 83
Relative risk, deﬁ
nition of, 388b
Renal calculi, in hyperparathyroidism,
838
Renal carcinoma, metastatic to tongue,
563f
Renal failure, uremic stomatitis in, 851,
851f
Renal osteodystrophy, in
hyperparathyroidism, 839
Reparative dentin, 124, 125f
Residual periapical cysts, 131, 700
clinical and radiographic features of,
132, 133f, 134f
Resins, dental, hypersensitivity to, 355
Resorption
root
impaction-related, 75, 75f
multiple idiopathic, 69, 69f
tooth, 65-70
clinical features of, 66-69, 66f, 67f
external, 65-66
clinical features of, 66-69, 66f
factors associated with, 66b
histopathologic features of, 69
radiographic features of, 66-69,
68f
inﬂ
ammatory, 66, 67f
internal, 65
histopathologic features of, 69,
69f
patterns of, 66, 67f
invasive cervical, 68-69
prognosis of, 70
radiographic features of, 66-69, 67f,
68f, 69f
replacement or metaplastic, 66
treatment of, 69-70
Restorative materials, dental
lichenoid contact stomatitis from, 354-
356, 355f, 356f
tooth discoloration from, 72-73, 73f
Restriction fragment length
polymorphism (RFLP), in
forensic identiﬁ
cation, 893-894
Retention, secondary, 75
Retention cysts, 321
Retention mucocele, 454
Reticular lichen planus
clinical features of, 783, 784f, 785
diagnosis of, 787, 787f
treatment and prognosis of, 787
Reticuloendothelioses, lipid, oral
manifestations of, 818-820
Reticulosis
midline malignant, 602-604
polymorphic, 602-604
Retinal analage tumor, 533
Retinoids, topical, for erosive lichen
planus, 787-788
Retinol
deﬁ
ciency of, clinical features of, 825
functions and sources of, 825
Retrocuspid papilla, 510, 510f
Reverse polarization of peripheral
columnar cells in follicular
ameloblastoma, 705, 705f
Rhabdomyomas, 550-552, 551f
cardiac, in tuberous sclerosis, 758
Rhabdomyosarcoma, 559-561, 560f,
560t, 561f
Rheumatoid arthritis, 878-880
Riboﬂ
avin
deﬁ
ciency of, clinical features of, 826
functions and sources of, 825
Ribs, biﬁ
d, in nevoid basal cell
carcinoma syndrome, 689,
689f
Rice bodies, in rheumatoid arthritis, 880
Rickets, 827
vitamin D-resistant, oral
manifestations of, 847-848,
847f, 848f
Rifampin
for leprosy, 201
for tuberculosis, 198
Riga-Fede disease, 82, 288-289, 288f
Riley-Day syndrome, Riga-Fede disease
in, 289
Rodent ulcer, 430
Romberg syndrome, 40-41, 41f
Root(s), tooth
dilaceration of, 97-98, 97f, 98f
resorption of
impaction-related, 75, 75f
multiple idiopathic, 69, 69f
supernumerary, 98-99, 99f
Rootless teeth, 109-110, 109f, 110f,
111f
Roseola, 240
Rough pattern, of hypoplastic
amelogenesis imperfecta, 102,
103f
Round cell liposarcoma, 554
Rubella, 261-263
Rubeola, 259-261, 260f, 261f
Rudimentary supernumerary teeth, 81
Russell bodies, in periapical granuloma,
129
Rutherfurd syndrome, gingival
ﬁ
bromatosis in, 166
S
Saint Anthony’s ﬁ
re, 182
Salicylic acid, topical, for verruca
vulgaris, 366
Salivary adenocarcinoma, 498-499,
499f
Salivary duct cyst, 457-459, 458f
Salivation, excessive, 463-464
San Joaquin Valley fever, 230-231
Sanﬁ
lippo-A syndrome, features of,
817t
Sanﬁ
lippo-B syndrome, features of, 817t
Sanguinaria, leukoplakia and, 389, 389fhttp://dentalebooks.com

Index

963
Sarcoidosis, 338-341
clinical features of, 339-340, 339f,
340f
diagnosis of, 340-341
histopathologic features of, 340, 340f
treatment and prognosis of, 341
Sarcoma(s)
alveolar soft-part, 562-563, 562f
ameloblastic, 722-723, 723f
bone, postirradiation, 664
Ewing, 667-669, 668f
granulocytic, in leukemia, 588
Kaposi’s, 240-241, 557-559, 557f,
558f
in HIV infection, 270-271, 270f,
271f
neurogenic, 555
soft tissue, 552-564.
See also
Soft tissue
sarcomas.
synovial, 560-561, 561f
Sarcomatoid squamous cell carcinoma,
423-425, 424f
Scaphocephaly, in Crouzon syndrome,
42
Scarlatina, 184-185, 185f
Scarlet fever, 184-185, 185f
Scheie syndrome, features of, 817t
Schirmer test, in Sjögren syndrome
diagnosis, 469
Schneiderian papilloma
inverted, 369-370, 370f
oncocytic, 370-371
Schwachman-Diamond syndrome,
neutropenia in, 582
Schwannoma, 526-528, 527f
malignant, 555
complicating neuroﬁ
bromatosis type
I, 531, 531f
Scintillation, before migraine, 871
Scirrhous change, in squamous cell
carcinoma, 419
Sclera, yellow color of, in jaundice, 822,
822f
Sclerodactyly, in CREST syndrome, 802,
802f
Scleroderma, 40, 798-801
limited, 801-803
localized, 799-800, 800f
Sclerosing basal cell carcinoma, 431
Sclerosing hemangioma, 514
Sclerosing osteomyelitis, focal chronic,
620
Sclerosing panencephalitis, subacute,
complicating rubeola, 260
Sclerotherapy
for lymphangiomas, 549
for vascular malformations, 543
Sclerotic lesions, in cemento-osseous
dysplasias of jaws, 644, 644f
Scorbutic gingivitis, 826, 827f
Scotoma, before migraine, 871
Scrofula, 196, 196f
Scrotal tongue, 13, 13f
Scrumpox, 244
Scurvy, 826, 827f
Sebaceous cyst, 32
Sebaceous hyperplasia, 375-376, 376f
Seborrheic keratosis, 374-375, 374f,
375f
Segmental odontomaxillary dysplasia,
41-42, 42f
Seizures, in tuberous sclerosis,
management of, 759
Senile lentigo, 377-378
Sensory deﬁ
cit, in postherpetic
neuralgia, 864
Septal papilloma, 369
Sequestration, bone, oral ulceration with,
319-320, 320f
Serologic comparison, in identiﬁ
cation,
893-894
Serum alkaline phosphatase levels,
elevated, in diagnosis of Paget’s
disease of bone, 625
Seventh nerve paralysis, 859-861
Severe congenital neutropenia, 582
Sex, AIDS cases and, 265, 265t
Sexual activity, HSV-2 exposure and,
241
Sexual practices, oral trauma from, 307-
308, 308f
Sexually transmitted disease (STD),
condyloma acuminatum as,
366
Sézary cells, in mycosis fungoides, 600
Sézary syndrome, 599, 600
Shagreen patches, in tuberous sclerosis,
758
Shell teeth, 107, 108f
Shingles, 250-253.
See also
Herpes
zoster.
facial pain in, 864
Shock, insulin, 845
Shock wave lithotripsy, for sialolithiasis,
461
Shovel-shaped incisors
clinical and radiographic features of,
89, 89f
treatment and prognosis of, 90
Sialadenitis, 461-462, 461f, 462f
myoepithelial, 465-466, 466f
Sialadenoma papilliferum, 486-487,
487f
Sialadenoscopy, for sialadenitis, 462
Sialadenosis, 470-471, 471f
diabetic, 844
Sialo-odontogenic cyst, 697-698, 698f
Sialocyst, 457-459, 458f
Sialolithiasis, 459-461, 459f, 460f
Sialometaplasia, necrotizing, 471-473,
472f
Sialorrhea, 463-464
Sialosis, 470-471, 470b, 471f
Sickle cell anemia, 576-578, 578f
bilirubin excess in, 821
Sickle cell crisis, 577-578
Sickle cell disease, 577
Sickle cell trait, 577
Sideropenic dysphagia, oral
manifestations of, 828-829
Silver, systemic intoxication from, 314
clinical features of, 315, 315f
Silver nitrate, mucosal necrosis from,
292
Simple bone cyst, 631-634
clinical and radiographic features of,
631-633, 632f, 633f
diagnosis of, 633
histopathologic features of, 633, 633f
treatment and prognosis of, 633-634
Simple hyperplasia, 39
Simple odontogenic ﬁ
broma, 727
Simplex types, of epidermolysis bullosa,
761, 762t
Sinonasal papillomas, 368-369
Sinonasal undifferentiated carcinoma
(SNUC), 426, 427-428, 427f
Sinus(es)
cutaneous, from dental abscesses, 136,
137f
maxillary, carcinoma of, 426-427,
426f
paranasal, 207f
Sinus mucoceles, 320-321, 321f
Sinus thrombosis, cavernous, 138-141.
See also
Cavernous sinus
thrombosis.
Sinusitis, 207-209, 209f
allergic fungal, 234
Sipple syndrome, 532
Sistrunk procedure, for thyroglossal duct
cysts, 36
Sjögren syndrome, 466-470
classiﬁ
cation criteria for, 468b
clinical and radiographic features of,
467-469, 467f
graft-versus-host disease mimicking,
791
histopathologic features of, 469-470,
469f
laboratory values in, 469
Mikulicz disease differentiated from,
465-466
treatment and prognosis of, 470
Skeletal anomalies, in nevoid basal cell
carcinoma syndrome, 689,
689f, 690f
Skin
follicular cysts of, 32-33, 32f, 33, 34
hyperelasticity of, in Ehlers-Danlos
syndromes, 756, 756f
Skull
Paget’s disease of bone affecting, 624,
624f
racial and sexual characteristics of,
skeletal anthropologic
variations associated with, 891t
Small cell carcinoma of skin, 432-433
Smokeless tobacco, squamous cell
carcinoma from, 410-411
Smokeless tobacco keratosis, 398-401
clinical features of, 398-399, 399f,
400f
histopathologic features of, 399, 400f
treatment and prognosis of, 399-401http://dentalebooks.com

964 Index
Smoker’s melanosis, 316-317, 316f
Smoker’s palate, 403-404
Smoking
leukoplakia and, 388-389
squamous cell carcinoma from, 410
Snow-capped patterns, of
hypomaturation amelogenesis
imperfecta, 103, 104f
SNUC (sinonasal undifferentiated
carcinoma), 426, 427-428,
427f
Snuff dipper’s cancer, 422-423
Snuff dipper’s lesion, 398-401.
See also

Smokeless tobacco keratosis.
Snuff pouch, 398-401.
See also

Smokeless tobacco keratosis.
Soft palate, ﬁ
stulas of, lateral, 16-17, 17f
Soft tissue osteomas, 552
Solar elastosis, 404, 406
basal cell carcinoma and, 431
Solar keratosis, 404-405, 404f, 405f
Solar lentigo, 377-378
Solid variant, of adenoid cystic
carcinoma, 496
Solitary bone cyst, 631-634.
See also

Simple bone cyst.
Solitary circumscribed neuroma, 525-
526, 526f
Solitary exostoses, 20
Solitary ﬁ
brous tumor (SFT), 546
Somatostatin analogues, for acromegaly,
833
Sort tissue chondromas, 552
South Americana blastomycosis, 229-
230, 229f
Speckled leukoplakia, 392, 393f
Sphenopalatine neuralgia, 868-869
Spindle and epithelioid cell nevus, 386
Spindle cell carcinoma, 423-425, 424f
Spindle cell lipoma, 524
Spindle cells
in Kaposi’s sarcoma, 558, 558f
in malignant ﬁ
brous histiocytoma,
554, 554f
in synovial sarcoma, 562, 562f
Spindle-shaped epithelial cells
in adenomatoid odontogenic tumors,
714-715, 715f
in neuroﬁ
broma, 528, 529f
Spindle torus, 21
Spit tobacco keratosis, 398-401.
See also

Smokeless tobacco keratosis.
Spitz nevus, 397
Spleen, platelet sequestration in,
thrombocytopenia from, 585
Split papules, in secondary syphilis, 189
Split tongue, 311, 312f
Spontaneous sequestration, 319-320,
320f
Sporadic Burkitt’s lymphoma, 601
Sprue, celiac, iron-deﬁ
ciency anemia in,
828
Squamous cell carcinoma, 409-421
from actinic cheilosis, 406
adenosquamous carcinoma as, 425
Squamous cell carcinoma—cont’d
basaloid, 425-426, 426f
cause of, 409-412
clinical and radiographic features of,
412-417, 413f, 414f, 415f,
416f, 417f
cutaneous, development of, from
epidermolysis bullosa, 764
developing from xeroderma
pigmentosum, 748
endophytic lesion in, 414, 414f
evolving from dentigerous cysts,
682
exophytic lesion in, 413-414, 413f,
414f
histopathologic features of, 419-420,
420f
incidence of, 409, 409f
intraoral, clinical and radiographic
features of, 415-416, 415f,
416f
keratinizing, nasopharyngeal, 429
keratoacanthoma type, 406-408
of lip vermilion, clinical and
radiographic features of,
414-415, 414f, 415f
of maxillary sinus, 426, 427
metastasis of, 417-418, 417f
multiple, 421
oral, HIV-associated, 279, 279f
oropharyngeal, clinical and
radiographic features of,
416-417, 417f
polypoid, 423-425, 424f
proliferative verrucous leukoplakia
transforming into, 392
risk of, 409
sarcomatoid, 423-425, 424f
smokeless tobacco-related, 400-401,
410-411
staging of, 418-419t
tobacco smoking and, 410
treatment and prognosis of, 420-421
verrucous carcinoma as, 422-423
well-differentiated, arising in
odontogenic cysts, 700, 701f
Squamous cells, in mucoepidermoid
carcinoma, 488, 488f
Squamous eddies, in seborrheic
keratosis, 375
Squamous epithelium, stratiﬁ
ed
in buccal bifurcation cysts, 699
in glandular odontogenic cysts, 698,
698f
Squamous odontogenic tumors, 718-
719, 718f
Squamous papilloma, 362-364, 363f,
364f, 368, 369
SSPE (subacute sclerosing
panencephalitis), complicating
rubeola, 260
Stafne defect, 24-25, 25f, 26f
“Staghorn” blood vessels, in
hemangiopericytoma–solitary
ﬁ
brous tumor, 546, 546f
Stannous ﬂ
uoride, tooth discoloration
from, 71
Staphylococcal impetigo, 181-182
“Starry sky” pattern, in Burkitt’s
lymphoma, 601-602, 602f
Static bone cyst, 24-25
Stevens-Johnson syndrome, 777, 778f
Stomatitis
anaphylactic, from systemic drug
administration, 347-348
aphthous, recurrent, 331-336.
See also

Recurrent aphthous stomatitis.
contact
allergic, 350-351
from artiﬁ
cial cinnamon ﬂ
avoring,
352-354, 353f, 354f
lichenoid, from dental restorative
materials, 354-356, 355f, 356f
cotton roll, 293, 293f
denture, 214t, 216-217, 218f
gangrenous, 201-203
necrotizing, 158, 201-203
HIV-associated, 273-274, 274
nicotine, 403-404, 403f
ulcerative, chronic, 788-790, 789f,
790f
lichen planus resembling, 785
uremic
morsicatio buccarum differentiated
from, 286
oral manifestations of, 851, 851f
Stomatitis areata migrans, 779-781
Stomatitis medicamentosa, 347
Stomatitis venenata, 350-351
Stomatodynia, 873-875, 874b
Stomatopyrosis, 873-875, 874b
Storiform arrangement, of tumor cells in
ﬁ
brous histiocytoma, 514, 514f
Storiform-pleomorphic type, of
malignant ﬁ
brous histiocytoma,
554
Strawberry gingivitis, 345, 345f
Strawberry hemangioma, 539-540, 540f
Strawberry tongue, in scarlet fever, 185,
185f
Streptococcal pharyngitis, 183-184
Streptococcal tonsilitis, 183-184, 184f
Streptomycin, for tuberculosis, 198
Stress, lichen planus and, 783
String of pearls, in allergic mucosal
reactions to systemic drug
administration, 349
Sturge-Weber angiomatosis, 543-544,
543f, 544f
Stylalgia, 23-24
Stylohyoid syndrome, 24
Subacute necrotizing sialadenitis,
461-462
Subacute sclerosing panencephalitis
(SSPE), complicating rubeola,
260
Subchondral cysts, in osteoarthritis, 878
Subemergence, 75
Submandibular gland, acinic cell
adenocarcinoma of, 491http://dentalebooks.com

Index

965
Submandibular tumor(s), 475, 475t
Submucosal hemorrhage, 305-307,
306f, 307f
Submucous ﬁ
brosis, oral, 401-403,
402f
Submucous palatal cleft, 3-4, 4f
Subpontic osseous hyperplasia, 20
Subpontic osseous proliferation, 20
Sulfasalazine
for Crohn’s disease, 849
for pyostomatitis vegetans, 850
for rheumatoid arthritis, 880
Sulfonamides, for
paracoccidioidomycosis, 230
Sulfur granules, in actinomycosis, 203
Sumatriptan, for cluster headache, 869
Sunlight, avoidance of
in Darier’s disease, 752
for xeroderma pigmentosum, 748
Superﬁ
cial basal cell carcinoma, 431
Superﬁ
cial mucocele, 455, 455f
Superﬁ
cial spreading melanoma
clinical features of, 434-435, 434f
histopathologic features of, 436, 436f
Superﬁ
cial Wegener’s granulomatosis,
345
Supernumerary roots, 98-99, 99f
Supernumerary teeth, 77, 80-81, 80f,
81f
treatment of, 82
Supplemental supernumerary teeth, 81
Surgical ciliated cyst, 320, 322f
Susuk implantation, 311, 312, 313f
Sutton’s disease, 333
Sweating, gustatory, 876-877
Swift disease, from mercury exposure in
infants and children, 315
Symblepharons, in mucous membrane
pemphigoid, 772, 772f, 773f
Syndactyly, in Apert syndrome, 44, 44f
Syngnathia, in Kabuki syndrome, 6
Synovectomy, total, for synovial
chondromatosis, 658
Synovial chondromatosis, 657-658, 658f
Synovial sarcoma, 560-561, 561f
Synovitis, in rheumatoid arthritis, 879
Synovitis-acne-pustulosis hyperostosis-
osteomyelitis (SAPHO)
syndrome, 144
clinical and radiographic features of,
146
Syphilis
clinical features of, 188-191
congenital, 188
clinical features of, 190-191, 191f
stigmata of, 192t
diagnosis of, 193
histopathologic features of, 191-193,
192f
latent, 190
primary, clinical features of, 188, 189f
secondary, clinical features of,
188-190
squamous cell carcinoma and,
411-412
Syphilis—cont’d
tertiary, clinical features of, 190, 190f,
191f
treatment and prognosis of, 193
Syphilitic hypoplasia of enamel, 60
Systemic diseases, oral manifestations of,
816-858
Systemic lupus erythematosus (SLE),
graft-versus-host disease
mimicking, 791
Systemic sclerosis, 798-801
clinical and radiographic features of,
798-800, 798f, 799, 800f
diagnosis of, 800-801
histopathologic features of, 800,
801f
treatment and prognosis of, 801
T
T. pallidum
hemagglutination assay
(TPHA) for syphilis, 192
T. pallidum
particle agglutination assay
(TPPA) for syphilis, 192
T-cell lymphoma
angiocentric, 602-604
cutaneous, 598-600, 599f, 600f
Talisman, 311
Talon cusp
clinical and radiographic features of,
87-88, 88f
treatment and prognosis of, 90
Target lesions, in erythema multiforme,
777, 777f
Taste
altered or diminished, 875-876, 875b,
876t
distorted, 875-876
loss of, from antineoplastic therapy
clinical features of, 296
treatment and prognosis of,
298-299
phantom, 875-876
Tattoo
amalgam, 308-311, 309f, 310f, 311f
intraoral, intentional, 309-310, 310f
Taurodontism, 94-96, 94f, 95b, 95f
amelogenesis imperfecta with, 104-
105, 105f
Tay-Sachs disease, 819, 820
TB.
See
Tuberculosis.
Tea, tooth discoloration from, 70
Telangiectasia
in CREST syndrome, 802, 802f
hereditary hemorrhagic, 754-755,
754f, 755f
in Merkel cell carcinoma, 432
Temporal arteritis, 871-872
Temporomandibular joint (TMJ)
ankylosis of, 882
dysfunction of, 880-882, 881b
glossopharyngeal neuralgia
differentiated from, 863
osteoarthritis of, 877-878
in rheumatoid arthritis, 879
synovial chondromatosis of, 658
Tendoperiostitis, chronic, 144
clinical and radiographic features of,
146
histopathologic features of, 146-147
treatment and prognosis of, 147
Teratoid cyst, 34
Teratoma
deﬁ
nition of, 34
dermoid cyst as, 33-34
Terminal duct carcinoma, 497-498
Tetracycline
for mucous membrane pemphigoid,
775
for recurrent aphthous stomatitis,
336
tooth discoloration from, 73, 73f
Thalassemia, 578-580, 579f
α
-Thalassemia, 580
β
-Thalassemia, 579-580
Thalidomide, for recurrent aphthous
stomatitis, 336
Thermal burns, 290-291, 291f
Thermal injury, pulpitis from, 120
Thiamin
deﬁ
ciency of, clinical features of, 826
functions and sources of, 825
Thrombocytopenia, 584-586, 585f
HIV-associated, 275
leukemia and, 588
Thrombosis, cavernous sinus, 138-141.
See also
Cavernous sinus
thrombosis.
Thrombotic thrombocytopenic purpura
(TTP), 584-586
Thymoma, in myasthenia gravis, 872
Thymus gland, hyperplasia of, in
myasthenia gravis, 872
Thyroglossal duct (tract) cyst, 35-36,
36f
Thyroid, lingual, 12-13, 12f
Thyroid replacement therapy, for
hypothyroidism, 835
Thyroid storm, 836
Thyroiditis, Hashimoto’s, 834
Thyrotoxicosis, 835-836
Tic douloureux, 861-863
Tingible bodies, in lymphoid hyperplasia,
572
Tinnitus, in temporomandibular joint
dysfunction, 881
TNM classiﬁ
cation, of cutaneous
melanomas, 438t
Tobacco
smokeless, keratosis from, 398-401.
See also
Smokeless tobacco
keratosis.
tooth discoloration from, 70, 71f
use of
leukoplakia and, 388-389
squamous cell carcinoma from,
410-411
Tobacco pouch keratosis, 398-401.
See
also
Smokeless tobacco
keratosis.
with verrucous carcinoma, 422http://dentalebooks.com

966 Index
α
-Tocopherol
deﬁ
ciency of, clinical features of, 827
functions and sources of, 825
Tongue
ageusia of half of, 875
biﬁ
d, 311, 312f
black hairy, 13-15, 14f, 15f
carcinoma of, 415, 415f
central papillary atrophy of, 214t, 216
coated, 14-15, 14f
in dyskeratosis congenita, 747, 747f
enlargement of, in hypothyroidism,
834-835, 835f
eosinophilic granuloma of, 287, 290f
ﬁ
ssured, 13, 13f
in erythema migrans, 780, 780f
forked, 311, 312f
geographic, 779-781
hairy, 13-15, 14f, 15f
in hereditary hemorrhagic
telangiectasia, 754, 754f
large, 9, 9f
metastases to, 563, 563f
missing, 9
neurilemomas of, 527
neuroﬁ
broma of, 528, 528f
in pernicious anemia, 830, 830f
piercings of, 311-312, 312f
small, 9, 9f
split, 311, 312f
strawberry, in scarlet fever, 185, 185f
wandering rash of, 779-781
woody, in Ludwig’s angina, 139
Tongue-tie, 11-12, 11f
Tongue torches, 330-331
Tonsilitis, streptococcal, 183-184, 184f
Tonsillar concretions, 185-186
Tonsillolithiasis, 185-186, 186f
Tooth (teeth), abnormalities of, 54-119
Tooth-whitening products, mucosal
burns from, 291, 291f
Toothpaste
allergic contact stomatitis to, 351,
351f
sanguinaria, leukoplakia and, 389,
389f
Torus mandibularis, 19, 22-23, 22f, 23f
Torus palatinus, 19, 21-22, 21f
Tourette syndrome, Riga-Fede disease in,
289
Toxic epidermal necrolysis, 777-778
Toxoplasmosis, 235-237, 236f, 237f
TPHA (
T. pallidum
hemagglutination
assay) for syphilis, 192
TPPA (
T. pallicum
particle agglutination
assay) for syphilis, 192
Trabecular carcinoma of skin, 432-433
Trabecular juvenile ossifying ﬁ
broma,
648, 649, 650f
Tranquilizers, discolorations of oral
mucosa related to, 317, 318,
318f
Transfusions
blood, for thalassemia major, 580
platelet, for thrombocytopenia,
585-586
Transient lingual papillitis, 330-331,
331f
Transient osteopetrosis, 616
Transplantation, bone marrow.
See
Bone
marrow transplantation.
Trauma
coronal discoloration from, 72
leukoplakia and, 390, 390f
Trauma-hemorrhage theory, of simple
bone cyst pathogenesis, 631
Traumatic bone cyst, 631-634.
See also

Simple bone cyst.
Traumatic ciliated cyst, 320
Traumatic ﬁ
broma, 507-509
Traumatic granuloma, 287, 288f
Traumatic neuroma, 524-525, 524f,
525f
Traumatic sequestration, 319-320
Traumatic ulcerations, 287-289, 288f,
289f
Traumatic ulcerative granuloma with
stromal eosinophilia (TUGSE),
287
Treacher Collins syndrome, 45-46, 45f
Trench mouth, 157-159
Triamcinolone
for giant cell granuloma, 628
for recurrent aphthous stomatitis, 335
Triazoles, for candidiasis, 222-223t,
223-224
Trichiasis, in mucous membrane
pemphigoid, 772, 773f
Trichilemmomas, in multiple
hamartoma syndrome, 760,
760f
Tricho-dento-osseous syndrome, 105,
105f
Trichoepitheliomas, 485
Tricholemmal cyst, 32-33
Tricyclic antidepressants
for atypical facial pain, 866
for postherpetic neuralgia, 865
Trigeminal neuralgia, 861-863, 861b,
863b
atypical, 865-866
Trigeminal neuropathic pain, 865-866
Trigonocephaly, in Crouzon syndrome,
42-43
Trismus
from antineoplastic therapy, 297
in oral submucous ﬁ
brosis, 402
Trisodium phosphonoformate
hexahydrate (foscarnet), for
herpes lesions in
immunocompromised patients,
247
Triton tumor, malignant, 555
True cementoma, 731-732
TTP (thrombotic thrombocytopenic
purpura), 584-586
Tubercle, in tuberculosis, 197
Tuberculate supernumerary teeth, 81
Tuberculoid leprosy, 199
Tuberculosis (TB), 195-198
clinical and radiographic features of,
196-197, 196f, 197f
Tuberculosis (TB)—cont’d
diagnosis of, 198
histopathologic features of, 197-198,
197f, 198f
HIV-associated, 274
miliary, 196
primary, 195
secondary, 196
treatment and prognosis of, 198
Tuberous sclerosis, 757-759, 758f, 759f
Tubular pattern in adenoid cystic
carcinoma, 496
Tufted hemangioma, 540
TUGSE (traumatic ulcerative granuloma
with stromal eosinophilia),
287
Tumor-node-metastasis (TNM) staging
system for oral carcinoma,
418-419t
Tumor stage, of mycosis fungoides, 599,
599f, 600
Tumor suppressor genes, squamous cell
carcinoma and, 412
Tumor(s)
Ackerman’s, 422-423
brown, of hyperparathyroidism, 839,
893f
ghost cell
dentinogenic, 695-697, 695f, 696f,
697f
epithelial odontogenic, 695
giant cell, 629-635.
See also
Giant cell
tumors.
glomus jugulare, 535-536
glomus tympanicum, 535-536
Merkel cell, 432-433
odontogenic, 701-732.
See also

Odontogenic tumors.
calcifying cystic, 695-697, 695f,
696f, 697f
keratocystic, 683
Pindborg, 716-718, 716f, 717f
salivary gland, 473-499
acinic cell adenocarcinoma as, 491-
492, 491f, 492f
adenoid cystic carcinoma as, 495-
497, 495f, 496f
basal cell adenoma as, 484-485,
485f
benign mixed tumor as, 477-480.
See also
Pleomorphic adenoma.
canalicular adenoma as, 484, 484f
classiﬁ
cation of, 473b
ductal papillomas as, 485-487,
486f, 487f
intraductal papilloma as, 485-487
inverted ductal papilloma as, 486-
487, 487f
labial, 475, 477t
lobular carcinoma as, 497-498
malignancy of, frequency of, 474t
malignant mixed, 492-495.
See also

Malignant mixed tumors.
of minor glands, 475, 476t, 477t
monomorphic adenoma as,
483-484http://dentalebooks.com

Index

967
Tumor(s)—cont’d
salivary gland—cont’d
mucoepidermoid carcinoma as,
487-491.
See also

Mucoepidermoid carcinoma.
oncocytoma as, 480-481, 481f
oncocytosis as, 481-482, 482f
palatal, 475, 476t
papillary cystadenoma
lymphomatosum as, 482-483,
482f, 483f
parotid, 473, 474t
pleomorphic adenoma as, 477-480.
See also
Pleomorphic adenoma.
polymorphous low-grade
adenocarcinoma as, 497-498,
497f, 498f
primary epithelial, sites of
occurrence of, 474t
salivary adenocarcinoma as, 498-
499, 499f
sialadenoma papilliferum as, 486-
487, 487f
sublingual, 475
submandibular, 45t, 475
terminal duct carcinoma as,
497-498
Warthin tumor as, 482-483, 482f,
483f
soft tissue, 507-570.
See also
Soft tissue
tumors.
Turner’s hypoplasia, 56-58, 57f
Turner’s tooth, 56-58
Tympanic plexus neuralgia, 863
Tyndall effect, in blue nevus, 387
Tzanck cells
in herpes simplex infection, 245
in pemphigus vulgaris, 768
U
Ulcer, rodent, 430
Ulceration(s)
aphthous
clinical features of, 334, 334f
in Crohn’s disease, 849, 849f
herpetiform, 333
HIV-associated, 278, 278f
major, 333
clinical features of, 334, 334f
minor, 333
clinical features of, 333-334, 334f
recurrent, 331-336
with bone sequestration, 319-320,
320f
in graft-versus-host disease, 792
oral, in cyclic neutropenia, 583, 584f
“snail track,” in pyostomatitis vegetans,
850, 850f
traumatic, 287-289, 288f, 289f
in Wegener’s granulomatosis, 346,
346f
Ulcerative stomatitis, chronic, 788-790,
789f, 790f
lichen planus resembling, 785
Ultraviolet B (UVB) therapy, for
psoriasis, 794
Ultraviolet (UV) light exposure
chronic, actinic lentigo from, 377
nevoid basal cell carcinoma syndrome
trigged by, 691
Ultraviolet (UV) radiation
leukoplakia from, 389
melanoma and, 433
squamous cell carcinoma and, 411
Undifferentiated nonkeratinizing
carcinoma, nasopharyngeal,
429
Unicystic ameloblatoma, 708-710, 708f,
709f
Universal Tooth Numbering System,
896, 896t
Urbach-Wiethe syndrome, oral
manifestations of, 820-821
Uremic stomatitis
morsicatio buccarum differentiated
from, 286
oral manifestations of, 851, 851f
Uveoparotid fever, associated with
sarcoidosis, 339
Uvula, cleft or biﬁ
d, 3, 4f
V
Vaccine
bacillus Calmette-Guérin, for
tuberculosis, 198
MMR, 261
varicella, 250
VZV, live attenuated, for herpes zoster,
253
Vacuoles, cytoplasmic, in hereditary
mucoepithelial dysplasia, 749,
749f
Vagoglossopharyngeal neuralgia,
863-864
Valacyclovir
prophylactic, for
immunocompromised patients,
247
for recurrent herpes labialis, 247
Valley fever, 230
van der Woude syndrome, 5-6, 6f
Varicella, 248-250, 248f, 249f
Varicella-zoster virus (VZV, HHV-3),
240, 248-250
HIV-associated, 276
Varices, 15-16, 15f
Varicosities, oral, 15-16, 15f
Vascular hyperplasia, intraoral, in
Sturge-Weber angiomatosis,
543-544, 544f
Vascular leiomyomas, 549-550
Vascular malformations
classiﬁ
cation of, 539b
clinical and radiographic features of,
540, 540f
histopathologic features of, 542, 542f
intrabony, clinical and radiographic
features of, 540-541, 541f
treatment and prognosis of, 543
Vascular type, of Ehlers-Danlos
syndrome, 756t, 757
Vasodilators, for Bell’s palsy, 860
Venereal wart, 366-367, 366f, 367f
Venous malformations, 540, 540f
histopathologic features of, 542, 542f
Vermilionectomy
for actinic cheilosis, 406
for cheilitis glandularis, 463
Verocay bodies
in neurilemoma, 527, 527f
in palisaded encapsulated neuroma,
526
Verruca vulgaris, 364-366, 365f
HIV-associated, 276
Verruciform leukoplakia, 391, 392f,
393f
Verruciform xanthoma, 372-374, 373f
Verrucous carcinoma, 392, 422-423,
422f, 423f
Verrucous hyperplasia, in leukoplakia,
394
Verrucous leukoplakia, 391, 391f, 392f,
393f
Vesicles, formation of, in erythema
multiforme, 778, 779f
Vesiculoerosive lesions, nonspeciﬁ
c,
drugs associated with, 348b
Vesiculoulcerative disease, chronic,
clinical, microscopic, and
immunologic features of,
766t
Vestibular schwannomas, 527-528
Vidarabine (adenosine arabinoside), for
herpes lesions in
immunocompromised patients,
247
Vincent’s infection, 157-159
Viral infections
causing neutropenia, 582
cytomegalovirus as, 255-256
enteroviruses as, 256-259.
See also

Enteroviruses.
herpes simplex virus infection as,
241-248
herpes zoster as, 250-253.
See also

Herpes zoster.
human herpes virus infections as,
240-241
human immunodeﬁ
ciency virus
infection as, 264-281
infectious mononucleosis as, 253-255,
254f
mumps as, 263-264, 264f
rubella as, 261-263
rubeola as, 259-261, 260f, 261f
varicella as, 248-250, 248f, 249f
Virus(es)
molluscum contagiosum, epithelial
hyperplasia from, 371-372
oncogenic, squamous cell carcinoma
and, 412
Visceral signs, in Niemann-Pick disease,
819
Vitamin A
deﬁ
ciency of
clinical features of, 825
squamous cell carcinoma and, 411
functions and sources of, 825http://dentalebooks.com

968 Index
Vitamin B
1
deﬁ
ciency of, clinical features of, 826
functions and sources of, 825
Vitamin B
2
deﬁ
ciency of, clinical features of, 826
functions and sources of, 825
Vitamin B
3
deﬁ
ciency of, clinical features of, 826,
826f
functions and sources of, 825
Vitamin B
6
deﬁ
ciency of, clinical features of, 826
functions and sources of, 825
Vitamin B
12
deﬁ
ciency, pernicious
anemia from, 829
Vitamin C
deﬁ
ciency of, clinical features of, 826,
827f
functions and sources of, 825
Vitamin D
deﬁ
ciency of, clinical features of, 827
functions and sources of, 825
for pseudohypoparathyroidism, 838
Vitamin D–resistant rickets, oral
manifestations of, 847-848,
847f, 848f
Vitamin deﬁ
ciency, oral manifestations
of, 825-827
Vitamin E
deﬁ
ciency of, clinical features of, 827
functions and sources of, 825
Vitamin K
deﬁ
ciency of, clinical features of, 827
functions and sources of, 825
Vocal cords, thickened, in lipoid
proteinosis, 820
Von Recklinghausen’s disease of skin,
529-531
von Willebrand’s disease, 573, 573t,
574
Vulvodynia, 874
VZV (varicella-zoster virus), 240,
248-250
W
Waldeyer’s ring, 37
nasopharyngeal carcinoma of, 428
Waldeyer’s tonsillar tissue,
nasopharyngeal carcinoma of,
428
Wandering rash of tongue, 779-781
Wart
common, 364-366, 365f
venereal, 366-367, 366f, 367f
Warthin-Finkedey giant cells, in rubeola,
261, 261f
Warthin tumor, 482-483, 482f, 483f
Warty dyskeratoma, 752-753, 752f
Wegener’s granulomatosis, 345-347,
345f, 346f
Well-differentiated liposarcoma, 554
“White line,” 285
White sponge nevus, 743-744, 743f,
744f
White strawberry tongue, in scarlet
fever, 185, 185f
Wickham’s striae, in lichen planus, 783,
783f
Witkop von Sallmann syndrome,
744-745, 744f, 745f
Witkop’s classiﬁ
cation of amelogenesis
imperfecta, 99, 99t
Woody tongue, in Ludwig’s angina, 139
X
X-irradiation, squamous cell carcinoma
and, 411
X-linked pattern, of hypomaturation
amelogenesis imperfecta, 103,
104f
X-linked smooth pattern, of hypoplastic
amelogenesis imperfecta,
101-102
X-ray, digital, direct, in mass fatality
incident identiﬁ
cation, 902
X-ray ﬂ
uorescence, of dental remains,
888, 888f
X-ray generation devices, portable hand-
held, in mass fatality incident
identiﬁ
cation, 902
Xanthoma
in multiple hamartoma syndrome,
760
verruciform, 372-374, 373f
Xanthoma cells, in verruciform
xanthoma, 373, 373f
Xeroderma pigmentosum, 747-748,
748f
Xerostomia, 464-465, 464t, 465t
from antineoplastic therapy
clinical features of, 295-296, 296f
treatment and prognosis of, 298
in diabetes, 844
in graft-versus-host disease, 792
in Sjögren syndrome, 467
XRF methodology, in mass fatality
incident identiﬁ
cation, 902
Z
Zelballen,
in paragangliomas, 535, 536f
Zimmermann-Laband syndrome,
gingival ﬁ
bromatosis in, 166
Zinsser-Cole-Engman syndrome,
746-747
Zostavax, for herpes zoster, 253
Zoster sine herpete, 251
Zsigmondy/Palmer System for dental
numbering, 896, 896t
Zygomycosis, 232-233, 233f
complicating diabetes, 844http://dentalebooks.com

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